Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1.[O-]CC.[Na+]>C(O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][N:25]([CH2:2][C:3]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])[S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=1)(=[O:23])=[O:24])[CH3:31]
Reactant: CCOC(=O)c1cc(I)cnc1CBr
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN(Cc1ncc(I)cc1C(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(bromomethyl)-5-iodonicotinate (Preparation 10, 9.25 g) and ethyl (((4-methylphenyl)sulfonyl)amino)acetate (7.0 g) are dissolved in anhydrous ethanol (50 mL) and a solution of sodium ethoxide (3.4 g) in ethanol (45 mL) is added over 15 min. The mixture is stirred overnight and then poured into ice water. The mixture is extracted with ethyl acetate (3×100 mL) and the organic layer is concentrated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25](F)[C:24]([CH3:28])=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30].O>C1COCC1>[Cl:20][C:21]1[C:22]([N+:29]([O-:31])=[O:30])=[CH:23][C:24]([CH3:28])=[C:25]([CH:26]=1)[O:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A flask was charged with tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (905 mg, 3.7 mmol, commercially available from Alrich), sodium hydride, 95% (24 mg, 4.6 mmol) and THF (10 mL), and the mixture was stirred under N2 for 15 minutes, after which time a solution of 1-chloro-5-fluoro-4-methyl-2-nitrobenzene (700 mg, 3.7 mmol, commercially available from Aldrich) in THF (10 mL) was added to the sodium hydride mixture at 0° C. The reaction mixture was heated to 65° C. for 15 hours. Water was added to the cooled reaction mixture and the mixture was extracted with ethyl acetate. The organic solvent was concentrated under reduced pressure and the resulting solid was purified by silica column chromatography eluting with 5% methanol in dichloromethane, to give 1.2 g (78 5 yield) of tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy) propyl)piperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.92 (s, 1H), 3.92 (t, 2H), 3.06 (m, 4H), 2.62 (m, 4H), 2.36 (m, 2H), 2.34 (s, 3H), 1.84 (m, 2H), 1.42 (s, 9H). MS (EI): 414 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[S:8][C:5]2=[N:6][CH:7]=1.[Br:20]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
6-Methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (2.9 g, 10.7 mmol), N-bromosuccinimide (NBS, 1.91 g, 10.7 mmol), CCl4 (200 mL) and benzoyl peroxide (0.021 g) were added into a three-neck flask (500 mL) under argon. The resulting yellow mixture was refluxed for 2 h. Additional NBS (1.91 g) and benzoyl peroxide (0.021 g) were added. Two hours later, more NBS (0.95 g) and benzoyl peroxide (0.021 g) were added and the mixture was continually refluxed for 3 h. The mixture was then cooled to room temperature. The solution was transferred into another flask and concentrated in vacuo to afford crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), which was directly used for next step.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:31].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:33]1([CH3:38])[C:32]([C:30]([CH2:29][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:31])=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (4.00 g) obtained from Step 1 of Example 89 was suspended in toluene (56 ml), 2-bromo-2′-methylacetophenone (2.72 g), 1N aqueous sodium hydroxide (28 ml) and tetra n-butylammonium bromide (40 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 4.54 g of the titled compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]1[CH2:18][C:19](O)=[O:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][OH:46])=[CH:41][CH:40]=1>C(Cl)Cl.CN(C=O)C>[OH:46][CH2:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][CH2:37][NH:36][C:19](=[O:20])[CH2:18][CH:3]2[C:2](=[O:1])[NH:7][CH:6]=[CH:5][N:4]2[S:8]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)O)cc1
Reactant: NCCc1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetic acid (620 mg, 2.0 mmol), EDC (Aldrich, 575 mg, 3.0 mmol), HOBt (Aldrich, 270 mg, 2.0 mmol), and [4-(2-amino-ethyl)-phenyl]-methanol (362 mg, 2.4 mmol) was added CH2Cl2 (15 mL) and DMF (2 mL). The reaction mixture was stirred at room temperature overnight and diluted with CH2Cl2 (80 mL). The organic phase was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chomatography (6%-10% MeOH—CH2Cl2) to afford the title compound. MS (ESI): 444 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCCN1CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCN2CCCC2)c1

