Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:26](O)=[O:27])=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)C.[C:29](Cl)(=[O:33])[C:30](Cl)=O>ClCCl.CN(C=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][N:7]1[C:8]2[C:4](=[CH:3][CH:11]=[CH:10][CH:9]=2)[C:5]([C:26](=[O:27])[NH:7][CH2:6][CH:5]2[O:33][CH2:29][CH2:30][CH2:4]2)=[C:6]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C(=O)O)c2c(CC)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(=O)NCC2CCCO2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 47 %

Procedure:
To a stirred solution of ethyl N-(3,4-dichlorobenzyl)-2-ethoxycarbonylindole-3-carboxylic acid (100 mg) in dichloromethane (4 ml) at ambient temperature, under argon, was added DMF (1 drop) and oxalyl chloride in dichloromethane (2M, 153 μl). The reaction was stirred at ambient temperature for 7 hours, then concentrated in vacuo and dissolved in dichloromethane (4 ml). Tetrahydrofurfurylamine (53 μl) was added, followed by triethylamine (71 μl) and the reaction stirred under argon for 16 hours. The reaction was diluted with dichloromethane (30 ml), washed with HCl (2M, 30 ml) and water (30 ml), dried (MgSO4) and concentrated in vacuo to give a crude residue which was purified by column chromatography, using ethyl acetate:iso-hexane as eluent (gradient 10/90-50/50), to give the product as an off-white solid (57 mg, 47%); M/z (+) 475.3 (MH+),
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:18](Cl)=[C:17]([C:20]#[N:21])[C:16]([C:22]([F:25])([F:24])[F:23])=[N:15]2)=[CH:12][CH:13]=1)(=[O:7])=[O:6].[CH3:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30].[F-].[Cs+].Cl>CS(C)=O.C(#N)C.O>[C:20]([C:17]1[C:16]([C:22]([F:24])([F:23])[F:25])=[N:15][N:14]([C:11]2[N:10]=[CH:9][C:8]([S:5]([NH2:4])(=[O:6])=[O:7])=[CH:13][CH:12]=2)[C:18]=1[O:30][CH2:29][C:28]([CH3:32])([CH3:31])[CH3:27])#[N:21]
Reactant: CC(C)(C)CO
Reactant: CN(C)C=NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C#N)c2Cl)nc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)COc1c(C#N)c(C(F)(F)F)nn1-c1ccc(S(N)(=O)=O)cn1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
6-[5-chloro-4-cyano-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid dimethyl-aminomethyleneamide (81.3 mg, 0.2 mmol) and 2,2-dimethyl-1-propanol (35.3 mg, 0.4 mmol) were dissolved in dry DMSO (0.5 ml) and cesium fluoride (60.7 mg, 0.4 mmol) was added to the solution. The resulting mixture was stirred at 20° C. for a period of 24 hours. Analytical HPLC indicated the reaction completion. The reaction mixture was poured into water (2 ml) and the resulting mixture was extracted with ethyl acetate (2 ml). The ethyl acetate mixture was filtered into a vial and evaporated to dryness under nitrogen atmosphere to leave a residue. Acetonitrile (2 ml) was added, and the mixture shaken to dissolve the residue. 2N HCl (1.5 ml) was added into the acetonitrile mixture, and the reaction mixture warmed to 70° C. for a period of 18 hours. After cooling down, the acetonitrile was evaporated under reduced pressure, and ethyl acetate (5 ml) was added to the evaporated mixture with stirring. The ethyl acetate layer was then separated, washed with saturated sodium chloride (5 ml), dried over magnesium sulfate and concentrated. HPLC purification of the residue obtained above gives the title compound. (37.6 mg, 46%). MS: 404.5, r.t.: 2.7.
Reaction SMILES: Br[C:2]1[N:18]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10]C(OC(C)(C)C)=O)[C:4]=2[C:3]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[O:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.CC([O-])(C)C.[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:9]1[C:4]2[C:3]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:33][CH:32]=3)=[C:2]([C:45]3[O:44][CH:48]=[CH:47][N:46]=3)[N:18]([C@@H:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c(Br)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: c1cocn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(-c3ncco3)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 100 °C
Yield: 37.1 %

