Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:37]1([CH2:1][C:3]2[S:7][C:6]([C:8]3[CH:9]=[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=3)[NH:13][CH:12]=[C:11]4[CH:20]3[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:28])=[O:27])[CH2:22][CH2:21]3)=[CH:5][CH:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(CN3CCCC3)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (8.3 mg, 0.016 mmol) in methylene chloride (5 mL) was added pyrrolidine (0.001 mL, 0.016 mmol). The reaction mixture was stirred at room temperature for 1 hour before NaBH(OAc)3 (10.2 mg, 0.048 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (7 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([NH:16][C:17]1[S:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1)=[O:8]
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxybenzoic acid (3.69 g), ethyl 2-aminothiazole-4-carboxylate (3.0 g) and 4-(dimethylamino)-pyridine (702 mg) were dissolved in dichloromethane (80 mL), and to the solution was added 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride) (3.34 g). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was successively washed with 2 M hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[Cl:29][C:30]1[CH:38]=[C:37]([CH3:39])[C:33]([C:34](O)=[O:35])=[C:32]([CH3:40])[N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:29][C:30]1[CH:38]=[C:37]([CH3:39])[C:33]([C:34]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:10][CH2:11]2)[CH3:5])=[O:35])=[C:32]([CH3:40])[N:31]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Yield: 77 %

Procedure:
To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (63 mg, 0.17 mmol) in DMF (1.5 mL) was added 6-chloro-2,4-dimethyl-nicotinic acid (40 mg, 0.22 mmol), HOBT (31 mg, 0.23 mmol), EDCI (44 mg, 0.23 mmol) and DIPEA (85 μL, 0.50 mmol). After the mixture was stirred at room temperature overnight brine (5 mL) was added, and the mixture was extracted with CH2Cl2 (2×5 mL). The organic extracts were combined and dried (Na2SO4). After filtration the solvent was removed under vacuum, and the residue was purified by flash chromatography on a silica gel column (20:1:0.1, CH2Cl2/MeOH/NH4OH) to afford the title compound as a white solid (72 mg, 80%). 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.6 Hz), 1.00 (m, 1H), 1.19 (m, 1H), 1.54 (m, 1H), 1.71 (m, 1H), 1.80 (br d, 2H, J=12.6 Hz), 2.11 (t, 1H, J=11.2 Hz), 2.29 (s, 3H), 2.35 (s, 3H), 2.48 (t, 1H, J=11.2 Hz), 2.51 (s, 3H), 2.65-2.85 (m, 3H), 3.15-3.45 (m, 2H), 3.72 (s, 3H), 3.78 (m, 1H), 3.97 (s, 2H), 6.62-6.78 (m, 4H), 6.98 (s, 1H), 7.02 (d, 1H, J=4.8 Hz), 8.05 (br. S, 1H), 8.25 (s, 1H), 8.28 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.74, 19.16, 19.22, 22.51, 30.07, 31.01, 31.72, 40.04, 44.27, 47.85, 52.20, 55.93, 59.41, 60.20, 114.75 (2C), 120.74 (2C), 122.85, 125.47, 132.90, 133.43, 142.69, 145.73, 147.66, 148.42, 149.78, 150.59, 154.22, 155.58, 167.68. ES-MS m/z 550 (M+H). Anal. Calcd. For C31H40N5ClO2.0.7CH2Cl2: C, 62.46; H, 6.85; N, 11.49. Found: C, 62.68; H, 6.89; N, 11.73.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][CH2:16][CH3:17])[C:3](=[O:13])[CH2:4][C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].CC(C)=O.[CH2:22](I)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C(O)C>O1CCCC1.C(Cl)Cl>[CH2:35]([CH:4]([C:3]([N:2]([CH3:1])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])[C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCN(C)C(=O)CC(=O)N(C)CCCC
Reactant: CCCCCCCCCCCCCCI
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(C(=O)N(C)CCCC)C(=O)N(C)CCCC

