Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:12])=O.[C:15]([CH:18]1[CH2:22][CH2:21][O:20][C:19]1=O)(=O)[CH3:16].[OH-].[NH4+]>CC1C=CC=CC=1>[Cl:12][CH2:21][CH2:22][C:18]1[C:19](=[O:20])[N:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:9][C:15]=1[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(N)nc1
Reactant: CC(=O)C1CCOC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2nc(C)c(CCCl)c(=O)n2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
A mixture of 17 parts of 5-methoxy-2-pyridinamine, 61 parts of phosphoryl chloride and 348 parts of methylbenzene was stirred for 2 hours at 60° C. 18 Parts of 3-acetyl-4,5-dihydro-2(3H)-furanone were added and the reaction mixture was stirred overnight at 90° C. The whole was poured into crushed ice and treated with ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in a mixture of hexane and ethyl acetate (50:50 by volume). The precipitated product was filtered off and dried, yielding 10 parts (30.4%) of 3-(2-chloroethyl)-7-methoxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one; mp. 150° C. (intermediate 3)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[NH:15][CH:14]=1.[OH-].[Na+]>CC(C)=O.O>[Br:12][C:13]1[C:21]2[C:20]([Cl:22])=[N:19][CH:18]=[N:17][C:16]=2[N:15]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methylbenzenesulfonyl chloride (5.21 g, 27.3 mmol) was added to a suspension of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (6.34 g, 27.3 mmol) in acetone (70 mL). After addition of an aqueous solution of sodium hydroxide (1.11 g, 27.8 mmol in 15 mL water), the reaction mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water (125 mL), stirred for 10 minutes, and filtered. The collected solids were washed with water to afford the product as a solid, Yield: 8.88 g, 23.0 mmol, 84%. LCMS m/z 385.9, 387.9, 389.8 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.42 (s, 1H), 8.06 (br d, J=8.4 Hz, 2H), 7.46-7.51 (m, 2H), 2.37 (br s, 3H).
Reaction SMILES: [C@@H:1]1([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CN(C=[O:34])C>>[Si:22]([O:34][O:6][CH2:5][C@H:4]1[O:7][C@@H:1]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:2][CH2:3]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1cn([C@H]2CC[C@@H](COO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of 3′-deoxythymidine (2.0 g, 8.84 mmol) in anhydrous DMF (15 mL) were added imidazole (0.90 g, 13.26 mmol) and tert-butyldimethylsilyl chloride (TBDMSCl) (1.73 g, 11.49 mmol) at r.t., followed by stirring for 4 h. After evaporating the solvent, the residue was partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4 and evaporated to dryness. The organic residue was purified by silica gel column chromatography with MeOH/CH2Cl2 (0-3%) to give the corresponding product (2.60 g, 7.63 mmol, 87%). 1H NMR (CDCl3, 300 MHz) δ 8.80 (br s, 1H, NH), 7.57 (q, 1H, H6, J=1.2 Hz), 6.07 (dd, 1H, H1′, J=4.8 and 6.3 Hz), 4.10-4.18 (m, 1 H, H4′), 3.98 (dd, 1H, H5′, J=2.4 and 11.4 Hz), 3.70 (dd, 1H, H5′, J=3.0 and 11.4 Hz), 2.30-2.4 (m, 1H, H2′), 1.93-2.04 (m, 3H, H2′ and 2H3′), 1.91 (d, 9H, 3CH3), 0.10 (2s, 6H, 2CH3).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:10]([O:28]CC2C=CC=CC=2)=[N:9]1)C1C=CC=CC=1.C(N1C(=O)C(C2C=CN=CC=2)=C(C2C=CC(Cl)=CC=2)C(OCC2C=CC=CC=2)=N1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:13](=[O:14])[NH:8][NH:9][C:10](=[O:28])[C:11]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccncc2)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: O=c1c(-c2ccncc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH][nH]c(=O)c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-benzyl-6-(benzyloxy)-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (2.8 g, 5.8 mmol) in toluene (35 ml) was added AlCl3 (3.1 g, 23.2 mmol). After stirring at 80° C. for 30 min. After this time, the reaction mixture was cooled to RT and 40 ml water was added. A precipitate formed which was subsequently collected by filtration. The title compound, 4-(4-chlorophenyl)-5-(pyridin-4-yl)-1,2-dihydropyridazine-3,6-dione was obtained as a yellow powder (1.1 g, 63%).