Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1)[CH:6]=O.[C:17]([O:21][C:22](=[O:36])[CH:23](P(OCC)(OCC)=O)[CH2:24][CH2:25][CH2:26][Cl:27])([CH3:20])([CH3:19])[CH3:18].O.[OH-].[Li+].O>C1COCC1.C(O)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:36])/[C:23](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH2:24][CH2:25][CH2:26][Cl:27])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOP(=O)(OCC)C(CCCCl)C(=O)OC(C)(C)C
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (50 g) in THF (600 mL) and ethanol (200 mL), 5-chloro-2-(diethoxyphosphoryl)valeric acid tert-butyl ester (83.5 g) and lithium hydroxide monohydrate (29.1 g) were added to the one by one, and the reaction solution was agitated at room temperature overnight. Water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 54.9 g of the title compound was obtained by purifying the residue by silica gel chromatography (elution solvent: heptane:ethyl acetate=1:1), and re-crystallizing the obtained solid from the mixed-solution of ethyl acetate and hexane. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:14])[C:12]=1[CH3:13])[NH:9][CH2:8][C:7]1([CH2:17][CH2:16][CH2:15]1)[CH2:6]2.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[S:27].O>ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[C:11]=2[CH3:14])[CH2:6][C:7]2([CH2:15][CH2:16][CH2:17]2)[CH2:8]1)=[S:27]
Reactant: COc1cc2c(c(C)c1C)NCC1(CCC1)C2
Reactant: S=C=Nc1ccccc1Br
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(c(C)c1C)N(C(=S)Nc1ccccc1Br)CC1(CCC1)C2

Procedure:
To a solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (810 mg) in 4 mL dichloromethane was added 1-bromo-2-isothiocyanatobenzene (525 μL) at room temperature. The mixture was allowed to reflux overnight. Water was used to quench the mixture and EtOAc was used for extraction. The combined organic phases were washed with brine, dried and evaporated. The residue was passed through a column ( dichloromethane:EtOAc=10:2) to give N-(2-bromophenyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-carbothioamide (1.5 g) as a white solid. 1H-NMR (300 MHz, CDCl3) δ=8.54-8.22 (d, J=6.95 Hz, 1H); 7.61-7.39 (m, 2H); 7.38-7.22 (m, 1H); 7.15-6.87 (m, 1H); 6.69 (s, 1H); 5.72-5.38 (d, J=13.1 Hz, 1H); 3.86 (s, 3H); 3.39-3.25 (d, J=13.1 Hz, 1H); 2.85-2.67 (m, 2H); 2.46-2.28 (m, 1H); 2.14 (s, 3H); 2.12 (s, 3H); 2.07-1.79 (m, 3H); 1.79-1.62 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]=O)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[OH:1][C:2]1[C:3]([CH2:12][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: O=Cc1cc2c(cc1O)CCCO2
Reactant: Nc1ccccc1
Solvent: CO
Product: Oc1cc2c(cc1CNc1ccccc1)OCCC2
Yield: 45 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-7-carboxaldehyde (429 mg, 2.41 mmol) and aniline (224 mg, 2.42 mmol) in methanol (30 mL) was warmed and the methanol, which distilled over, was collected. When 10 mL of methanol had been collected, the mixture was allowed to cool and the intermediate Schiff's base crystallized out. This material was collected and redissolved in fresh methanol (30 mL). Sodium borohydride (1 molar equiv.) was added in portions and the color immediately discharged. The mixture was concentrated to 50% of its original volume, then poured into an excess of water (100 mL). The aqueous solution was rendered acidic with 2N HCl, filtered to remove any insoluble material, then basified with 7%, NaHCO3. The product, which precipitated, was collected by filtration and dried to afford 6-hydroxy-7-phenylaminomethyl-3,4-dihydrobenzopyran (277 mg, 49%), m.p. 135°-137° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClS(O)(=O)=O.[C]=O.Cl.[C:22](OCC)(=[O:24])C>[Ni](Cl)Cl.O.C1C=CC=CC=1.C(O)=O>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:22]=[O:24]
Reactant: Cc1cc(C)cc(C)c1
Reactant: CCOC(C)=O
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=S(=O)(O)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: O=CO
Product: Cc1cc(C)c(C=O)c(C)c1

Procedure:
A benzene solution of 180 g (1.5 moles) of mesitylene, 90 g of aluminum chloride and 13 g of nickel dichloride was stirred at 70° C. to 80° C. Simultaneously, 125 ml of formic acid was added dropwise to 230 ml of chlorosulfonic acid to generate carbon monoxide and hydrogen chloride gas which were blown into the above benzene solution for 6 hours. Next, water and ethyl acetate were added to the solution which was separated into an organic and an aqueous layer. The organic layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/1) to give 34.5 g (0.233 mole) of 2,4,6-trimethylbenzaldehyde as a colorless oil.
