Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH:16]3[CH:13]([CH2:14][C:15]3=[O:18])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:17][C@H:16]3[C@H:13]([CH2:14][C@H:15]3[OH:18])[CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC(=O)C3C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H](O)[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of 3-[(4-methylphenyl)sulfonyl]-3-azabicyclo[3.2.0]heptan-6-one (120 mg, 0.45 mmol) in EtOH:DCM (6 mL, 5:1) at 0° C. was added NaBH4 (21 mg, 0.54 mmol) portion-wise. After stirring at 25° C. for 0.5 hr, the solution was concentrated and then partitioned between DCM and water. The aqueous layer was extracted several times with DCM. The organic fractions were combined, concentrated and purified by column chromatography (silica, 0-0.5% MeOH in DCM (0.5% NH4OH)) affording the title compound as a white solid (109 mg, 90%): LC/MS (ES) m/e 268 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:41])[O:36][C:34](=[O:35])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:41])[C:32]3[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=3[C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3C(=O)O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
In dichloromethane (25 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (3.60 g), followed by addition of phthalic anhydride (1.80 g.). The mixture was stirred at room temperature for 2 hours, after which time it was treated in a manner similar to that described in Example 8. The procedure provided 7β-(2-thienylacetamido)-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid (3.44 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([N:30]2[CH2:35][CH2:34][C@@:33]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)([CH2:36][CH2:37][OH:38])[O:32][C:31]2=[O:46])[CH3:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:38][CH2:37][CH2:36][C@@:33]1([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)[O:32][C:31](=[O:46])[N:30]([C@H:28]([C:25]2[CH:26]=[CH:27][C:22]([C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[F:14])=[CH:23][CH:24]=2)[CH3:29])[CH2:35][CH2:34]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A solution of 4-nitrophenyl chloroformate (133 mg, 0.66 mmol) in dichloromethane (1 mL) was added to a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol) and pyridine (608 mg, 7.7 mmol) in dichloromethane (2.8 mL). The mixture was stirred at it overnight. The reaction was quenched with 1 N HCl (7 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with brine, dried and concentrated to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude), which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[F:15]>[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[F:15]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(F)c(C(=O)OC)cc1N
Yield: 88.3 %

Procedure:
5-Amino-2-fluoro-4-methylamino-benzoic acid methyl ester (115 mg) was prepared by following General Procedure B starting from 2-fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (150 mg) and Pd/C (10% by weight, 15 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O:13][C:14]([NH:16][CH:17]([NH2:19])[CH3:18])=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:1][CH:2]=[C:3]([CH2:7][NH:19][CH:17]([NH:16][C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[CH3:18])[CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: CC(N)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(NCc1cccnc1)NC(=O)OC(C)(C)C