Procedure:
To a suspension of (R)-tert-butyl 3-(6-bromo-4-(tert-butoxycarbonylamino)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (119) (100 mg, 0.15 mmol), oxazole (52 mg, 0.75 mmol), t-BuOK (35 mg, 0.3 mmol) in dioxane (4 mL) was added tetrakis (36 mg, 0.03 mmol). The resulting mixture was purged with N2 (2×) before heated to 100° C. under N2 atmosphere for 30 hrs. The mixture was cooled down to r.t and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0 to 50% EA in PE) to afford (R)-tert-butyl 3-(4-amino-6-(oxazol-2-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (123) (30 mg, 42% yield) as a white solid. LC-MS (ESI): m/z (M+1) 539.1.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[Cl:18])(=[O:9])=[O:8].[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:14]([F:17])=[CH:13][C:12]=1[Cl:18])(=[O:8])=[O:9]
Reactant: CS(=O)(=O)Oc1ccc(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Yield: 95.9 %

Procedure:
A 95% sulfuric acid (35 ml) was added to 2-chloro-4-fluorophenyl methanesulfonate (22.5 g), to which was then added dropwise a mixture of 95% sulfuric acid (7.5 ml) and 61% nitric acid (10.3 g) under ice-water cooling and stirring to effect nitration reaction. After the completion of the addition, the reaction mixture was stirred for further 30 minutes at room temperature and then poured onto ice pieces and extracted with toluene. The toluene extract as separated was washed with 1N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. The toluene was distilled off to afford the titled compound (25.9 g) as pale yellow crystals with melting point 64°-65.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:15]>O>[NH:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[O:9][C:10]1=[O:15]
Reactant: COC(=O)c1ccsc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2sccc2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Methyl 2-amino-thiophene-3-carboxylate (5 g, 31.72 mmol) was added to a solution of potassium hydroxide (3.55 g, 63.45 mmol) in 10 mL water. The solution was heated at 90° C. until to get a clear solution. The solution was then cooled to 0° C. and trichloromethyl chloroformate (5.74 mL, 47.57 mmol) was added slowly. The solution was allowed to come to room temperature and further stirred for 30 min. The precipitated solid was collected by vacuum filtration to yield 4.7 g (88%) of 1H-thieno[2,3-d][1,3]oxazine-2,4-dione. MP 233° C. 1H-NMR (DMSO-d6) δ 7.15 (d, J=6.0 Hz, 1H), 7.19 (d, J=6.0 Hz, 1H) ppm.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[F:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][NH:34][CH2:35][C@@H:22]23)[CH:27]=1>>[F:7][C:8]1[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:25]3=[C:26]([CH2:28][O:29][CH2:30][CH2:31][N:24]3[C@H:23]3[CH2:32][CH2:33][N:34]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[CH2:35][C@@H:22]23)[CH:27]=1
Reactant: Fc1c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Reactant: CC(C)=CCBr
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(Nc3cccc(C(F)(F)F)c3F)cc3c1N2CCOC3

Procedure:
Using 4-bromo-2-methyl-2-butene and following the procedures described in EXAMPLE 144, (7bR,11aS)-N-[2-fluoro-3-(trifluoromethyl)phenyl]-1,2,7b,8,9,10,11,11a-octahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indol-6-amine free base from EXAMPLE 95 was converted into the title compound of EXAMPLE 146. 1H NMR(CDCl3) δ: 7.22-7.15 (m, 1H), 7.07-6.95 (m, 2H), 6.93 (d, 1H, J=1.9 Hz), 6.79 (d, 1H, J=2.2 Hz), 5.80 (broad s, 1H), 5.36 (t, 1H, J=7.5 Hz), 4.64 (ABq, 2H, JAB=14.3 Hz), 4.27 (app d, 1H, J=13.2 Hz), 3.85-3.70 (m, 2H), 3.54 (d, 1H, J=7.3 Hz), 3.45-3.35 (m, 3H), 3.22 (dd, 1H, J=12.8, 1.4 Hz), 2.92-2.78 (m, 2H), 2.61-2.45 (m, 1H), 2.28 (t, 1H, J=7.9 Hz), 2.18-2.12 (m, 1H), 1.81 (s, 3H), 1.67 (s, 3H). LRMS (ES)+: 476.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[O:11]1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[NH:1][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:10]([O:11][CH3:21])[C:3]=2[CH:4]=1
Reactant: Cc1cc(C)c(N)c(C2OC(=O)c3ccccc32)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC1c2ccccc2C(=O)Nc2c(C)cc(C)cc21
Yield: 53.4 %