Reaction SMILES: C([C:3]1[C:4]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])=[N:5][CH:6]=[C:7]([CH:9]([Cl:11])[Cl:10])[N:8]=1)=O.Cl.[NH2:24][OH:25].O>CS(C)=O>[N:24](=[C:3]1[N:8]=[C:7]([CH:9]([Cl:11])[Cl:10])[CH:6]=[N:5][CH:4]1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[OH:25]
Reactant: O=Cc1nc(C(Cl)Cl)cnc1N1C(=O)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1N=CC(C(Cl)Cl)=NC1=NO
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of 10 g of 3-formyl-5-dichloromethyl-2-phthalimidopyrazine in 50 ml of dimethyl sulfoxide was heated at 50° C., 7 g of hydroxylamine hydrochloride were added, and the mixture was stirred for 15 minutes at 70° C. Thereafter, 700 ml of water were added to the reaction solution, the mixture was filtered and the filtrate was washed with a little diethyl ether. 6.8 g of colorless crystals (65%) of 3-oximinodichloromethyl-2-phthalimidopyrazine were obtained. 1H-NMR (270 MHz, DMSO-d6): δ7.7 (s, 1H), 8.0 (m, 4H), 8.3 (s, 1HO), 9.1 (s, 1H), 12.0 (s, OH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:33])([F:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:14][C:15]([F:32])([F:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 15-(trifluoromethyl)pentadecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 4-[15-(trifluoromethyl)pentadecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][OH:21])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][O:21][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(Br)c21
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (2.0 g, 5.02 mmol) in THF (10 mL) was added LAH (5.27 mL of 1.0 M in THF, 5.27 mmol) slowly at room temperature. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by the addition of H2O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na2SO4 was added to the mixture and the resulting mixture was filtered. The filtrate was concentrated to give 1.79 g (100%) of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol as yellow oil. A mixture of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.79 g, 5.02 mmol), imidazole (0.854 g, 12.55 mmol) and tert-butyldimethylsilyl chloride (0.909 g, 6.03 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with H2O (5×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 7% EtOAc in hexanes) to give 2.29 g (97%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 6.95 (dd, J=8.37, 4.17 Hz, 1H), 6.57 (d, J=10.41, 8.37 Hz, 1H), 3.98–3.54 (m, 4H), 3.00 (m, 2H), 2.00–0.90 (m, 6H), 0.80 (s, 9H), 0.74 (d, J=7.32 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:6]=1[CH2:25][CH3:26].COC(=O)CC1C2C(=NC=CC=2)NC=1CC.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.FC(F)(F)C1C=CC(CBr)=CC=1>CN(C=O)C.O>[CH2:25]([C:6]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][C:3]([OH:27])=[O:2])[CH3:26]
Reactant: CCc1c(CC(=O)OC)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCc1[nH]c2ncccc2c1CC(=O)OC
Agent: FC(F)(F)c1ccc(CBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(=O)O)c2cccnc2n1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
[2-Ethyl-1-(4-trifluoromethyl-benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice-cooled stirring solution of (2-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (80 mg, 0.37 mmol) in DMF (1 ml) is added BEMP (171 μl, 0.59 mmol). The solution is stirred at room temperature for 40 minutes and then re-cooled. 4-(Trifluoromethyl)benzyl bromide (91 μl, 0.59 mmol) is added and stirring continues while the reaction mixture gradually warmed up to room temperature overnight. The resulting mixture is poured into water (30 ml) and extracted with 1:1 EtOAc/ether. The organic layer is washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is loaded on a pre-packed Isolute™ silica column and eluted with DCM to yield the titled compound as a pale yellow oil. (MH+ 377)
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[S:29]([CH3:32])(=[O:31])=[O:30].C(N(CC)CC)C.C(Cl)CCl>ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][C:5]3([C:4]4=[CH:3][CH:2]=[CH:1][N:9]4[C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[O:6]3)[CH2:14][CH2:15]2)=[O:25])=[CH:22][C:21]=1[S:29]([CH3:32])(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cc(C(=O)O)ccc1F
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (257 mg, 0.928 mmol), 4-fluoro-3-methylsulfonyl-benzoic acid (203 mg, 0.928 mmol), triethylamine (518 μL, 3.71 mmol), and EDC (196 mg, 1.02 mmol) were combined in dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 4 d. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified column chromatography utilizing a gradient of 0-75% ethyl acetate in hexanes to yield (4-fluoro-3-methylsulfonyl-phenyl)-spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl-methanone (222 mg, 54%) as a colorless oil. ESI-MS m/z calc. 440.1. found 441.1 (M+1)+; Retention time: 1.51 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH2:9])[CH:4]=[CH:5][N:6]=1.[C:10]1([C:16]2[O:17][C:18]3[C:19](=[C:21]([C:25](O)=[O:26])[CH:22]=[CH:23][CH:24]=3)[N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]1[N:3]([CH2:7][CH2:8][NH:9][C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:18]3[O:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:20][C:19]=23)=[O:26])[CH:4]=[CH:5][N:6]=1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: Cc1nccn1CCN
Product: Cc1nccn1CCNC(=O)c1cccc2oc(-c3ccccc3)nc12
Yield: 35 %

Procedure:
N-[2-(2-Methylimidazol-1-yl)ethyl]-2-phenylbenzoxazole-4-carboxamide was prepared from 2-(2-methylimidazol-1-yl)ethylamine and 2-phenylbenzoxazole-4-carboxylic acid using the conditions described in Step C of Example 1. This compound was obtained in 35% yield as a white solid; mp 125-127° C.; 1H NMR (300 MHz, CD3OD) δ 8.11 (dd, J=7.8, 1.0 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.63-7.52 (m, 3H), 7.42 (t, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.86 (s, 1H), 4.22 (t, J=5.8 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.34 (s, 3H); MS (APCI) m/z 347 [M+H]+
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[C:32](=[O:37])[CH2:31][C:30]2=O>ClCCl.C(N(CC)CC)C>[O:37]=[C:32]1[CH:33]2[CH2:36][CH:29]([CH2:35][CH2:34]2)[C:30]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH:2]([F:1])[F:17])=[N:4][C:5]=2[CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:31]1
Reactant: COCCCc1nc(C(F)F)ccc1C(=O)O
Reactant: O=C1CC(=O)C2CCC1C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCc1nc(C(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 181 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester in 750 ml of a 2:1 methanol/water mixture is treated with 43.9 g of lithium-hydroxide monohydrate, and the mixture stirred at ambient temperature for 1 hour. Then the methanol is removed by distillation in vacuo, and the reaction mixture then diluted with crushed ice and acidified with aqueous 6N hydrochloric acid. The product is filtered and washed thoroughly with water. Crystallisation from n-hexane:methylene chloride gives 138.3 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid as white crystals (melting point 86-87° C.). A solution of 101.2 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid in 1250 ml of dichloromethane is charged initially, 1 ml of dimethylformamide are added and the mixture is subsequently treated with 38.4 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is stirred at room temperature for 1 hour and then cooled to 0° C. and treated with 57 g of bicyclo[3.2.1]octane-2,4-dione and 87 ml of triethylamine and the mixture then stirred for 2 hours at ambient temperature. The mixture is then diluted with methylene chloride, and washed with cold 1N hydrochloric acid, dried over magnesium sulphate and concentrated in vacuo to give 150.9 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester as an oil which is used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.N1C=CN=C1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.C1(C)C=CC=CC=1.O>[Si:28]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:6][CH2:7]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 12A (6.5 g, 26.5 mmol) in DMF (20 mL) was added imidazole (3.61 g, 53.0 mmol), followed by tert-butylchlorodimethylsilane in toluene (9.22 mL, 26.5 mmol) portionwise while cooling with an ice bath. Upon completion of the addition, the resulting mixture was stirred at 40° C. for 3 h. There was still some starting material left, so more 50% tert-butylchlorodimethylsilane in toluene (2.5 mL) was added, and the mixture was stirred briefly at room temperature. The mixture was diluted with water and extracted with hexane (3×). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide 12B (9.1 g, 96% yield) as a white solid. MS (ES): m/z=360.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (dd, 2H, J=5.5, 3.1 Hz); 7.62 (dd, 2H, J=5.5, 3.1 Hz); 3.96-4.15 (m, 1H); 3.56-3.72 (m, 1H); 2.17-2.29 (m, 2H); 1.85-1.92 (m, 2H); 1.61-1.69 (m, 2H); 1.31-1.43 (m, 2H); 0.82 (s, 9H); 0.00 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.O1CCOCC1.[CH2:16]([NH2:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:34][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCNc1nc(N)nc(N)n1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in Reference Example 1, 60 mL of water, 60 mL of 1,4-dioxane, and 26.9 g (0.1 mol) of octadecylamine was warmed with stirring and allowed to react at a reflux temperature for 3 hours. Further, an aqueous solution of 4.0 g (0.1 mol) of sodium hydroxide in 20 mL of water was dropwise added thereto over 1 hour and the mixture was allowed to react for additional 2 hours. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and 100 mL of water and 100 mL of toluene were added to extract the product in the organic layer. After washing the organic layer with water sufficiently, the solvent was distilled off from the organic layer to obtain 34.4 g (yield 91%) of the titled compound. Melting point: 91° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH2:34])=[O:33].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:34][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:6][N:7]=1)=[O:33]
Reactant: NC(=O)c1cccc(Cl)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)nc2)c2cccnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cc2c[nH]c3ncccc23)cn1)c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3-chloro-benzamide (544, 15 mg, 0.096 mmol) in dioxane (0.4 mL). Tris(dibenzylideneacetone)-dipalladium(0) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg), and sodium tert-butoxide (15 mg) were added. Cesium carbonate (20 mg) was added and the mixture was heated at 100° C. overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO (0.2 mL) and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 5-40% acetonitrile with 0.1% trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0111. MS (ESI) [M+H+]+=363.1.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: N[C@H]1CC[C@@H](c2ccccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H]1COc2c(N[C@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (180 mg, 0.649 mmol), cis-3-(2-pyridyl)cyclopentylamine (158 mg, 0.973 mmol) and triethylamine (0.200 mL, 0.976 mmol) in anhydrous DMSO (3 mL) was stirred at 80° C. for 8 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (diastereomer mixture, 55.6 mg, 20%) as a yellow powder.