Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]([C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1)[C:35](=[O:37])[CH3:36]>>[CH3:45][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:38]1[CH:39]=[CH:40][C:41]([NH:42]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:43][CH:44]=1)[C:35](=[O:37])[CH3:36]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CC(=O)N(CCCN(C)C)c1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCCN(C)C)C(C)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-aniline Rf value: 0.2 (aluminium oxide, methylene chloride/ethanol=40:1) C31H34N4O4
Reaction SMILES: [CH2:1]([C@:3]1([C:31]([O:33][CH3:34])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH3:2].[H-].[Na+].I[CH3:38]>C1COCC1>[CH2:1]([C@:3]1([C:31]([O:33][CH3:34])=[O:32])[CH2:7][CH2:6][CH2:5][C@H:4]1[N:8]([CH3:38])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11])[CH3:2]
Reactant: CC[C@]1(C(=O)OC)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@]1(C(=O)OC)CCC[C@H]1N(C)S(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To 204 mg (0.423 mmol) of methyl (1S,2R)-1-ethyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (Example 56, Step 3) in THF (1.5 mL) was added 60% sodium hydride (22 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (35 μL, 80 mg 0.56 mmol) was added and the reaction was stirred overnight and then quenched with saturated aqueous ammonium chloride. These steps were repeated twice more, until starting material was consumed, and the residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate/hexanes to give methyl (1S,2R)-l -ethyl-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (174 mg, 0.350 mmol, 83%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) □ ppm 0.85 (t, J=7.33 Hz, 3H) 1.29-1.40 (m, 1H) 1.48-1.60 (m, 4H) 1.78-1.87 (m, 1H) 2.20-2.30 (m, J=7.01, 7.01, 7.01, 7.01 Hz, 2H) 2.57 (s, 3H) 2.75 (s, 3H) 3.71 (s, 3H) 5.55 (s, 2H) 7.11 (ddd, J=9.41, 2.78, 2.46 Hz, 2H) 7.42 (s, 1H) 7.55 (ddd, J=8.27, 6.88, 1.26 Hz, 1H) 7.70-7.76 (m, 3H) 7.90 (d, J=7.58 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][N:11]=2)[N:6]=1.O>C1COCC1>[Cl:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][N:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: FC(F)(F)c1cccnc1-c1cnc2c(Cl)cc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c2ncc(-c3ncccc3C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium methoxide (4M, 0.45 mL, 1.8 mmol) to a solution of 2,4-dichloro-7-[3-(trifluoromethyl)pyrdin-2yl]-1,5-naphthyridine (575 mg, 1.6 mmol) in THF (10 mL). Stir at room temperature for 1 hour, add water (15 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the residue by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:14]([O:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCc1ccoc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-hydroxymethylfuran (1.01 g., 10.3 mmol) and pyridine (0.87 g., 10.3 mmol) in 30 ml dry tetrahydrofuran at 0° under argon was added lauroyl chloride (2.36 g., 10.8 mmol). This solution was allowed to warm to room temperature, during which time a white precipitate formed. After one hour, the mixture was filtered and the solution partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, three times with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This material was further purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:11]([C:17](=[O:19])[CH3:18])=[CH:12][C:13]=1[C:14](=[O:16])[CH3:15])[NH:8][CH2:9][CH3:10])C=C.CN1C(=O)[CH2:24][CH2:23][CH2:22]1>C(O)C.[Pd]>[C:17]([C:11]1[CH:12]=[C:13]([C:14](=[O:16])[CH3:15])[C:5]([OH:4])=[C:6]([CH2:22][CH2:23][CH3:24])[C:7]=1[NH:8][CH2:9][CH3:10])(=[O:19])[CH3:18]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1cc(NCC)c(C(C)=O)cc1C(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(O)c(C(C)=O)cc(C(C)=O)c1NCC
Temperature: 25 °C
Yield: 63 %