Procedure:
Into a 1 liter reactor, scavenged by an argon stream, is introduced 0.1 mole of N,N'-dimethyl-N,N'-dibutyl-propane diamide dissolved in 400 ml of tetrahydrofuran. Cooling takes place to -50° C. with the aid of an acetone and solid carbon dioxide bath and a N-butyl lithium solution prepared from 0.1 mole of N-butyl lithium is poured into 100 ml of anhydrous tetrahydrofuran. Under the same conditions, pouring takes place of a solution of tetradecyl iodide prepared from 0.1 mole of tetradecyl iodide and 100 ml of anhydrous tetrahydrofuran. When pouring is ended, the temperature is allowed to rise to ambient temperature, followed by refluxing the tetrahydrofuran for 3 hours. It is left to cool and then hydrolyzed with a water-ethanol mixture. The tetrahydrofuran is expelled and in this way a precipitate is formed. It is taken up with methylene chloride, washed with water, the organic layer is dried and then the solvent is expelled prior to distillation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:15])[C:12]#[C:13][CH3:14].[CH3:16]C(C)([O-])C.[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:15][CH3:16])[C:12]#[C:13][CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CC#CC1(O)C(=O)Nc2ccc(Br)cc21
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CC1(OC)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 58.9 %

Procedure:
To a solution of 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (1.0 g, 3.75 mmol) in dry DMF (15 cm3) at 0° C., was added potassium tert-butoxide (1M in THF, 4.1 cm3, 4.1 mmol). After 15 min. methyl p-toluenesulfonate (0.85 g, 4.6 mmol) was added and the mixture was allowed to warm up to room temperature. After 16 h the mixture was poured into saturated ammonium chloride, extracted with EtOAc (×3), washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:3) to afford 5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.62 g, 2.21 mmol, 59%): (CDCl3) δ inter alia 1.87 (s, 3H), 3.19 (s, 3H), 3.35 (s, 1H), 6.72 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=8.3, 2 Hz), 7.63 (d, 1H, J=2 Hz): MS (EI) m/z 279 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:12][CH2:11]2)[N:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH:10]1([NH:9][C:4]2[N:3]=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[N:7]=[C:6]([NH2:8])[N:5]=2)[CH2:12][CH2:11]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(N)nc(NC2CC2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(N)nc(NC2CC2)n1

Procedure:
To a suspension of 49.8 g of 2,4-diamino-6-cyclopropylamino-1,3,5-triazine and 45.5 g of triethylamine in 1200 ml of tetrahydrofuran are slowly added dropwise, at about 60° C. (in about 6 hours), 31.7 g of acetic acid anhydride dissolved in 100 ml of tetrahydrofuran. The reaction mixture is subsequently refluxed for 18 hours, filtered hot and then concentrated by evaporation until crystallisation commences. After the addition of about 300 ml of diethyl ether, the product if filtered off as white crystalline powder. It has a melting point of 190°-195° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]([C:50]1[CH:65]=[C:64]([C:66](=[NH:69])[NH:67]O)[CH:63]=[C:62]([CH3:70])[C:51]=1[O:52][CH2:53][C@@H:54]([OH:61])[CH2:55][NH:56][C:57](=[O:60])[CH2:58][OH:59])[CH3:49]>CN(C=O)C.C1COCC1.CC(=O)OCC>[CH2:48]([C:50]1[CH:65]=[C:64]([C:66]2[N:69]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=3)[O:11][N:67]=2)[CH:63]=[C:62]([CH3:70])[C:51]=1[O:52][CH2:53][C@@H:54]([OH:61])[CH2:55][NH:56][C:57](=[O:60])[CH2:58][OH:59])[CH3:49]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (200 mg, 770 μmol) in DMF (3 mL) and THF (10 mL), DIPEA (200 mg, 1.54 mmol) and TBTU (272 mg, 847 μmol) are added. The mixture is stirred at rt for 10 min before N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (251 mg, 770 μmol) is added. The mixture is stirred at rt for 30 min, diluted with EA (100 mL) and washed with brine. The org. extract is concentrated and the residue is dissolved in dioxane (50 mL). The mixture is stirred at 100° C. for 2 h before it is concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (180 mg) as a resin; LC-MS: tR=1.08 min, [M+H]+=513.13; 1H NMR (CDCl3): δ0.84 (t, J=7.3 Hz, 6H), 1.31 (t, J=7.5 Hz, 3H), 1.68-1.88 (m, 4H), 2.38 (s, 3H), 2.55-2.64 (m, 1H), 2.74 (q, J=7.5 Hz, 2H), 3.50-3.58 (m, 1H), 3.74-3.94 (m, 4H), 4.01 (s, 3H), 4.17-4.25 (m, 3H), 7.09 (t br, J=5.5 Hz, 1H), 7.31 (d, J=1.3 Hz, 1H), 7.43 (d, J=1.3 Hz, 1H), 7.86 (d, J=1.8 Hz), 7.88 (d, J=2.0 Hz).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].C(N(CC)CC)C>C(#N)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:20]([C:11]2[N:10]([CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)=[O:21])[CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[C:25]=1[O:26][CH3:27]
Reactant: c1ccc(COCn2ccnc2)cc1
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(C(=O)c2nccn2COCc2ccccc2)cc([N+](=O)[O-])c1OC
Reaction time: 3 h

