Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.[Na].[CH3:25][OH:26]>>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([O:26][CH3:25])=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reactant: CO
Agent: [Na]
Product: COc1nnc2n1CCN(C(=O)c1cccc(C(F)(F)F)c1Cl)C2

Procedure:
3-Bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.250 g, 0.610 mmol, see Example 1 for methods of preparation) was added to a solution of sodium (0.042 g, 1.831 mmol) in methanol (8 mL), under argon and refluxed for 1 hour. More sodium (0.040 g) was added and the reaction was refluxed for 22 hours. The reaction was quenched with water and extracted with Dichloromethane (three times), the combined organics were dried and evaporated, and the residue was purified on the mass-directed automated (preparative) HPLC (MDAP) and triturated with diethyl ether to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(methyloxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.082 g) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.Cl[C:20]1C(C(F)(F)F)=CC([N+]([O-])=O)=[CH:22][N:21]=1.CNC>>[CH3:20][N:21]([CH3:22])[C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: CNC
Solvent: O=S(Cl)Cl
Product: CN(C)c1ncc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
5-Nitro-3-(trifluoromethyl)pyridin-2(1H)-one was treated with thionyl chloride and then the resulting 2-chloro-5-nitro-3-(trifluoromethyl)pyridine was treated with dimethylamine to obtain N,N-dimethyl-5-nitro-3-(trifluoromethyl)pyridin-2-amine.
Reaction SMILES: [H-].[Na+].[Na+].[I-].[CH2:5]([OH:9])[CH2:6][CH2:7]O.[H][H].[CH2:12](Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C=O)C.O>[CH2:12]([O:9][CH2:5][CH2:6][CH2:7][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCl
Reactant: OCCCO
Reactant: [H][H]
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOCCCCCCCCCC
Reaction time: 18 h

Procedure:
To a mixture of NaH (2.6 g, 70 mmol) and anhydrous NaI (9.9 g, 70 mmol) in dry DMF (80 mL) under N2 was added dropwise a solution of 1,3-propanediol (4.75 mL, 70 mmol) in DMF (20 mL). The mixture was stirred until hydrogen evolution had ceased, decyl chloride (1.34 g, 7.6 mmol) was added and stirring was continued at 50° C. for 18 hours. Then, the reaction mixture was poured into H2O (300 mL) and extracted with diethyl ether (3×250 mL). The organic extracts were combined, washed with sat. NaCl (100 mL), dried (MgSO4) and evaporated to dryness. The residue was subjected to silica-gel column chromatography [eluent: ethyl acetate/hexane, 30/70, v/v] to furnish decyl ether Compound 17 as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:10]2)[N:3]=1.C([O-])(=[O:23])C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:4]3[N:5]=[CH:6][NH:7][C:2](=[O:23])[N:3]=3)[CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccc(N2CC[C@@H](Nc3ncnc(Cl)n3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(N[C@@H]2CCN(c3ccc(F)cc3)C2)nc[nH]1
Yield: 15 %

Procedure:
To (R)-4-chloro-N-[1-(4-fluorophenyl)pyrrolidin-3-yl]-1,3,5-triazin-2-amine synthesized in Reference Synthesis Example 337, sodium acetate (153 mg, 1.11 mmol), acetic acid (2.0 mL), and water (0.40 mL) were added and the resultant mixture was stirred at 90° C. for 5 hours. After completion of the reaction, the reaction solution was added to saturated sodium bicarbonate aqueous solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the obtained solid was washed with ethyl acetate to obtain the title compound (65.0 mg, two step yield 15%).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:12])[N:3]=1.Cl.[NH:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=2)=[N:17][N:16]=[N:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]2[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:2]3[C:11]4[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=4[N:5]=[C:4]([CH3:12])[N:3]=3)=[CH:27][CH:26]=2)=[N:14][N:15]=[N:16]1
Reactant: Cc1nc(Cl)c2c(n1)CCCC2
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Temperature: 95 °C
Yield: 30.6 %

