Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:9]=2[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:4].[OH-].[Na+].Cl>CO.O>[CH3:16][O:15][C:10]1[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]2[C:13]([CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6](=[O:23])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCCCCOc1c(OC)ccc2cc(C(=O)OC)c(=O)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCOc1c(OC)ccc2cc(C(=O)O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (240 mg) obtained in Example 1-1 was dissolved in methanol (7 ml) and water (3 ml), to which sodium hydroxide (120 ml) was added, and the solution was stirred at room temperature for 1.5 hours. While the reaction vessel was cooled with ice, the solution was acidified with the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give the title compound (228 ml) (Table 6).
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:2][CH:3]4[O:7][CH2:6][CH2:5][O:4]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1OCCO1
Temperature: 100 °C
Yield: 39.5 %

Procedure:
A solution of 2-(bromomethyl)-1,3-dioxolane (190 mg, 1.1 mmol) in DMF (1 ml) was added to 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (258 mg, 0.81 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (200 mg, 1.5 mmol) in DMF (2 ml). The mixture was heated at 100° C. for 4 hours and then allowed to cool. The volatiles were removed by evaporation and the residue partitioned between water and methylene chloride. The organic phase was separated, passed through phase separating paper and purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazoline (130 mg, 38%).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=1>C1COCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][C:2]([NH:1][C:4]2[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)=[O:3])[CH:16]=1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: OCc1cccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1cccnc1
Temperature: -78 °C
Yield: 96 %

Procedure:
A solution of ethyl 4-isocyanatobenzoate 280 (2.0 g, 10.46 mmol) and pyridin-3-ylmethanol in THF was stirred at room temperature for 18 h then concentrated. The crude material was taken up in 2N HCl, heated to reflux for 16 h then cooled to −78° C. and lyophilized to give a solid material which was triturated with acetone to give title compound 281 (3.098 g, 96% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][CH2:3]1.C(OC)(OC)OC.CC(O)=O.[O:43]1[CH2:46][C:45](=O)[CH2:44]1.C([BH3-])#N.[Na+]>C1COCC1.CO>[Cl:31][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH:45]3[CH2:46][O:43][CH2:44]3)[CH2:3][CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]2=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]2[N:18]=1
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CCC(N)CC3)c2Cl)nn2c(C#N)cnc12
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CCNc1nc(Nc2cc(C#N)cc(N3CCC(NC4COC4)CC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-((3-(4-aminopiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 329) (48 mg, 0.110 mmol) was taken up in THF (2 mL) and Methanol (2 mL) and trimethyl orthoformate (0.5 mL, 4.52 mmol), AcOH (0.05 mL, 0.873 mmol) in a round bottom flask. Oxetan-3-one (0.1 mL, 1.560 mmol) was added. The reaction mixture was stirred at room temperature for 15 mins. Sodium cyanoborohydride (50 mg, 0.796 mmol) was added and the reaction was stirred at room temperature for 2 hrs. LC/MS showed about 40% conversion to the desired product. Another batch of oxetan-3-one (0.1 mL, 1.560 mmol), trimethyl orthoformate (0.5 mL, 4.52 mmol), AcOH (0.05 mL, 0.873 mmol) and sodium cyanoborohydride (50 mg, 0.796 mmol) were added to the reaction mixture and let stirred for another 30 mins. LC/MS showed completed conversion to the product. The mixture was concentrated to almost dryness, diluted with EtOAc and washed with NaHCO3, then brine, dried over MgSO4 and concentrated. The crude was then purified by PREP-HPLC to give 21.3 mg of desired product
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O.[CH:20]1([C:23](=O)[CH2:24][C:25](=[O:27])C)CC1>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[C:24]([CH:25]=[O:27])=[C:23]([CH3:20])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C=O)CCC3
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 60 mg (0.19 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone (the preparation of which is described in example 1) in 2 ml acetic acid was added 32 mg (0.25 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 24 mg (31%) cyclopropyl-[(4-(3,4-dichloro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-methanone as a light brown solid. ES-MS m/e (%): 402 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:3]1=2.C(OOC(=O)C1C=CC=CC=1)(=[O:21])C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)(Cl)Cl>[OH:7][B:5]1[C:4]2[CH:8]=[C:9]([CH:12]=[O:21])[CH:10]=[CH:11][C:3]=2[C:2]([CH3:13])([CH3:1])[O:6]1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: Cc1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(O)c2cc(C=O)ccc21
Temperature: 25 °C
Yield: 654.5 %