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][C:19]([CH3:21])=[CH2:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([N:24]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([N:24]([C:25]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[C:32](=[O:33])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-9-methyl-8-(2-methylallyloxy)-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.65 g, 6.84 mmol, 1.00 equiv) in EtOAc (68 ml) was added Pd/C (10%; 0.364 g, 0.342 mmol, 0.0500 equiv). The atmosphere was replaced with hydrogen (1 atm, balloon) and the mixture was stirred vigorously overnight. The reaction was filtered through a plug of Celite® and the plug was then flushed with EtOAc (100 mL). The filtrate was concentrated to give tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (3.62 g, 99%) as a white, crystalline solid: IR (ATR) 2987, 2933, 2914, 2876, 1749, 1723, 1413, 1391, 1367, 1317, 1271, 1257, 1238, 1229, 1196, 1147, 1097, 1084, 1065, 1058, 854, 744 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.33-3.27 (m, 1H), 3.40-3.33 (m, 1H), 1.92-1.79 (m, 1H), 7.35-7.22 (m, 2H), 7.22-7.11 (m, 3H), 5.11 (dd, J=8.5, 6.4 Hz, 1H), 4.88 (dq, J=9.0, 6.3 Hz, 1H), 3.46-3.40 (m, 1H), 4.07 (dd, J=11.8, 6.4 Hz, 1H), 3.84 (dd, J=11.8, 8.6 Hz, 1H), 3.52 (d, J=10.6 Hz, 1H), 3.18-3.08 (m, 2H), 2.35 (s, 1H), 1.98 (s, 1H), 1.48 (s, 21H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 169.98, 152.62, 140.12, 129.25, 128.32, 125.99, 84.52, 82.99, 78.82, 75.39, 70.96, 57.47, 47.05, 34.98, 29.16, 27.92, 19.49, 18.95; HRMS-ESI (m/z) [M−H]− calc'd for C29H44NO8; 534.3072. found, 534.3069.
Reaction SMILES: [Cl:1][O:2][Cl:3].[NH2:4][C:5](=[NH:12])[NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].C([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])C.CN(C)[CH:22]=[O:23]>N1C=CC=CC=1>[Cl:1][O:2][Cl:3].[NH:15]1[CH2:16][CH2:17][CH2:19][C@H:18]1[C:22]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5](=[NH:4])[NH2:12])=[O:23]
Reactant: N=C(N)NCCCCN
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Agent: ClOCl
Solvent: c1ccncc1
Product: N=C(N)NCCCCNC(=O)[C@@H]1CCCN1
Reaction time: 18 h

Procedure:
3.7 g (10 mmoles) of benzyloxycarbonyl-L-prolyl-p-nitrophenyl ester (Goodman and Stueben: J. Am. Chem. Soc., 81, 3980, 1959) are dissolved in a mixture of 10 ml of dimethylformamide and 5 ml of pyridine, 2.03 g (10 mmoles) of agmatine-dichlorohydrate (in formula II A represents an H2N--C(NH)-- residue, B a chlorine atom and n=2) and 1.4 ml (10 mmoles) of triethylamine added, and stirred for 16 to 20 hours. The reaction mixture is evaporated at reduced pressure. The residue is dissolved in a mixture of 50 ml of 0.1 N hydrochloric acid and 20 ml of ethyl acetate, the aqueous layer is extracted twice with 20 ml of diethyl ether, neutralized with solid sodium hydrogen carbonate and then extracted five times with 20 ml of chloroform. The combined chloroform layers are washed twice with water and evaporated at reduced pressure. The evaporation residue, benzyloxycarbonyl-L-prolyl-agmatine-hydrochloride (RF3 0.32 to 0.42), is dissolved in 40 ml of methanol, 10 ml of 1 N hydrochloric acid added, and the mixture hydrogenated in the presence of palladium charcoal. When the reaction is concluded, the catalyst is filtered, washed with water, and the filtrate evaporated at reduced pressure. The evaporation residue is worked up with diethyl ether, filtered, washed with diethyl ether and dried over potassium hydroxide at reduced pressure. Yield: 2.1 g (70 percent) of the named compound. M.p.: 186° to 189° C.; RF4 0.15 to 0.25; [α]D20 =-33.25° (c=1, methanol).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].N1C=CN=C1.CN(C)C=O>O>[Si:1]([O:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(CCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyldimethylsilyl chloride (150 g) was added to a mixture of 3-hydroxypropiophenone (125 g), imidazole (142 g) and dimethylformamide (330 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (600 ml) and extracted with diethyl ether (600 ml). The organic layer was separated, washed with water (4×30 ml), dried (Na2SO4) and evaporated to give 3-(tert-butyldimethylsilyloxy)propiophenone as an oil (186 g, b.p. 114°-118° C. at 0.01 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[CH2:9]([N:11]([CH2:14][CH2:15]Cl)[CH2:12][CH3:13])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:10][CH2:9][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:5][N:6]=1
Reactant: CCN(CC)CCCl
Reactant: Nc1nnc(S)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSc1nnc(N)s1
Yield: 81.9 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (13.3 g), diethylaminoethylchloridehydrochloride (17.2 g), and potassium hydroxide (11.2 g) were stirred in methanol (200 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 19.0 g of the aimed compound.