Procedure:
The product of step (b) (0.013 mole) was heated in NMP (25 ml) at reflux under nitrogen for 1 hour. After cooling to room temperature, the mixture was diluted with ethanol (25 ml), and hydrogenated over 5% Pd/C at 15-20 psi for 21/2 hours. After filtration, the mixture was poured into water, the grey solid isolated by filtration, and recrystallised from ethanol to give the title compound. Yield 63%, mp 114°-115° C.
Reaction SMILES: [CH:1]([C:3]12[CH2:17][CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)=O.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH:5]1[C:4]2[C:3]3([CH2:1][N:27]4[CH2:26][CH2:25][CH:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH2:29][CH2:28]4)[CH2:17][CH:10]([C:11]4[C:16]3=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=CC12CC(c3ccccc31)c1ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a methanol solution (80 mL) of 9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 5a) (5.00 g, 22.7 mmol) was added a large excess of freshly activated 3 A molecular sieves (approx. 10 g) under an atmosphere of nitrogen. 4-Phenylpiperidine (4.57 g, 28 mmol, 1.25 eq) was added followed by four portions of sodium cyanoborohydride (1.43 g, 22.7 mmol) over 1.3 h. The resulting suspension of sieves and reagents was stirred for 3 days at room temperature. The reaction was treated with 2.5N NaOH (100 mL) and the aqueous phase was extracted with ethyl acetate (1×400 mL). The organic phase was washed with water (3×100 mL), dried over anhydrous sodium sulfate, filtered and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (300 mL, eluent: 50% methylene chloride in hexane) to recover 1.20 g (15%) of the title compound. TLC analysis (Rf 0.19, 50% methylene chloride in hexane). 1H NMR (CDCl3, 300 MHz) 7.22 (m, 9H), 6.93 (m, 4H), 4.27 (s, 1H), 3.43 (s, 2H), 3.13 (m, 2H), 2.62 (d, J=1.4 Hz, 2H), 2.51 (m, 1H), 2.34 (m, 2H), 1.76 (m, 4H) MS (CI, CH4) m/z 366 (M+1,100), 394 (M+29,16) The free base was dissolved in the minimum of methanol and chloroform, acidified with ethereal HCl and the resulting hydrochloride salt precipitated with ether dilution. The solid was filtered, rinsed with fresh ether, and dried in vacuo (50° C., 10 pascal, 18 h) to yield a solid, mp>300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[O:12]1[CH:13]=[N:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ncon2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of 4-nitrobenzonitrile (1 g, 0.0068 mol) in ethanol (20 mL) and water (8 mL) was added hydroxylamine hydrochloride (1.9 g, 0.0272 mol) followed by sodium carbonate (2.2 g, 0.0204 mol). The resulting mixture was heated to reflux at 85° C. under an atmosphere of nitrogen for 2 hours The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The volatiles were evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H). To a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 0.0066 mol) in THF (15 mL) was added triethyl orthoformate (2.93 g, 0.0198 mol). The resulting mixture was cooled to between 0 and 5° C. Boron trifluoride dimethyl ether (0.9 g, 0.0079 mol) was then added dropwise and the resulting mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.65 g (55%) of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole. To a stirred solution of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole (0.2 g, 0.001 mol) in THF (15 mL) was added ammonium chloride (0.214 g, 0.004 mol) in water (5 mL) followed by zinc powder (0.262 g, 0.004 mol) portionwise. The resulting mixture was stirred at ambient temperature for 1 hr and then heated to 65° C. for 5 hours. The mixture was then filtered through celite and the organic layers were concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were washed with brine solution, dried over Na2SO4 and evaporated under reduced pressure to afford 0.155 g (92%) of 4-[1, 2, 4]oxadiazol-3-yl-phenylamine. 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([N:8]([CH3:10])[CH3:9])=[N:7][C:2]=1[F:1]
Reactant: CN(C)c1cccc(F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CN(C)c1ccc(Br)c(F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 190 %

Procedure:
To a solution of Intermediate (6-fluoro-pyridin-2-yl)-dimethyl-amine (12.4 g, 88.4 mmol) in acetonitrile (400 mL) at 0° C. was added a solution of N-bromosuccinimide (7.87 g, 44.2 mmol) in acetonitrile (95 mL) dropwise over 15 min. The resulting solution was stirred at 0° C. for 1 hour. Another portion of N-bromosuccinimide (7.87 g, 44.2 mmol) in acetonitrile (95 mL) was subsequently added at 0° C. dropwise over 15 min. The solution was slowly warmed to room temperature and stirred overnight. The solution was concentrated in vacuo and diluted with dichloromethane (500 mL). This was washed with water (300 mL) and the aqueous layer back extracted with dichloromethane (3×200 mL), before drying over MgSO4, filtering, and concentrating in vacuo. The material was passed through a silica pad, eluting with 0-10% ethyl acetate in heptanes. The organics were concentrated in vacuo to afford desired material (18.4 g, 95% yield) that solidified upon standing. 1H NMR (CDCl3, 400 MHz) 5=7.48-7.67 (m, 1 H) 6.21 (dd, J=8.59, 1.56 Hz, 1 H) 3.05 (s, 6 H); MS (FID)=218.0 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[C:28](=[O:29])[CH2:27][CH:26]([NH:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:25]2)=[CH:18][C:17]=1[F:16]
Reactant: O=C(NC1CC(=O)N(c2ccc(O)c(F)c2)C1)c1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(N4CC(NC(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.14 g, 0.6 mmol), N-(1-(3-fluoro-4-hydroxyphenyl)-5-oxopyrrolidin-3-yl)benzamide (Step 4, 0.20 g, 0.6 mmol) and DMAP (78 mg, 0.6 mmol) in 2 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc in hexanes then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 502.3 (M+H). Calc'd Exact Mass for C28H24FN3O5: 501.51.
Reaction SMILES: C([N:8]1[CH2:31][CH:30]([CH:32]=[CH2:33])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH2:32]([CH:30]1[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9][NH:8][CH2:31]1)[CH3:33]
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CNCC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Temperature: 75 °C
Yield: 84.1 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (150 mg, 0.33 mmol), ammonium formate (74 mg, 1.17 mmol) and Pd (17 mg, 0.02 mmol) (10% on activated carbon) was added methanol (2 mL) and the reaction mixture was heated at 75° C. for 30 minutes. The reaction mixture was cooled, microfiltered and concentrated in vacuo, then diluted with DCM (20 mL), washed with aq. 1M NaOH (10 mL), extracted with DCM (120 mL), washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to give (10-ethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (100 mg, 83%) as a colorless oil. ESI-MS m/z calc. 360.5. found 361.3 (M+1)+; Retention time: 1.25 minutes (3 min run).
Reaction SMILES: [H][H].[F:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(OCC)(=O)C.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:3])[CH:14]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAC was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1.O=S(Cl)Cl.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>>[CH3:32][N:2]([CH3:1])[C:3]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][C:6]2[NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:40][CH2:39][C:38]([F:42])([F:41])[F:37])=[CH:21][N:20]=[N:19]4)[CH:13]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: NCC(F)(F)F
Reactant: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNCC(F)(F)F)c1)=N2