Procedure:
To 10 mL of dimethylformamide were added 0.57 g of 4-chloro-5,6,7,8-tetrahydro-2-methylquinazoline, 0.45 g of N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amine hydrochloride and 1.30 g of anhydrous potassium carbonate. The resulting mixture was heated at 95° C. for 5 days and then cooled to room temperature. The resulting mixture was run through a silica plug (methanol/chloroform/ammonia eluant) and after all solvent was removed by evaporation the resulting residue was purified on silica to yield 0.19 g (31%) of the desired product. The compound was characterized as its potassium salt: 1H NMR (DMSO-d6, 400 MHz) δ 7.50 (m, 1H), 7.32 (m, 3H), 7.11 (d, J=8.2 HZ, 2H), 7.02 (m, 3H), 4.57 (d, J=6.0 Hz, 2H), 2.48 (m, 4H);, 2.24 (s, 3H), 1.71 (m, 4H); negative FAB-MS m/e 433(M-H); 396(M-K). Anal. calcd for C23H22KN7.0.85H2O: C, 61.53; H, 5.30; N, 21.84. Found: C, 61.74; H, 5.25; N, 21.47.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 1-(3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-methylpentane, 30 ml of 47% aq HBr and 30 ml of acetic acid was refluxed with heating for eight hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: benzene) to give 4.2 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane.
Reaction SMILES: [C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]3)=[C:31]([F:43])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[C@@H:11]([NH:13]C(OC(C)(C)C)=O)[CH3:12])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:52]>C1COCC1>[ClH:52].[C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][S:38](=[O:41])(=[O:42])[CH2:37][CH2:36]3)=[C:31]([F:43])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[C@@H:11]([NH2:13])[CH3:12])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: COc1ccccc1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a mixture of the 2(S)-tert-butoxycarbonylamino-propionic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12b) (0.98 g, 1.56 mmol), anisole (1 mL) and THF (30 mL), is added hydrogen chloride (4 M in dioxane, 11 mL, 46.8 mmol) in a dropwise manner. The mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-half of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether and ethyl acetate, and dried under vacuum to give the title compound in 38% yield (0.34 g). 1H NMR (400 MHz, CD3OD): δ 7.51 (dd, 1H), 7.37 (t, 1H), 7.26 (dd, 1H), 6.02 (ABq, 2H), 4.87 (m, 1H), 4.29 (app q, 1H), 4.19 (m, 2H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.37 (m, 2H), 3.23 (tt, 1H),3.12 (m, 2H), 2.54 (s, 3H), 2.35 (m, 2H), 2.18 (m, 2H), 1.59 (d, 3H). MS-APCI (m/z+): 530.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][CH:41]=[C:42]([CH2:44][O:45]C3CCCCO3)[N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:42]1[N:43]=[C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[S:40][CH:41]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1
Reactant: CC(C)(O)c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.1 g, 30.5 mmol) in dichloromethane (300 mL) was added carbon tetrabromide (8.81 g, 33.6 mmol) and triphenylphosphine (11.14 g, 33.6 mmol). The reaction was stirred at ambient temperature overnight then poured into a saturated solution of sodium bicarbonate. The organic layer was separated, concentrated to dryness and purified by column chromatography, eluting with a gradient of hexane to 3:1 hexane:ethyl acetate. The title compound (5.21 g, 74%) was obtained as a colourless oil; LC-MS Retention time 2.08 min, (M+H)+ 230, 232
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].Cl.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]2[S:35][C:34]3[N:36]4[C:27](=[CH:28][N:29]=[C:30]4[CH:31]=[CH:32][CH:33]=3)[CH:26]=2)=[O:24])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1.[I-].[Na+]>C(N(CC)CC)C.C(#N)C>[C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]2[S:35][C:34]3[N:36]4[C:27](=[CH:28][N:29]=[C:30]4[CH:31]=[CH:32][CH:33]=3)[CH:26]=2)=[O:24])[CH2:20][CH2:21]1)#[N:9]
Reactant: N#Cc1ccccc1OCCCCl
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccccc1OCCCN1CCC(NC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Yield: 82.9 %

Procedure:
2-(3-Chloropropan-1-yl)oxybenzonitrile (503 mg) was added, at room temperature, to an acetonitrile solution (20 ml) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (662 mg), triethylamine (1.09 g) and sodium iodide (285 mg). The mixture was heated under reflux for 7.5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The extract solution was washed with a saturated aqueous saline solution, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (ethyl acetate/methanol=2/1) to afford the object compound (816 mg, 83%) as a reddish purple oily product.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
The product from step (iii) (10.38 g) was added dropwise to a solution of the product from step (ii) (28 g) at 0° C. in DCM (400 mL) and triethylamine (11.81 mL) over 1 hour then heated under reflux overnight. The reaction was cooled to rt and the solution washed with saturated sodium hydrogen carbonate, dried and solvent removed. The crude product was purified on silica to give the subtitle compound as a solid (26 g); MS multimode (+) 399.
Reaction SMILES: [SH2:1].[Na].CS(O[CH:8]([CH2:10][CH:11]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:12]=[O:13])[CH3:9])(=O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:9][CH:8]1[S:1][CH:12]([OH:13])[CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10]1
Reactant: S
Reactant: CC(CC(C=O)Sc1ccccn1)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CC(Sc2ccccn2)C(O)S1
Yield: 25456.4 %