Procedure:
3-Fluoro-4-nitro-benzoic acid methyl ester (xiv) (1.08 g, 5.41 mmol) and 2-pyrrolidin-1-yl-ethylamine (1.36 g, 11.9 mmol) in MeOH (19 mL) were stirred under microwave irradiation at 100° C. for 10 min. The RM was diluted with EtOAc and washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dry loaded on silica gel and purified by chromatography with DCM and MeOH to yield the title product as an orange solid (tR 2.45 min (conditions 8), MH+=294).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([C:8]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[OH:21])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ncc(Br)cc1Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: O=C(Nc1ccc(O)cc1O)c1ncc(Br)cc1Cl

Procedure:
Using 5-bromo-3-chloropyridine-2-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:16])[CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:16])[CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
(S)-3-(1-Hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.5 g, 6.5 mmol) was purified by preparative HPLC. The residue was dissolved in 50% AcOH/H2O and the diastereomers were separated using a gradient of 10-50% AcOH/H2O (0.05% TFA) over 80 minutes on a 2″ column at 40 mL/min. The collected fractions were lyophilized to yield each diastcrcomcr as an oil (565 mg, SS, 1st eluting peak; 565 mg, SR, 2nd eluting peak). Each diastereomer was dissolved in DCM (4 mL) and HCO3 resin (1 gΠ1.95 mmol/g) was added to recover residual TFA. The mixture was stirred for 1 hour. The product was filtered off and solvent was removed to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: Cc1cc(N)n(-c2ccc(F)cc2)n1
Reactant: CC(=O)N1C=NC(=O)C1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(F)cc1

Procedure:
5-Amino-1-(4-fluorophenyl)-3-methylpyrazole (25 g.) and 1-acetyl-2-imidazolinone (20.2 g.) were reacted as described in Example I to give 21.97 g. product, mp 189°-191°
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:24]1C=CC=C[CH:25]=1>>[CH3:25][NH:24][CH2:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCCc1cc2ccccc2o1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CNCCc1cc2ccccc2o1
Yield: 59 %

Procedure:
A solution of 5.03 g of 3-benzofuranethanol and 8 g of p-toluenesulfonyl chloride in 20 ml of pyridine was kept in a refrigerator for one week. Most of the pyridine was removed under vacuum, and the residue dissolved in ether and washed successively with 5% hydrochloric acid, water, and 5% sodium bicarbonate solution and dried. Removal of the solvent left 5.93 g of crude 3-benzofuranethanol, p-toluenesulfonate which was heated with 8 g of methylamine in 25 ml of tetrahydrofuran to 100° for 4 hours. The mixture was concentrated, made basic with aqueous sodium hydroxide, and extracted with methylene chloride. The crude amine so obtained was short-path distilled (bath 120°, 0.5 micron) to give 3.17 g (59% yield) of N-methyl 3-benzofuranethylamine. NMR spectrum (in CDCl3): τ2.4-3.0 (m, 5); 7.2 (s, 4); 7.6 (s, 3) and 9.0 (s, 1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH2:15]([CH:17](CC)C(O)=O)[CH3:16].C(C(CC)C(O)=O)C.C(=O)CC=O>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[CH:16][CH:15]=[CH:17][N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC(CC)C(=O)O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Agent: O=CCC=O
Solvent: CC(=O)O
Product: c1ccc(CSc2nc3ncccn3n2)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A solution of 2.0 g (9.6 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 2.3 ml (9.6 mmol) of malonaldehyde bis(diethylacetate) in 20 ml of glacial acetic acid was heated at reflux for 17 hours. After cooling to room temperature, the solvent was removed by evaporation at reduced pressure. The brown solid residue was recrystallized from isopropyl alcohol to afford 0.4 g (17%) of the desired product as a light brown crystalline solid, m.p. 104°-106° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with 124b (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexanes (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with a ice cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromo-methyl)-3-nitro-1H-pyrazole. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 124c as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t, 2H, J=6.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[F:11].CC1C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[N:6]=[C:5]2[F:11]
Reactant: C1=COCCC1
Reactant: Fc1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Fc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A mixture of 5-bromo-3-fluoro-1H-indazole (6.0 g, 27.9 mmol), p-TsOH (530.7 mg, 2.79 mmol) and 3,4-dihydro-2H-pyran (3.05 g, 36.3 mmol) in dichloromethane (80 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane (370 mL) and washed with water (230 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:100 to 1:15) to afford the title compound as a yellow solid (6.2 g, yield 74.3%). 1H NMR (DMSO-d6, 400 MHz): δ 7.96 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m, 1H), 2.20-2.15 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)(=O)=O.C(OCC)(=O)C>CN(C=O)C.Cl.O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CCC2CCNCC2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution. After stirring at room temperature for 30 minutes, 184 g (0.60 mmol) of t-butyl 4-(2-((methylsulfonyl)oxy)ethyl)-1-piperidinecarboxylate was added to the obtained mixture, and they were stirred at 70° C. overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 10 ml of 4N solution of hydrogen chloride in dioxane, and the obtained solution was stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the title compound was obtained.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:33]([O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=3)[CH3:12])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]
Reactant: CC[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(=O)OC
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: CC[C@H](Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Reactant: C1CCNCC1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCCCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and piperidine following the procedure outlined in Example 15 (modifications: 40° C., 18 h). 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.39 (s, 3H), 7.88 (d, 1H), 7.01 (d, 1H), 4.51 (s, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 2.25 (br, 4H), 2.17 (t, 2H), 2.13 (s, 6H), 1.74 (m, 2H), 1.49-1.23 (m, 12H); MS (ESI): 479.4.
Reaction SMILES: [CH:1]([C:3]1[C:23]([O:24][CH3:25])=[CH:22][C:6]2[CH2:7][C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:5]=2[CH:4]=1)=O.Cl>[Pd].CC(O)=O>[CH3:25][O:24][C:23]1[C:3]([CH3:1])=[CH:4][C:5]2[CH2:11][CH:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][C:6]=2[CH:22]=1
Reactant: CCOC(=O)CC1Cc2cc(C=O)c(OC)cc2Cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC1Cc2cc(C)c(OC)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-2-formyl-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate (220 mg, 0.65 mmol), 10% Pd/C (90 mg), glacial HOAc (15 mL), and conc HCl (2 mL) was shaken at RT under hydrogen (60 psi). After 20 hr, the mixture was filtered through celite®, and the filtrate was concentrated to afford the title compound (200 mg, 95%) as a colorless oil: MS (ES) m/e 325.2 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].I[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:18]1([CH2:17][C@H:8]([C@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: ICC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@@H](O)[C@@H](CC1CCCC1)C(=O)OC(C)C
Temperature: 20 °C