Procedure:
To a solution of 3,3,6-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (6.87 g, 39 mmol) in CCl4 (100 mL) at rt was added benzoyl peroxide (0.944 g, 3.9 mmol) followed by NBS (13.9 g, 78 mmol). The reaction mixture was refluxed for 16 h, cooled to rt and treated with Na2CO3. The aqueous layer was acidified with 3 N HCl to pH of 3 and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with DCM-MeOH (20:1) to give 1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde (4.85 g; yield 65.4%) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 10.06 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.0 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 1.58 (s, 6H) ppm. MS: m/z=191.1 (M+1, ESI+).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=CC=1.C1(C(=O)CC#[N:33])CCC1>>[CH:20]1([C:7]2[CH:1]=[C:6]([NH2:33])[N:9]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:8]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: N#CCC(=O)C1CCC1
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Product: Nc1cc(C2CCC2)nn1-c1ccc2ncccc2c1
Yield: 40 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 3-cyclobutyl-3-oxo-propionitrile (1.7 g, 1.1 eq) were combined to provide 5-cyclobutyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (1.3 g, 40% yield). 1H NMR (300 MHz, CDCl3) δ 8.92 (dd, J=4.5, 1.2 Hz, 1H), 8.16-8.20 (m, 2H), 8.00-8.04 (m, 2H), 7.43 (dd, J=8.4, 1.2 Hz, 1H), 5.64 (s, 1H), 3.83 (br s, 2H), 3.53 (m, 1H), 2.40-2.20 (m, 4H), 2.08-1.92 (m, 2H); MS (ESI) m/z: 265.1 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:12]([C@H:27]([NH2:31])[C:28]([OH:30])=[O:29])[CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][SH:19])=[O:15]>CC(C)=O.O.CC(C)=O>[NH2:31][C@H:27]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][C:14]([NH:16][C@H:17]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[CH2:18][S:19][C:1](=[O:3])[CH3:2])=[O:15]
Reactant: CC(=O)Cl
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O
Yield: 85 %

Procedure:
Using in the procedure of Example 1 acetyl chloride, in place of pivaloyl chloride, L-glutathione reduced (15.4 g) provides, after usual work-up, a crude white solid which is dissolved in warm acetone/water (2/1; 40° C.; 300 ml). The obtained solution is further diluted with more acetone (100 ml) and cooled on ice-water bath. After about two hours the white crystalline precipitate is collected, washed with the solvent (40 ml) and dried under vacuum affording γ-L-glutamyl-S-acetyl-L-cysteinyl-glycine (14.8 g yield=85%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Cl[CH:21]([CH3:25])[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][CH:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)C(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Reaction time: 3 h

Procedure:
A mixture of 4.0 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 2.0 g. of 3-chloro-2-butanone, 2.1 g. of potassium carbonate, 1.0 g. of potassium iodide and 30 ml. of acetone was refluxed with stirring for 3 hours. The precipitate was separated by a filtration and the filtrate was concentrated under a reduced pressure and the residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate:n-hexane of 2:3) to obtain 4.2 g. of Compound No. 24 shown in Table 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[NH:20][S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28]C)=[O:27])(=[O:23])=[O:22])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[NH:20][S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(Nc2ccc(C(F)(F)F)cc2NS(=O)(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a vial are placed methyl 2-({[2-[(4-cyanophenyl)amino]-5-(trifluoromethyl)phenyl]amino}sulfonyl)benzoate (289 mg, 0.608 mmol), 1M NaOH (10 mL), and MeOH (10 mL). The mixture is efficiently shaken at rt for 16 h. 1M HCl is added to adjust the pH to 1. The precipitated was filtered and purified by preparative thin layer chromatography. The yield is 65 mg of 2-({[2-[(4-cyanophenyl)amino]-5-(trifluoromethyl)phenyl]amino}sulfonyl)benzoic acid, 23%. 1H NMR (400 MHz, DMSO-d6): □ 10.92 (s, 1 H), 9.98 (s, 1 H), 7.58-7.56 (m, 3 H), 7.44-7.43 (m, 2 H), 7.38-7.30 (m, 3 H), 7.21-7.17 (m, 1 H), 7.02-7.00 (m, 2 H). HRMS for C21H14F3N3O4S 462.0754 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:21]4[CH:20]=[C:19]([CH3:28])[CH:24]=[CH:23][CH:22]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C)c2)c1
Yield: 17 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using m-tolylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (17 mg, 17%) which was obtained as an off-white solid. MS: m/e=334.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc(Cl)nc1