Procedure:
The title compound was prepared from 7-dimethylamino-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 17) (133 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and 2,2,2-trifluoroethylamine (10 eq.) as described in Example 45. Obtained as a light yellow solid (19 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11]#[N:12])[CH:14]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(S(=O)(=O)NCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanamine (600 mg, 3.13 mmol) and TEA (800 mg, 8 mmol) in THF (10 mL), was added a solution of 3-cyano-benzenesulfonyl chloride (580 mg, 2.88 mmol) in THF (10 mL) at 0° C. The mixture was stirred at rt for 2 h, quenched with water, and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-50% EtOAc in hexanes) gives 68A (708 mg, 71%). MS (ESI) m/z 365.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:16].CO>[Ni]>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[O:11][C:10]([CH2:12][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)o1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
A suspension of 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde described in Preparation Example 168 (4.3 g, 20.9 mmol), Raney nickel (1.5 g) and 7N ammonia-methanol solution (40 mL) was stirred at room temperature for 15 hours under hydrogen atmosphere (1 atm). The reaction solution was filtered through Celite pad to remove the catalyst, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, filtered by NH silica gel lined over a glass filter, and then, this filtrate was concentrated to obtain the title compound (3.5 g, 16.9 mmol, 81%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][SiH:10]([CH:12]([SiH:17]([Cl:19])[Cl:18])[Si:13]([Cl:16])([Cl:15])[Cl:14])[Cl:11]>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.C1C=CC=CC=1>[Cl:11][Si:10]1([Cl:9])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[Si:17]([Cl:18])([Cl:19])[CH:12]1[Si:13]([Cl:16])([Cl:14])[Cl:15]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C(c2ccccc2)[Si]1(Cl)Cl
Yield: 43.9 %

Procedure:
Hydrosilation of phenylacetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pd(PPh3)4. Into the same apparatus as described in Example 1 were added 1.0 g of bis(dichlorosilyl)trichlorosilylmethane, 0.102 g of Pd(PPh3)4, and 25 ml of dried benzene to form a mixture. The mixture was brought to reflux temperature and 0.32 ml of phenylacetylene added over a 10 minute period. The mixture was stirred at reflux temperature for an additional 8 hours and then the solvent removed at atmospheric pressure. The residue was vacuum distilled at 67 Pa to yield a mixture comprising 0.348 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-4-phenyl-1,3-disilacyclopent-4-ene (TCD-GC area 43.9%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1I)[CH3:2].[CH3:14][N:15]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:34])[N:15]([CH3:14])[CH:24]=1)[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Product: CCc1ccc(S(C)(=O)=O)cc1-c1cn(C)c(=O)c2ccccc12

Procedure:
The the title compound of Example 312, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 312, step 4 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 1.10 (3H, t, J=8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H, m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz). LCMS: 342 (M+1)+
Reaction SMILES: IC.[CH3:3][C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]1=[O:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1cccn(C)c1=O
Temperature: 55 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
Iodomethane (10.62 mL, 111.6 mmol) was added to a mixture of 3-methyl-2-pyridone (4.06 g, 37.20 mmol) and potassium carbonate (15.43 g, 111.6 mmol) in acetone (150 mL) in a sealable flask. The mixture was vigorously stirred in an oil bath at 55° C. for 16 hours. The reaction mixture was cooled to ambient temperature then filtered through glass fiber filter paper and the filtrate was concentrated under vacuum until a solid formed (5.4 g). The solid was partitioned between water (50 mL) and dichloromethane (100 mL). The aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated under vacuum to give 1,3-dimethylpyridin-2(1H)-one as an oil (3.6 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:20]2[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:20]2[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2OC(F)(F)F)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A mixture of tert-butyl 9-[2-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (190 mg, 0.464 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give the desired product (158 mg, 98.8%) as a solid.