Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(N(C)C)=O)=NC(N(C)C)=O.[C:28](O)(=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A solution of Intermediate 35 (21.06 g), 1,1′-azobis(N,N-dimethylformamide) (64.11 g) and p-anisic acid (23.03 g, Tokyo Kasei Kogyo) in tetrahydrofuran (400 ml) was added with tri(n-butyl)phosphine (35.6 ml) at room temperature and stirred at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, then added with ethyl acetate (200 ml) and successively washed with saturated aqueous sodium hydrogencarbonate twice (200 ml each) and 0.1 N aqueous sodium hydroxide (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (32.92 g).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)\[NH2:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:1]/[N:2]=[C:3](/[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][CH:10]=1)\[NH2:4])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/O)cn1
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1ccc(/C(N)=N/OC(C)=O)cn1
Reaction time: 120 h

Procedure:
To a suspension of methyl 4-[[5-[(Z)—N′-hydroxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate (obtained as described in step 1, 0.15 g, 0.56 mmol, 1 equiv.) in dichloromethane (30 mL) was added acetic anhydride (1.98 mL, 20.3 mmol, 36 equiv.). The mixture was stirred for 5 days, before concentration under vacuum giving methyl 4-[[5-[(Z)—N′-acetoxycarbamimidoyl]-2-pyridyl]amino]-4-oxo-butanoate which is used in the next step without extra purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24][CH2:23]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=[C:2]([N:25]2[CH2:24][CH2:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([C:19]([F:18])([F:31])[F:30])[CH:21]=3)[CH2:26]2)[N:7]=1
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 62.4 %

Procedure:
In a tube, a mixture of 1d (0.374 g, 1.25 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.301 g, 1.5 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.037 g, 0.04 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title compound (0.326 g, 0.78 mmol, 63%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J=7.2 Hz, 2H), 7.24 (s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1>C(O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:20]1[CH:19]=[C:18]([Cl:23])[N:17]=[C:16]([Cl:15])[N:21]=1)[CH3:3]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 27.8 g. (0.2 mole) of glycine ethyl ester hydrochloride and 42.4 g. (0.4 mole) of sodium carbonate in 300 ml. of ethanol was added 36.6 g. (0.2 mole) of 2,4,6-trichloropyrimidine. After stirring at room temperature for 2 hours the mixture was filtered. The filtrate was diluted with 300 ml. of water and the precipitate thus formed was collected, dried, and triturated with 600 ml. of boiling petroleum ether. The insoluble material was filtered off and recrystallized from ethanol-petroleum ether to afford 4.7 g. of product, m.p. 89°-91°C.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][C:11]([CH3:15])([OH:14])[CH2:12][OH:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.C1C=CC=CC=1>O>[CH2:2]([O:9][CH2:10][C:11]1([CH3:15])[CH2:12][O:13][C:17]([CH3:19])([C:16]([O:21][CH2:22][CH3:23])=[O:20])[O:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(O)(CO)COCc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C)OCC(C)(COCc2ccccc2)O1
Temperature: 90 °C

Procedure:
Dry hydrogen chloride gas was passed into a mixture of 3-benzyloxy-2-methylpropane-1,2-diol (14.9 grams) and ethyl pyruvate (9.15 grams) for 1 hour. The mixture was heated at 90° C for a further 1 hour and then cooled to 50° C. Benzene (100 milliliters) was added to the mixture and the water formed in the reaction was removed azeotropically. The cooled solution was washed with potassium carbonate solution and dried. The solvent was removed under reduced pressure and the residue was fractionally distilled to yield the desired product boiling point 124-126° C at 0.3 Torr.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[S:36](=[O:40])(=[O:39])([OH:38])[OH:37].O>CO>[S:36]([O-:40])([O-:39])(=[O:38])=[O:37].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14].[NH2:12][C:13]([C:15]1[C:23]2[C:19](=[CH:20][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C@@H:30]4[CH2:35][CH2:34][CH2:33][NH2+:32][CH2:31]4)=[CH:26][CH:25]=3)[N:22]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=S(=O)(O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: NC(=O)c1cccc2cn(-c3ccc([C@@H]4CCC[NH2+]C4)cc3)nc12
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])[O-]
Temperature: 40 °C
Reaction time: 24 h