Reaction SMILES: [OH:1][C:2]1([CH2:26][OH:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.C=O.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[CH2:26][O:27][CH2:30]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)c(F)c2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCO4)c(F)c2)C(=O)O1
Yield: 57 %

Procedure:
The compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-hydroxymethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.3 mmol), paraformaldehyde (0.3 mmol), p-toluene sulfonic acid (0.3 mmol), 4° A molecular sieves (0.5 g) in benzene (10 ml) and by purifying on silica gel column chromatography to provide title compound in 57% yield.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:14](=[O:23])[NH:15]2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][NH:26][C:25]=1/[CH:24]=[C:13]1\[C:14](=[O:23])[NH:15][C:16]2[C:12]\1=[C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccccc3)c21
Yield: 81 %

Procedure:
Using Method S above, phenyl boronic acid (75.2 mg, 0.617 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 6) using DPPFPdCl2 (17 mg) (Aldrich) as catalyst in aqueous 2M Na2CO3 (0.42 mL, 0.84 mmol) and DME (15 mL) at reflux for 18 h to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-phenyl-2H-indol-2-one (yield: 120 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[O:39])[N:34]([CH:40]1[CH2:45][CH2:44][C:43](=[O:46])[NH:42][C:41]1=[O:47])[CH2:33]2.O>CN(C=O)C>[O:47]=[C:41]1[CH:40]([N:34]2[CH2:33][C:32]3[C:36](=[CH:37][CH:38]=[C:30]([CH2:29][NH:28][C:10](=[O:12])[CH2:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:13])=[CH:8][CH:7]=4)[CH:31]=3)[C:35]2=[O:39])[CH2:45][CH2:44][C:43](=[O:46])[NH:42]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A mixture of (α,α,α-trifluoro-p-tolyl)acetic acid (0.33 g, 1.6 mmol) and CDI (0.27 g, 1.7 mmol) was stirred in DMF (20 ml) at 40° C. under N2 for 2 hours. After 2 hours, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.50 g, 1.6 mmol) was added. After 2 h, TEA (0.16 g, 1.6 mmol) was added to the mixture and stirring continued for 16 h at this temperature. Water (40 mL) was added, resulting in precipitation of the product. The solids were filtered, washed with water (50 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamide as an off-white solid (0.22 g, 29% yield); mp 217-219° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.95 (96.06%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.63 (s, 2H), 4.25 (d, 1H, J=17.4), 4.31-4.45 (m, 3H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.37-7.43 (m, 2H), 7.51 (d, 2H, J=7.8), 7.67-7.70 (m, 3H), 8.74 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.9, 42.3, 47.0, 51.6, 122.0, 122.9, 124.4 (q, J=269.3), 125.0 (q, J=3.75), 127.1, 127.2 (q, J=31.5), 129.9, 130.4, 141.1, 142.3, 143.6, 167.9, 169.5, 171.0, 172.9; LCMS: MH=460; Anal. Calcd for C23H20F3N3O4+0.5 CH2Cl2: C, 56.24; H, 4.22; N, 8.37. Found: C, 56.10; H, 3.92; N, 8.50.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[CH:21]([O:23][CH3:24])=O.[H-].[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[CH:21]\[O:23][CH3:24])/[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1CCc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/C=C(/C(=O)OC)c1ccccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of methyl 2-(2-[4-fluorophenyl]ethyl)phenylacetate (2.83g) and methyl formate (12.8ml) in dry DMF (20ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (0.50g) in dry DMF (30ml) cooled in an ice bath. Effervescence and foaming built up slowly, and, when it had subsided, the mixture was allowed to warm to room temperature and stir for 3.5 hours. The mixture was diluted with water, acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated. A stirred solution of the resulting viscous yellow oil (3.34g) in DMF (30ml) was treated successively with potassium carbonate (3.05g) and dimethyl sulphate (1.54g). After 2 hours, the reaction mixture was poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using 30% ether in petrol to give (E)-methyl 2-(2-[2-(4-fluorophenyl)ethyl]phenyl)-3-methoxypropenoate (2.64g, 81% yield) as a colourless solid m.p. 411/2°-421/2° C., lH NMR (CDCl3); delta 2.76 (4H,br s), 3.70 (3H,s), 3.82 (3H,s), 7.58 (1H,s), ppm.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][C:21](=[CH:24][C:25](O)=[O:26])[CH2:20][CH2:19]3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:60][NH:61][O:62][CH3:63]>ClCCl>[CH3:63][O:62][N:61]([CH3:60])[C:25](=[O:26])[CH:24]=[C:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:28])([F:29])[F:2])[CH:5]=3)[CH2:15][CH2:14]2)[CH2:19][CH2:20]1
Reactant: O=C(O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