Procedure:
A solution of 10.0 g of 1-[(benzyloxy)- methyl]imidazole in 50 ml of acetonitrile is added dropwise within 10 minutes while cooling with ice to a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g of triethylamine in 80 ml of acetonitrile so that the temperature does not exceed 25° . The mixture is subsequently stirred for an additional 3 hours, whereupon the solvent is distilled. After treatment with water, the mixture is extracted with ethyl acetate. After two-fold washing with water, the organic phase is dried over sodium sulfate and evaporated. The resulting oil is chromatographed on 600 g of silica gel with toluene/ethyl acetate (95:5). There is obtained 1-[(benzyloxy)methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl) ketone as a yellowish oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11]O)[N:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:32][C:33]1[N:37]([CH3:38])[N:36]=[N:35][N:34]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][S:32][C:33]2[N:37]([CH3:38])[N:36]=[N:35][N:34]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)n(CCO)n1
Reactant: Cn1nnnc1S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)n(CCSc2nnnn2C)n1
Temperature: 5 °C
Reaction time: 4 h
Yield: 45.4 %

Procedure:
3-Acetyl-5-methyl-1-(2-hydroxyethyl)pyrazole (1.74 g), triphenyl-phosphine (4.071 g) and 5-mercapto-1-methyltetrazole (3.605 g) were dissolved in dry THF (125 ml) and cooled to 5° C. under an atmosphere of argon. A solution of diethylazodicarboxylate (2.70 g) in THF (25 ml) was added dropwise to the stirred, cooled solution. Stirring was continued at 5° C. for 4 h. The reaction mixture was then partitioned between ethyl acetate and water. The organic solution was washed with NaHCO3 solution, brine, dried (MgSO4) and evaporated. Silica gel column chromatography provided the title compound (1.25 g), umax (CH2Cl2) 1683 cm−1; dH (CDCl3) 2.30 (3H, s), 2.55 (3H, s), 3.80 (2H, t), 3.92 (3H, s), 4.59 (2H, t), 6.51 (1H, s); m/z 266.0953 (M+), calculated for C10H14N6OS 266.0950.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)[C:25]([CH:32]=O)=[CH:24]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:23]1[C:31]2=[N:30][CH:29]=[CH:28][CH:27]=[C:26]2[C:25]([CH:32]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=3)=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]2=[O:1])=[CH:24]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCCOc1ccc(NC2=C(C(=O)OCC)C(=O)CO2)cc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCCOc1ccc(NC2=C(C(=O)OCC)C(=O)C(=Cc3c[nH]c4ncccc34)O2)cc1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
To a solution of ethyl 4-oxo-2-{[4-(1-propoxy)phenyl]amino}-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.072 g, 0.50 mmol) in ethanol (6.0 mL), L-proline (0.0060 g, 0.05 mmol) was added at ambient temperature. The mixture was refluxed for 16 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol then dried to afford the titled compound as solid (0.060 g, y. 28%).
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[CH3:23])[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Solvent: ClCCl
Product: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 52 %