Procedure:
2.92 g of 3-pyridyl carboxaldehyde are added to a solution of 4.82 g of N-(tert.butoxycarbonyl)ethanediamine in 50 ml of toluene in the presence of a dehydrating agent (4 Å molecular sieves) at about 5° C.
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[F:1][CH2:2][O:3][C:4]1[CH:13]=[CH:12][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)c1ccc(OCF)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: OCc1ccc(OCF)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a cooled (−78° C.) solution of methyl 4-(fluoromethoxy)-3-(trifluoromethyl)benzoate (2.44 g, 9.68 mmol) in DCM under nitrogen was added 2.0 M LAH (4.84 mL, 9.68 mmol) by syringed. The reaction was stirred for 15 min. The reaction was quenched with water (0.484 mL) and 10% NaOH (0.968 mL). The mixture was filtered and concentrated to give the title compound as an oil (1.84 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.52 (d, J=5.68 Hz, 2H), 5.32 (t, J=5.75 Hz, 1H), 5.85-6.08 (d, J=53.44 Hz, 2H), 7.39 (d, J=8.46 Hz, 1H), 7.56-7.69 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ ppm −151.41 (s, 1F), −60.26 (s, 3F).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (6.0 g) in DMF (45 ml), sodium hydride (60% in oil, 0.85 g) was added, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C., and then benzyl bromide (2.64 ml) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and then sequentially washed with an aqueous 10% citric acid solution, water and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain 3-benzyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester as colorless crystals (7.19 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.[N+]([O-])(O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccn(-c2cccnc2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, round bottom flask was charged 3-(3-chloro-1H-pyrazol-1-yl)pyridine (2.00 g, 11.1 mmol) and concentrated sulfuric acid (4 mL). This suspension was cooled to 5° C. and 2:1 concentrated nitric acid/sulfuric acid (3 mL, prepared by adding the concentrated sulfuric acid to a stirring and cooling solution of the nitric acid) was added dropwise at a rate such that the internal temperature was maintained <15° C. The reaction was allowed to warm to 20° C. and stirred for 18 hours. A sample of the reaction mixture was carefully diluted into water, basified with sodium hydroxide (50 wt % in water) and extracted with ethyl acetate. Analysis of the organic layer indicated that the reaction was essentially complete. The reaction mixture was carefully added to ice cold water (100 mL) at <20° C. It was basified with sodium hydroxide (50 wt % in water) at <20° C. The resulting light yellow suspension was stirred for 2 hours and filtered. The filter cake was rinsed with water (3×20 mL) and dried to afford an off-white solid (2.5 g, quantitative): mp 141-143° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.23-9.06 (m, 1H), 8.75-8.60 (m, 1H), 8.33 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.64 (ddd, J=8.5, 4.7, 0.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) δ 149.49, 140.75, 136.02, 134.43, 132.14, 131.76, 127.22, 124.31; EIMS m/z 224 ([M]+).
Reaction SMILES: [OH:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]([CH3:31])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[CH:7]=[N:6]1)[CH3:4])(=[O:35])=[O:34]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)O)c4=O)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C(C)OS(C)(=O)=O)c4=O)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
N,N-dimethyl-4-pyridinamine (0.01062 mol) and intermediate 5a (0.00708 mol) were suspended in CH2Cl2 (50 ml). A solution of methanesulfonylchloride (0.01062 mol) in CH2Cl2 (30 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for the weekend. N,N-dimethyl-4-pyridinamine (0.00352 mol) and methanesulfonylchloride (0.00358 mol) were added again. The mixture was stirred overnight, washed with water (2×100 ml), dried, filtered over decalite and the solvent was evaporated. The residue was dissolved in MIK (150 ml). Activated charcoal (0.5 g) was added. The mixture was boiled, filtered warm and stirred for 2 hours. The precipitate was filtered off and dried, yielding 1.7 g (50%) of [S-(R*,S*)]-2,4-dihydro-2-(2-methanesulfonyloxy-1-methylpropyl)-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (interm. 5d).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH2:35])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)C.[S:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)([OH:39])(=[O:38])=[O:37].CN(C)CCCN=C=NCC>CN(C)C=O.O>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH:35][C:44]([C:43]1[CH:42]=[CH:41][C:40]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:48][CH:47]=1)=[O:45])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(CN)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccc(S(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-(aminomethyl)-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (55 mg, 0.15 mmol) in a mixture of N,N-dimethylformamide (5 ml) and water (10 ml) was added 4-sulfobenzoic acid (37 mg, 0.153 mmol) and 1(3-dimethylaminopropyl)-3-ethylcarbodiimide (28 mg, 0.147 mmol), and the mixture was stirred for 4 hours. Solvent was removed under reduced pressure, and the residue was purified by HPLC, to provide 4-[N-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}methyl)carbamoyl]benzenesulfonic acid (39 mg). MS MH+548.57.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][Cl:32]>O>[Cl:32][CH2:31][CH2:30][O:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCl)ccc21
Temperature: 70 °C

Procedure:
1-Ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(1.2 g) and potassium carbonate(0.95 g) were added to 50% hydrous acetonitrile(24 ml). The mixture was heated to 70° C. to be dissolved. 1-Bromo-2-chloroethane(1.9 ml) was added, and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried by sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1→1:1). The purified product was condensed to dryness under reduced pressure to give the title compound(1.4 g) as a colorless oily matter.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(c2cccc(OC)c2)CCCCNC1