Procedure:
0.74 g of sodium hydrogen sulfide (Wako Pure Chemical Industries, Ltd.) was added to a solution of 0.60 mg of 5-oxo-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in 10 mL of N,N-dimethylformamide at a temperature of 0° C. to 10° C., and the obtained mixture was then stirred at the same temperature as described above for 1.5 hours. Thereafter, 30 mL of ethyl acetate and 30 mL of a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture, and the water layer was then removed. The organic layer was successively washed with 30 mL of water and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=5/1), so as to obtain 120 mg of 5-methyl-3-(pyridin-2-ylsulfanyl)thiolan-2-ol in the form of a light yellow oily product.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>CCOC(C)=O.CN(C=O)C>[CH3:14][C:2]([CH3:1])([CH3:15])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)C=Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(NC(=O)c2ccc(/C=C/C(C)(C)C)cc2)c1
Reaction time: 1 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-(3,3-dimethyl-but-1-enyl)-benzoic acid (1.5 g, 7.34 mMol) in a mixture of EtOAc and DMF (1:1, 25 mL) is added oxalyl chloride (0.364 g, 4.04 mMol) slowly drop-wise and the mixture is agitated for one hour. m-Anisidine (1.36 g, 11.01 mMol) is then added in EtOAc (5 mL) and the mixture is stirred for 6.0 hours before being quenched with saturated potassium carbonate solution. The precipitate is filtered, washed with water and vacuum dried to obtain the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[O:21][C:20]=3[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32])(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[O:21][C:20]=3[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:32]
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Yield: 100 %

Procedure:
[2-Methyl-4-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulene-6-carbonyl)-benzyl]-carbamic acid tert-butyl ester from Example E119.1 (62 mg, 0.14 mmol) in methanol (0.5 ml) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (53 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].[C:15]([O:20][CH3:21])(=[O:19])[CH2:16][CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:18]=[CH:17]/[CH2:16][C:15]([O:20][CH3:21])=[O:19])[CH3:9]
Reactant: C=CCC(=O)OC
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C/C=C/c1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Yield: 23 %

Procedure:
Under an argon atmosphere, a mixture of (2R)-2-{[(1R)-1-(2-bromophenyl)ethoxy]methyl}oxirane (1.00 g, 3.89 mmol) described in WO 2004/094362, methyl but-3-enoate (497 μL, 4.67 mmol), palladium acetate (II) (44 mg, 0.19 mmol), tris(2-methylphenyl)phosphine (59 mg, 0.19 mmol), and triethylamine (0.65 mL, 4.67 mmol) in acetonitrile (10 mL) was stirred with heating under reflux for 3 hours. The reaction solution was cooled to room temperature, filtered through Celite, and washed with acetonitrile. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a yellow oily substance (246 mg, yield 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:30].[NH2:31][CH2:32][CH2:33][OH:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:31][CH2:32][CH2:33][OH:34])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:30]
Reactant: NCCO
Reactant: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-[[(4-Chloro-3-methylphenyl)sulfonyl](2,5-difluorophenyl) methyl]-4-methylpyridine-2-carboxylic acid (300 mg, 0.66 mmol), 2-aminoethanol (60 μl, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 0.99 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), and triethylamine (275 μl, 1.98 mmol) were dissolved in methylene chloride (60 ml), and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (190 mg, 0.38 mmol, 58%) as a white amorphous substance.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:11][CH2:10]1)(C)(C)C.Cl.O1CCOCC1>>[ClH:32].[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]2[CH2:26][C:25]3[CH:24]=[N:23][N:22]([CH3:27])[C:21]=3[NH:20][C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])[CH2:13][CH2:14]1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)OC(C)(C)C)CC1)C2
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CN)CC1)C2
Yield: 100 %

Procedure:
A solution of [4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester from Example E10.1 (775 mg, 1.63 mmol) was reacted with 4N HCl/dioxan using an analogous procedure to that described for Example E4.2 to yield the title compound (655 mg, 100%).
Reaction SMILES: C1(NC=CP(=O)(OCC)OCC)CCCCC1.[H-].[Na+].[CH:20]([C:23]1[C:28]([CH:29]=O)=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:22])[CH3:21].O.O.[C:47]([OH:52])(=O)[C:48](O)=O>O1CCCC1.O>[CH:20]([C:23]1[C:28](/[CH:29]=[CH:48]/[CH:47]=[O:52])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:21])[CH3:22]
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: O=C(O)C(=O)O
Agent: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
750 mg (2.9 mmol) of diethyl 2-(cyclohexylamino)vinylphosphonate, dissolved in 30 ml of dried tetrahydrofuran, are added dropwise at -5° C. under nitrogen to a suspension of 110 mg (3.6 mmol) of 80% pure sodium hydride in 15 ml of dry tetrahydrofuran. After 30 minutes, 810 mg (2.4 mmol) of the compound from Example 3 in 40 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is heated to reflux for 30 minutes. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate. After concentrating in vacuo, the residue is taken up in 70 ml of toluene, a solution of 4.5 g (3.5 mmol) of oxalic acid dihydrate in 30 ml of water is added and the mixture is heated to reflux for 30 minutes.