Procedure:
In 300 ml of methyl alcohol was dissolved 22.45 g of 3-(2-amino-3, 5-dimethylphenyl)-1, 3-dihydroisobenzofuran-1-one. The solution was heated at reflux for 10 hours in the presence of 20.23 g of p-toluenesulfonic acid monohydrate. The resulting solution was concentrated to dryness under reduced pressure. The obtained solid was dissolved in 200 ml of dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solution was filtered and the resulting filtrate was concentrated to dryness under reduced pressure. To the obtained solid was added to diisopropyl ether and the solid was ground into powders. Thus, 12.65 g of 2,4-dimethyl-11-methoxy-5, 11-dihydro-6H-dibenz[b,e]azepin-6-one was obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1([Li])C=CC=CC=1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCOCC.[Cl-].[NH4+]>[F:31][C:32]1[CH:39]=[CH:38][C:35](/[CH:36]=[CH:2]/[O:3][CH3:4])=[CH:34][C:33]=1[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: CCOCC
Product: CO/C=C/c1ccc(F)c(Oc2ccccc2)c1
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
To a stirred suspension of (methoxymethyl)triphenylphosphonium chloride (2.48 g) in ether (50 ml) at room temperature under nitrogen is added phenyllithium (4 ml of a 1.8 M solution in ether, 7.2 mmol) and the resulting mixture stirred for 20 minutes. 4-fluoro-3-phenoxybenzaldehyde (1.30 g, 6.0 mmol) is then added and the reaction is stirred for 4 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride (20 ml) and diethyl ether (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (5:95) to afford the title compound as a colorless liquid (1.30 g, 89%) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl.[Pd]>[CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([CH:13]=[O:14])[CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O

Procedure:
A mixture of 59.74 g of 3-methyl-8-chlorocarbonylflavone (obtained from 3-methylflavon-8-carboxylic acid and thionyl chloride, white crystals, m.p. 156°-156.5° C.), 200 ml of xylene, 6 g of 5% palladium on barium sulfate and 0.4 ml of quinoline-S, maintained under stirring and under hydrogen flow, was heated for 6-7 hours at 85°-90° C. Upon completion of the reaction, the mixture was cooled, diluted with chloroform (20 ml), filtered, the solvent was evaporated under vacuum, and 260 ml of 20% sodium hydrogensulfite (W/V) and 600 ml of water were added to the residue. The mixture thus obtained was heated at reflux for 2 hours and then filtered while hot. The cooled filtrate was extracted several times with ethyl ether (4×200 ml), concentrated hydrogen chloride added and then heated to 95°-100° C. for 2 hours. After cooling, the solid thus formed was filtered and washed with water. The product (II) was obtained in a global yield equal to 78% of theoretical (41.46 g) and could be used as such in further syntheses. After recrystallization from methyl-tert-butyl-ether, it melted at 124°-126° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3].CC[O-].[Na+].Cl>C(O)C>[CH3:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:1][C:2]2=[O:3]
Reactant: CCOC(=O)C(=O)Nc1ccc(C)cc1C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(C)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a suspension of ethyl ((2-(aminocarbonyl)-4-methylphenyl)amino)(oxo)acetate (4.90 g, 19.6 mmol) in ethanol (100 mL) was added dropwise sodium ethylate (20% ethanol solution, 7.33 g, 21.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into 0.25N hydrochloric acid (200 mL) under ice-cooling, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water and ethanol to give the title compound as a pale-orange powder (2.90 g, 64%).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:39][CH2:38]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([S:43]([CH3:46])(=[O:45])=[O:44])[CH2:41][CH2:42]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.085 g) in ethyl acetate (3.0 mL), methanol (1.5 mL), and dioxane (6.0 mL), 10% palladium-carbon (0.085 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.063 g of methyl 2-(2-hydroxy-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[F:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (20 mg, 0.06 mmol, Step-1, single enantiomer) and isobutyryl chloride (120 mg, 1.1 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1N)=[O:5])[CH3:2].[I:17]CI.C(#N)C.N(OCCC(C)C)=O>CCCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[I:17])=[O:5])[CH3:2]
Reactant: ICI
Reactant: CCOC(=O)c1c(N)c(C#N)c(CC)n1C
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Temperature: 78 °C
Yield: 57.6 %