Procedure:
50 mg of tert-butyl(3S)-3-{4-[7-(aminocarbonyl)-2H-indazol-2-yl]phenyl}piperidine-1-carboxylate (Example 1, D3) as a compound stock solution was reacted with 1 mole equivalent of sulfuric acid, added as a 1 Molar solution in 1:1 (v/v) methanol:water solution. Excess solvent was removed under centrifugal evaporation and 1 mL of the methanol:water solution added at ambient room temperature (˜25° C.). The resultant solution stirred at 40° C. for 24 hours. The experiment was left to gently evaporate under atmospheric conditions where a colorless solid was observed.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Ic1ccc[se]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 15.1 g (58.7 mmol) of 2-iodoselenophene, 13.9 g (67.7 mmol) of 4-trifluoromethoxyphenylboronic acid, 3.90 g (3.38 mmol) of tetrakis(triphenylphosphine)palladium(0) and 150 ml of 2 N sodium carbonate soln. in 400 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with MTBE. The combined organic phases are washed with 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→1:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-trifluoromethoxyphenyl)selenophene is obtained as a yellowish solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37].O>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:33][C:34]#[C:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (27.4 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (1.37 g). To the solution was added 60% sodium hydride (0.27 g) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3-bromo-1-(trimethylsilyl)-1-propyne (1.48 ml), and the mixture was stirred at 65° C. for 90 hours. After cooled to room temperature, the reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=3/1) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(3-trimethylsilyl-2-propynyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.78 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: CCCc1cc2cc(OC)c(Cl)c(Cl)c2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCc1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 56.3 %

Procedure:
A mixture of 29 g of 6,7-dichloro-5-methoxy-2-n-propylbenzo[b]thiophene and 280 g of pyridine hydrochloride is heated at 190° for 5 hrs and allowed to cool. The reaction mixture is poured into 300 ml of water and extracted with three 33-ml portions of ether. The ether extracts are washed with 500 ml of 2 N hydrochloric acid, water, dried over anhydrous magnesium sulfate-charcoal, filtered and evaporated to give an oil. Crystallization of the oil with hexane followed by recrystallization from hexane give 15.5 g of 6,7-dichloro-5-hydroxy-2-n-propylbenzo[b]thiophene, mp 50°-51°.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)(=[O:5])[CH3:4].O.Cl>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)[CH3:4]
Reactant: CC(=O)c1cnccn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1cnccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
Sodium borohydride (0.69 g) was added in portions to a stirred solution of acetylpyrazine (1.49 g) in ethanol (300 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 20 min, then water (100 mL) was added and the mixture adjusted to pH 7 with 1N hydrochloric acid. The neutralized solution was concentrated in vacuo to a volume of 200 mL, saturated with sodium chloride, and extracted with ethyl acetate (3×500 mL). The organic extracts were dried (Na2 SO4) and concentrated to give a solid which was washed with dichloromethane (4×100 mL). The dichloromethane washings were concentrated to give 2-(1-hydroxyethyl)pyrazine (1.38 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(N(CC)CC)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:24][CH:20]([CH3:21])[CH2:22][CH3:23])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)CC

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml. methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of sec. butylamine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized with methanol, yield: 107 g. (68%); m.p. 33°-35° (methanol).
Reaction SMILES: CO.[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.[H][H]>[C].[Pd].O>[ClH:3].[NH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[CH:19][CH:20]=2)[CH2:6][CH2:5]1
Reactant: NC(=O)c1ccc(/C=C/C2CCNCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(CCC2CCNCC2)cc1
Yield: 56 %