To a solution of 200 mg (0.46 mmol) of (4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetic acid, hydrochloride in 5 mL of dichloromethane stabilized on amylene are successively added 63 mg (0.46 mmol) of 1-hydroxybenzotriazole, 88 mg (0.46 mmol) of 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide hydrochloride and 140 mg (1.4 mmol) of triethylamine. The mixture is stirred for 15 minutes then 45 mg (0.46 mmol) of N,O-dimethylhydroxylamine hydrochloride are added. The mixture is stirred overnight at room temperature, then evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed twice with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 98/2) to give 143 mg (71%) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)acetamide as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:19]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][C@@H:22]4[CH2:26][CH2:27][CH2:28][C@@H:21]34)[N:17]([CH2:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]3)[C:4]=2[C:5]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].[F-].[Cs+].[CH3:39][NH:40][CH3:41].CS(C)=O>C1COCC1.CCOC(C)=O>[Cl:16][C:14]1[CH:15]=[C:10]([C:5]2[C:4]3[N:17]([CH2:29][C@H:30]4[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:3]=3[C:2]([N:40]([CH3:41])[CH3:39])=[C:7]([C:8]#[N:9])[N:6]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CNC
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Cl)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C)c1c(C#N)nc(-c2cncc(Cl)c2)c2c1nc(N1CCO[C@@H]3CCC[C@H]31)n2C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
A dry vial, under an atmosphere of nitrogen, was charged with 7-chloro-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 11.2, step 1; 50 mg, 0.095 mmol), CsF (101 mg, 0.666 mmol), dimethylamine (0.476 mL of a 2M solution in THF, 0.952 mmol) and DMSO (1 mL). The vial was sealed and heated to 100° C. for 8 hours. The reaction was cooled to room temperature, diluted with EtOAc (25 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on a silica gel column with 0 to 100% EtOAc/hexanes to afford 4-(5-chloropyridin-3-yl)-7-(dimethylamino)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C29H36ClN7O [M+H]+=534. found=534.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[Br:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl.[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28]>>[CH3:24][O:25][C:26](=[O:32])[C@@H:27](/[N:28]=[CH:14]/[C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:7])[N:13]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: O=Cc1cccc(Br)n1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](/N=C/c1cccc(Br)n1)C(C)C
Temperature: 25 °C

Procedure:
Anhydrous magnesium sulfate (5.4 g), 6-bromopyridine-2-carboxaldehyde (5.0 g, 26.9 mmol) and triethylamine (3.75 mL, 26.9 mmol) were each added sequentially in one portion to a cooled (0° C.) solution of (L)-valine methyl ester hydrochloride (4.51 g, 26.9 mmol) and the reaction mixture was allowed to warm slowly to room temperature overnight under a nitrogen atmosphere. The mixture was then filtered and the filter cake washed with diethyl ether (100 mL) before evaporating the filtrate in vacuo. The residue was purified by column chromatography using 5:1 hexane/ethyl acetate as eluent to yield A469.1 (7.1 g, 88%). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 0.86 min, M+H+=202.08
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([S:13][CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[C:5]([C:11]#[N:12])=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: NN
Reactant: CSc1nc(N)nc(S(C)=O)c1C#N
Solvent: O
Solvent: CC#N
Product: CSc1nc(N)nc(NN)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-methanesulfinyl-6-methylsulfanyl-pyrimidine-5-carbonitrile (8:100 mg, 0.4 mmol.), hydrazine hydrate (0.8 mmol), and acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 4 hr. The precipitate was filtered and gave to white solid. No further purification was necessary (76 mg). LC-MS: (ES+) m/z 197 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1>CCN(CC)CC>[Cl:8][C:4]1[N:3]=[C:2]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
A mixture of 2,6-dichloropyrazine (5.00 g, 33.6 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (6.76 g, 33.6 mmol) and K-t-BuO (1 M in tert-butanol; 35 mL, 35 mmol) in Et3N (200 mL) was stirred at room temperature for 12 h. The reaction was quenched with water (50 mL) and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous KH2PO4, dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from ethanol/water to give 9.50 g (90%) of the title compound as a white solid: mp 86-87° C.; MS m/z 313 (M)+. Anal. (C14H20ClN3O3C, H, N.