Procedure:
0.5 gm (1.7 millimols) of 3-benzyl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were reacted in 5 ml of methylene chloride with a stoichiometric quantity (0.15 ml) of ethyl chloroformate for four hours at room temperature. After distilling off the methylene chloride and recrystallizing the residue from ether, the product was obtained with a yield of 52% of theory; m.p. 125° C.
Reaction SMILES: Cl[C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3]1=[O:18]>C(O)(=O)C.[Zn]>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:3](=[O:18])[CH2:2]2
Reactant: COC(=O)CN1C(=O)C(Cl)(Cl)c2cc(OC)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CN1C(=O)Cc2cc(OC)ccc21
Yield: 76 %

Procedure:
To a solution of methyl 2-(3,3-dichloro-5-methoxy-2-oxoindolin-1-yl)acetate (1.3 g, 4.27 mmol) in acetic acid (30 ml), zinc powder (1.118 g, 17.10 mmol) was added, and the mixture was reacted at room temperature for 15 minutes; then the insoluble inorganics were filtered off and washed with MeOH. The crude title compound was obtained after evaporation under reduced pressure and used in the next step without further purification (760 mg, 3.23 mmol, 76% yield). MS/ESI+ 236.0 [MH]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[C:14]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
tert-Butyl (3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with isobutyryl chloride (0.067 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give tert-butyl (3S)-3-(isobutyrylamino)pyrrolidine-1-carboxylate, LCMS [M+Na] 279.2. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the crude product (35 mg, 30%), which was used directly in the next step. LCMS calculated for C8H17N2O (M+H)+: m/z=157.1; Found: 157.2.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:10])[CH3:9].[CH3:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[OH:10][CH:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13](=[O:30])[N:12]([CH3:11])[C:16]=2[CH:17]=1)[CH3:9]
Reactant: CC(O)c1ccncc1Br
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
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: C1COCCO1
Product: CC(O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Temperature: 100 °C

Procedure:
A mixture of 1-(3-Bromo-pyridin-4-yl)-ethanol (240 mg, 1.188 mmol), 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (327 mg, 1.188 mmol), PalladiumTetrakis (270 mg, 0.030 mmol), sodium carbonate (2 M in water, 0.594 ml, 1.188 mmol) in 1,4-Dioxane (2 ml) was heated by microwave at 100° C. for 1 hr. After filtration, drying over Na2SO4, filtration again and concentration, the residue was purified by flash column (CH2Cl2-MeOH, v/v, 1%-4.5%) yielded an oil which was subsequently purified by chiral HPLC (Ethanol-Heptane, v/v, 20%, ChiralPak OD-H column) to peak 1 (enantiomer 1 retention time 9.21 min) and second peak (enantiomer 2, retention time 11.31 min). ESI-MS m/z: 271.2 [M+1]+, Retention time 0.93 min; 1H NMR (400.3 MHz, MeOD): δ 1.32 (d, J=6.4 Hz, 3H), 3.47 (s, 3H), 497 (q, J=6.4 Hz, 1H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.75 (d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.59 (d, J=5.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:35]1([C@H:41]2[CH2:45][NH:44][CH2:43][C@@H:42]2[OH:46])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]4[CH2:45][C@H:41]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[C@@H:42]([OH:46])[CH2:43]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O[C@H]1CNC[C@@H]1N1CCOCC1
Product: O=C1N=C(N2C[C@H](O)[C@@H](N3CCOCC3)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(3S,4S)-3-hydroxy-4-morpholin-4-ylpyrrolidin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-(3S,4S)-Morpholin-4-yl-pyrrolidin-3-ol following General Procedure C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCCC1
Temperature: 0 °C

Procedure:
20.1 Grams 2-chloro-5-nitrobenzoic acid was added in portions to 100 ml pyrrolidine. A cooling bath was applied as necessary during the addition. After the addition was complete, the reaction was heated on a steam bath for three hours, cooled, poured into ice water and made acidic with concentrated HCl until precipitation of product was complete. Recrystallization from ethanol gave 19.4 grams 5-nitro-2-(1-pyrrolidinyl)benzoic acid. m.p. = 224°-266° C dec. The nitro compound was reduced catalytically in ethanol with 5% palladium on carbon catalyst to give 5-amino-2-(1-pyrrolidinyl)benzoic acid. m.p. = 205°-208° C dec.