Procedure:
Using an analogous procedure to that described in Example 3, 6-chloropyrid-3-ylcarbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide (J. Med. Chem. 1996, 39, 3343-3356) to give the title compound; Mass Spectrum: M+H+ 400.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[CH2:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1)[CH3:40]
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: CCc1cccc(Br)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 40.1 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-bromo-3-ethylbenzene (596 mg) and DMSO (8 ml). The mixture was stirred at 130° C. under nitrogen for 4 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water and EtOAc were added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (312.5 mg) as a pale yellow crystalline solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C>ClC(Cl)C.[Br-].[Zn+2].[Br-]>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][N:43]1[C:44]2[C:39](=[CH:38][CH:37]=[C:36]([CH2:35][O:34][CH:10]3[CH:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])=[CH:18][CH:19]=4)[CH2:12][CH2:13][NH:8][CH2:9]3)[CH:45]=2)[CH2:40][CH2:41][CH2:42]1)[CH3:51]
Reactant: CCOC(=O)CN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: [Br-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Product: CCOC(=O)CN1CCCc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 1(e), the (3RS,4RS)-3-(1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with zinc bromide in dichloroethane to yield the (3RS,4RS)-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-acetic acid ethyl ester as a yellow oil; MS: 603 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[F:47][C:44]([F:45])([F:46])[C:39]([C:36]1[CH:35]=[CH:34][C:33]([CH2:32][N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:20]3[CH:19]=[C:18]([NH:17][C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:16])[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:31][CH2:30]2)=[CH:38][CH:37]=1)([OH:48])[C:40]([F:43])([F:42])[F:41]
Reactant: Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1cccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Temperature: 100 °C
Yield: 36.1 %

Procedure:
A mixture of phenyl pyridin-4-ylcarbamate (1.430 mmol, 306 mg) and (3-aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.954 mmol, 440 mg) in dioxane was heated in a Reactivial at 100° C. (heating block temperature) for 2 days. Chromatography on silica (eluting with a gradient of dichloromethane to dichloromethane/methanol) gave the title compound (200 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][S:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[N:10][C:5]([S:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(SCC(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(SCC(F)(F)F)nc1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (0.56 g, orange oil) from 1-(6-((2,2,2-trifluoroethyl)thio)pyridin-3-yl)ethanone (0.39 g, 1.64 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:45][CH2:46][CH3:47])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[N+:41]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:45][CH2:46][CH3:47])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:44])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:38]([O:39][CH3:40])=[CH:37][C:27]3[C:28](=[O:36])[N:29]4[CH2:35][CH2:34][CH2:33][C@H:30]4[CH2:31][NH:32][C:26]=3[CH:25]=2)=[CH:13][C:12]=1[NH2:41])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal III (688 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethyl acetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[3-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)propoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([O:20][C:8]3[C:9]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=4)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=3)=[CH:23][CH:24]=[N:25]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3cc(Cl)ccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4,7-dichloroquinoline (139 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (77 mg, yield 94%).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.Br[CH:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17](Br)Br.[I-].[Na+]>CN(C)C=O>[C:1]1(=[O:8])[C:6]2[C:5](=[CH:10][C:11]3[C:12]([CH:17]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:4](=[O:7])[CH:3]=[CH:2]1
Reactant: BrC(Br)c1ccccc1C(Br)Br
Reactant: O=C1C=CC(=O)C=C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C=CC(=O)c2cc3ccccc3cc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
In an atmosphere of argon, 60 g (550 mmole) of 1,4-benzoquinone, 100 g (240 mmole) of 1,2-bis(dibromomethyl)benzene and 235 g (1.6 mole) of sodium iodide were dissolved into 850 ml of dry dimethylformamide. After the exothermic reaction was completed, the reaction solution was heated to 70° C. and stirred for 8 hours. After the reaction was completed, the formed crystals were separated by filtration and washed with methanol and water and 23 g (the yield: 47%) of light yellow needle crystals of 1,4-anthraquinone were obtained.