Procedure:
Alternatively the title compound may be prepared by the following procedure. Charge the 3-amino-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared in preparation 37, diiodomethane, and acetonitrile to a 22 L round-bottom flask equipped with an addition funnel, thermocouple, overhead stirrer, and condenser. Dilute isoamyl nitrite with heptane and charge the resulting solution to the addition funnel. Warm the reaction mixture to 78° C. Add 0.65 L of the isoamyl nitrite solution over 1.75 hours, at which point vigorous evolution of nitrogen is observed. Suspend the addition of the isoamyl nitrite solution for about 20 minutes to allow the off-gassing to subside. Add the remainder of the isoamyl nitrite solution over 15 minutes. Stir the reaction mixture at reflux for an additional 2 hours, then cool to room temperature. Remove the solvent under reduced pressure and dilute the resulting concentrate with a mixture of 0.2 L pentane and 0.2 L methylene chloride. Pour the resulting mixture onto a 4 kg column of silica gel that is pre-wetted with cyclohexane. Elute the column with 5′ gallons of cyclohexane, and discard the eluent. Next, elute the column with 6 gallons of a 1:1 mixture of cyclohexane:methylene chloride, followed by 5 gallons of 3:2 cyclohexane:methylene chloride. Combine these fractions and remove the solvent under reduced pressure. Suspend the resulting solid in 0.5 L of heptane and stir for 45 minutes. Collect the product by filtration, rinse with heptane, and vacuum-dry at 40° C. to afford the title compound (432.8 g) in 57.6% yield. Mass spectrum (m/e): 333.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[O:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:21][CH:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[N:21][CH:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2ncc(CBr)o2)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cnc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 5-(bromomethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole (Example 370C): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (m, 3H), 7.04 (s, 1H), 6.65 (s, 1H), 5.42 (s, 2H), 2.62 (s, 3H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.CSC>O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH:18]([OH:20])[CH3:19])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A flame dried 250 mL flask was charged with 7.95 g (27.5 mmol) trans-(4-acetyl-cyclohexylmethyl)-carbamic acid benzyl ester, 60 mL anhydrous THF and 2.7 mL (2.7 mmol) 1M (S)-2-methyl-CBS-oxazoborolidine. The mixture was heated to 50° C. then 11 mL (22 mmol) 2M BH3.DMS was added dropwise over 10 minutes; the reaction mixture was stirred for an additional 30 minutes at 50° C. and then cooled. The reaction was quenched with 25 mL MeOH and concentrated to give an oil. The material was diluted with water and extracted with ethyl acetate (3×40 mL). The combined organics were washed with water (1×100 mL), brine (1×100 mL), dried over Na2SO4 and concentrated to give a white solid, which was then chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 7.0 g of a white solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 16 h

Procedure:
A solution of 80 mg (0.21 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) of triethylamine and 63.8 mg (0.43 mmol) of 2-methoxyphenyl isocyanate. After 16 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 10 mg (9.6% of theory) of the title compound are obtained.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([CH2:13][N:14](S(C2C=CC=CC=2)(=O)=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=[C:9]([CH3:29])[N:8]=1)=O)(C)C.C[O-].[Na+]>CO>[CH3:19][O:18][C:16]([C:15]1[C:5]([OH:4])=[C:7]2[C:12]([CH:11]=[CH:10][C:9]([CH3:29])=[N:8]2)=[CH:13][N:14]=1)=[O:17]
Reactant: COC(=O)CN(Cc1ccc(C)nc1C(=O)OC(C)C)S(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2ccc(C)nc2c1O
Temperature: 0 °C

Procedure:
To a stirred solution of crude 3-[(benzenesulfonyl(methoxycarbonylmethyl)amino)methyl]-6-methylpyridine-2-carboxylic acid isopropyl ester (from Step C) in MeOH (20 mL) at 0° C. was added a solution of NaOMe in MeOH (prepared from Na (200 mg) in MeOH (4 mL)) dropwise over 20 min. The resulting solution was left to stir at 0° C. for a further hour and concentrated. Ethyl acetate (50 mL) and ice-H2O (50 mL) were added. The layers were separated; the aqueous layer was extracted with ethyl acetate (2×), the pH adjusted to 6 (5 M HCl) and extracted with dichloromethane (20 mL×3). The extracts were combined, dried, and concentrated to give pure 8-hydroxy-2-methyl-[1,6]naphthyridine-7-carboxylic acid methyl ester as a cream solid (708 mg, 98% (2 steps)).—1H NMR (CDCl3): δ 8.87 (s, 1H), 8.26 (d, J=8.5, 1H), 7.62 (d, J=8.5, 1H), 5.40 (br, 1H), 4.13 (s, 3H), 2.91 (s, 3H).