Procedure:
To a cold (5° C.) solution of diisopropyl-(S)-(−)-malate (50.0 g, 229.1 mmol, 1.0 eq.) and (iodomethyl)cyclopentane (55.6 g, 264.6 mmol, 1.15 eq.) in anhydrous THF (250 mL) under N2 was added over a period of 90 min. a solution (1M) of lithium bis(trimethylsilyl)amide (481 mL; 1.0 M, 481.1 mmol, 2.1 eq.) in THF. The temperature was allowed to warm to 20° C. and the mixture was stirred for 15 hours until completion (monitoring by TLC (SiO2); cyclohexane 8-ethyl acetate 2; treated with molibdic acid).
Reaction SMILES: [CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)=[O:2]>CO.[Pd]>[CH:1]([NH:3][C:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)=[O:2]
Reactant: CC(Cc1cccc([N+](=O)[O-])c1)(NC=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1cccc(N)c1)(NC=O)c1ccccc1
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of N-formyl-1-(3-nitrophenyl)-2-phenyl-2-propylamine (5.0 g, 0.017 mol) in methanol (200 ml) was added 10% Pd/C catalyst (0.5 g) and the mixture hydrogenated at 50 psi in a Parr apparatus for 3 hours. The catalyst was removed by filtration and the solvent evaporated to a white solid, 4.6 g. This solid was recrystallised from isopropanol (50 ml) to give 2.6 g of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine, mp 114°-115° C. To a stirred solution of sodium nitrate (2.0 g, 0.03 mol) in sulphuric acid (15 ml) at 0° C. under nitrogen was added dropwise a solution of N-formyl-1-(3-aminophenyl)-2-phenyl-2-propylamine (7.0 g, 0.027 mol) in acetic acid (75 ml) and the solution was stirred 2.5 hours at a temperature less than 20° C. The above mixture was added to a solution of cuprous chloride (5.3 g, 0.054 mol) in concentrated HCl (50 ml) at 15° C., and the resulting solution was stirred at that temperature for 1 hour. The reaction mixture was poured into water (500 ml), basified with concentrated ammonium hydroxide, and extracted with chloroform (3×200 ml). The combined chloroform extracts were dried over magnesium sulphate and the solvent evaporated to a solid, 7.5 g. This solid was recrystallised from isopropanol (20 ml) to provide 3.2 g of N-formyl-1-(3-chlorophenyl)-2-phenyl-2-propylamine, mp 108°-109° C.