Procedure:
3-Ethyl-3-(3-methoxy-phenyl)-azepan-2-one (as described in Example 8, Step A) (1.05 g, 4.24 mmol) in anhydrous THF (4.2 mL) was added to a solution of LiAlH4 (0.193 g, 5.09 mmol) in anhydrous THF (4.2 mL) and refluxed for 24 h. The solution was cooled, quenched with H2O (0.18 mL), 15% NaOH (0.18 mL), H2O (0.54 mL), filtered and concentrated. The residue was purified using reverse phase chromatography (95/5-5/95 H2O/CH3CN with 0.1% TFA, flow=65 mL/min) and converted to its free base using saturated NaHCO3 solution, extracted with CH2Cl2 (3×) and dried (MgSO4) to give the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH2:19][CH3:20])[C:12](=O)[C:13]([O:15]CC)=[O:14]>C1(C)C=CC=CC=1>[CH2:19]([C:11]1[O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: NC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)C(Br)CC
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccccc2)nc1C(=O)O
Yield: 8.4 %

Procedure:
Intermediate 1E was prepared (as described below for the preparation of intermediate 2B) from 4.08 g of benzamide, 5.0 g of ethyl 3-bromo-2-oxo-pentanoate, and 10 mL of toluene. Solids were collected and washed with cold water after cooling of the NaOH solution. Heating these solids with citric acid as described followed by cooling and isolation of the resulting solids gave 410 mg (9% yield) of the title compound; 1H NMR (CDCl3, 300 MHz) δ8.06-8.03 (m, 2H), 7.49-7.43 (m, 3H), 3.14 (q, 2H, J=8.0), 1.34 (t, 3H, J=8.0); low resolution MS (ES+)m/e 217.8 (MH+).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C@@H:35]([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 34 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (1.0 g, 3.3 mmol) was reacted with (R)-tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (1.1 g, 3.0 mmol) to afford the desired product (510 mg, 34%) as a yellow solid: ESI MS m/z 497 [C27H19FN2O4S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3S)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3S)3-dimethylamino-pyrrolidine-1-carbonyl)5-methyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (94 mg, 80%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1>O>[CH3:7][C:6]1[N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:33]1[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-iodo-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (700.0 mg, 1.789 mmol) in THF (20 mL, 300 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (5.5 mL, 7.2 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 8.9 mmol), and allowed to stir at rt for 2 h. Water was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.30 (s, 12H), 1.48 (s, 9H), 1.84 (d, J=10.4 Hz, 2H), 1.99 (dtd, J=12.6, 12.3, 12.3, 4.5 Hz, 2H), 2.47 (s, 3H), 2.94 (br. s., 2H), 4.21 (d, J=13.6 Hz, 2H), 4.30-4.42 (m, 1H), 7.57 (s, 1H). MS (ES+): m/z=391.26/392.26/393.27 (50/100/50) [MH+]. HPLC: tR=1.70 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][C:3](=[O:23])[C:2]=1[S:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1ccccc1S
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 91°-92° C.). 1H NMR (DMSO-d6) δ 2.25 (m, 2 H), 2.38 (m, 1 H), 2.62 (m, 1 H), 3.44 (q, 2 H), 3.82 (s, 3 H), 6.06 (bd, 1 H), 6.90 (t, 1 H), 7.05-7.52 (m, 11 H), 7.81 (dd, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](O)=[O:27])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:26](=[O:27])[NH:34][CH:31]([CH3:33])[CH3:32])([CH3:25])[CH3:24])[CH:17]=1)[C:10]([CH3:29])([CH3:30])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)O)c1)N2
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)NC(C)C)c1)N2
Yield: 94.1 %

Procedure:
2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (820 mg, 2 mmol), isopropylamine (0.5 mL, 6 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1140 mg, 3 mmol) in dichloromethane (10 mL) and triethyl-amine (0.84 mL, 6 mmol) was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-isopropylcarbamoyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.85 g, 94%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H37N3O3 (M+H)+: 452.61, observed: 452.2.