Procedure:
10% Palladium-carbon (catalytic amount) was added to a methanol (15 ml)/water (5 ml) solution containing 4-[(E)-2-piperidin-4-ylvinyl]benzamide hydrochloride (800 mg), followed by stirring in a hydrogen gas atmosphere at room temperature under normal pressure for 4 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from ethanol/acetonitrile to obtain 4-(2-piperidin-4-ylethyl)benzamide hydrochloride (451 mg) (Reference Example 58).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].C[O:15]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:11]=[O:15])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(C)c([N+](=O)[O-])cc1Br
Reactant: COC(OC)N(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Temperature: 120 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
The crude 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (2.6 g, 11 mmol) was dissolved in N,N-dimethylformamide (15 mL) and N,N-dimethylformamide dimethylacetal (5 mL, 38 mmol) was added. The reaction was heated to 120° C. for 18 hours. The reaction was cooled to room temperature and the mixture was added directly to a 0° C. suspension of sodium periodate (12.2 g, 57.2 mmol) in water (20 mL) and N,N-dimethylformamide (5 mL). The reaction was stirred at 0° C. for 2 hours, then allowed to warm to room temperature and stir for another 6 hours. The reaction mixture was filtered, rinsing with ethyl acetate, toluene, and water. The filtrate was extracted with ethyl acetate (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (550 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 10.47 (s, 1 H), 8.41 (s, 1 H), 7.35 (s, 1 H), 4.05 (s, 3 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1
Reactant: CCOC(=O)C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H]1CCCNC1

Procedure:
280 mg (1.03 mmol) of ethyl (S)-(1-tert-butoxycarbonylpiperidin-3-yl)acetate (Example 16A) are stirred with 2 ml of dichloromethane and 2 ml of trifluoroacetic acid at RT for 1 h. The volatile components are removed on a rotary evaporator and the residue is dried under high vacuum. The resulting oil (290 mg, 99% of theory) is reacted further as it is.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[Cl:41][C:42]1[S:46][C:45]([S:47](Cl)(=[O:49])=[O:48])=[CH:44][CH:43]=1>O1CCCC1.O>[Cl:41][C:42]1[S:46][C:45]([S:47]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:49])=[O:48])=[CH:44][CH:43]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(Cl)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a suspension of sodium hydride (60% in oil, 24.0 mg) in tetrahydrofuran (2 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) under ice-cooling, and the mixture was stirred for 15 min. 15-Crown-5 (133 mg) and a solution of 5-chlorothiophene-2-sulfonyl chloride in tetrahydrofuran (1 mL) were added dropwise and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 229 mg, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[OH:32])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)=[CH:37][C:36]=1[Cl:51].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:48])([F:50])[F:49])=[CH:45][CH:46]=2)=[CH:37][C:36]=1[Cl:51])[CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][C:10]1=2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FC(F)(F)c1ccc(-c2ccc(CBr)c(Cl)c2)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
250 mg (0.57 mmol) of rac-ethyl 5-{(tert-butoxycarbonyl)[2-(2-hydroxyphenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 10A), 277 mg (0.68 mmol) of 4-(bromomethyl)-3-chloro-4′-(trifluoromethyl)biphenyl and 118 mg (0.85 mmol) of potassium carbonate in 10 ml of acetonitrile were heated to 110° C. and stirred at this temperature for 4 h. After cooling, the reaction mixture was filtered, the filter cake was washed repeatedly with acetonitrile and the combined filtrates were concentrated to dryness on a rotary evaporator. The residue obtained was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). The product obtained in this manner was re-purified by preparative HPLC (mobile phase: methanol/water 9:1). This gave 182 mg (0.26 mmol, 45% of theory) of the target compound.
Reaction SMILES: [C:1]([C:3]1[C:9]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:8]([O:16][CH3:17])[C:7]([O:18][CH3:19])=[CH:6][C:4]=1[NH2:5])#[N:2].[C:20]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:25][CH2:24]1)(=O)[CH3:21]>ClCCl.CO>[CH3:17][O:16][C:8]1[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[C:3]([C:4]([N:5]=[C:20]([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])[CH2:25][CH2:24]2)[CH3:21])=[CH:6][C:7]=1[O:18][CH3:19])[C:1]#[N:2]
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1OC
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1OC

Procedure:
The subtitle compound was prepared from 2-cyano-4,5-dimethoxy-3-(2,2,2-trifluoroethoxy)aniline and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 10(g) (73%). Rf 0.16 (dichloromethane:methanol 95:5, v/v). MS m/z 514 (MH)+.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>O1CCCC1>[NH2:19][CH:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (8.2 g), hydrazine hydrate (1.08 g) and tetrahydrofuran (160 ml) was stirred for 1.0 hour at room temperature and heated under reflux for 1.5 hours. After the precipitates were filtered off, the filtrate was evaporated to small volume and the equivalent volume of diisopropyl ether was added 15 thereto The precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-one (3.64 g).