Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[OH:8])[CH2:3][CH2:2]1.[O:29]=[C:30]1[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][N:31]1[CH2:47][C:48](O)=[O:49].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH:4]1[CH2:5][CH2:6][N:1]([C:48](=[O:49])[CH2:47][N:31]2[CH2:32][CH2:33][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:30]2=[O:29])[CH2:2][CH2:3]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(O)(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidin-4-ylbis(3-(trifluoromethyl)phenyl)methanol (0.40 mg, 1.00 mmol, Example 33A) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85-7.93 (m, 4H), 7.55-7.57 (m, 4H), 7.18-7.36 (m, 10H), 5.93 (s, 1H), 4.34-4.41 (m, 1H), 4.06-4.23 (m, 2H), 3.82 (d, J=13.5 Hz, 1H), 3.35 (t, J=6.9 Hz, 2H), 2.94-3.11 (m, 2H), 2.72 (t, J=6.4 Hz, 2H), 2.59-2.67 (m, 1H), 1.17-1.50 (m, 4H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[ClH:6].[CH3:7][N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][S:17][C:11]=2[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1>>[ClH:4].[Cl:6][C:16]1[S:17][C:11]2[CH:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9][N:8]([CH3:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CCc2ccsc2C(c2ccccc2)C1
Agent: Cl
Product: CN1CCc2cc(Cl)sc2C(c2ccccc2)C1

Procedure:
Sulphuryl chloride (0.16 ml) was added to a stirred solution of 6-methyl-8-phenyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrochloride (0.49 g free base converted to hydrochloride salt with ethanolic hydrogen chloride) at room temperature. After 2 hours the mixture was evaporated and the solid residue recrystallised twice from ethanol (5 ml) to give the title product as white crystals (m.p. 198°).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](O)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:11][CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of indole-2-carboxylic acid (485 mg, 3.01 mmol) in THF (20 mL), cooled to 0° C. under nitrogen, was added a suspension of LiAlH4 (248 mg, 6.2 mmol) in THF (6 mL). The resultant green suspension was stirred at room temperature for 4 hours. The reaction was quenched by slow addition of an 80% aqueous MeOH solution (1.0 mL) and the solvent was evaporated under reduced pressure. The residue was suspended in MeOH and filtered through Celite, rinsing with MeOH. Concentration of the filtrate under reduced pressure gave a yellow oil. Purification by flash column chromatography on silica (MeOH/CH2Cl2, 19:1 then 9:1) gave the alcohol as a beige solid (357 mg, 2.43 mmol, 81%). 1H NMR (CDCl3) δ 1.85 (t, 1H, J=6.0 Hz), 4.83 (d, 2H, J=6.0 Hz), 6.42 (d, 1H, J=1.5 Hz), 7.11 (td, 1H, J=6.9, 1.5 Hz), 7.20 (td, 1H, J=6.9, 1.5 Hz), 7.35 (dd, 1H, J=6.9, 1.5 Hz), 7.59 (d, 1H, J=6.9 Hz), 8.33 (br s., 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[NH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (470 mg, 1.50 mmol) was reacted with tert-butyl (trans-4-aminocyclohexyl)carbamate (643 mg, 3 mmol) to afford the desired product (498 mg, 68%) as a light orange solid. ESI MS m/z 490 [C24H32BrN3O3+H]+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1>C(#N)C>[OH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[N:5]([CH2:7][C:2]#[C:3][CH2:4][N:5]2[C:6]([CH3:9])([CH3:8])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]2([CH3:11])[CH3:10])[C:6]([CH3:9])([CH3:8])[CH2:7]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1CC#CCN1C(C)(C)CC(O)CC1(C)C
Yield: 45.8 %

Procedure:
A round-bottomed flask, equipped with magnetic stirrer and condenser, is charged with 833 g (5.30 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 418 g (1.05 mol) of 2-butyne-1,4-diol-ditosylate [C.A. Registry No. 6337-59-3] in 3.6 1 of acetonitrile under argon. The reaction mixture is refluxed overnight, then cooled, poured on ice and extracted repeatedly with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol gives 295 g (76%) of 1,4-bis(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)but-2-yne (209), m.p. 203.4° C., in the form of white crystals.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 136-139° C., 1H-NMR (CDCl3) δ: 2.43 (s, 3H); 4.65 (d, 2H, J=5.1 Hz); 4.25-4.55 (m, 2H); 5.15-5.35 (m, 1H); 6,16 (s, 1H); 6.93 (d, 1H, J=8.9 Hz); 7.03 (d, 1H) J=16 Hz); 7.04-7.15 (m, 3H); 7.15-7.26 (m, 2H); 7.33 (d, 1H, J=16 Hz); 7.64 (d, 1H, J=8.9 Hz).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[F:9][C:10]1[CH:22]=[C:14]2[C:15](O[C:18](=O)[N:19](C)[C:13]2=[CH:12][CH:11]=1)=[O:16].CS(C)=O>O>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH3:18])[C:3](=[O:5])[CH:2]3[CH2:6][CH2:7][CH2:8][N:1]3[C:15](=[O:16])[C:14]=2[CH:22]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2cc(F)ccc21
Solvent: O
Solvent: CS(C)=O
Product: CN1C(=O)C2CCCN2C(=O)c2cc(F)ccc21

Procedure:
A mixture of 6.2 g. of L-proline, 10.0 g. of 5-fluoro-N-methylisatoic anhydride and 30 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours, cooled and then diluted with 100 ml. of water. The reaction mixture is evaporated with benzene and the benzene layer is washed twice with water and concentrated. The residue is dissolved in ether and cooled. The crystals are filtered off and dried in a vacuum oven. The dextrorotatory 7-fluoro-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)dione melts at 131°-132°, [α]D25 + 417° (1.6%, methanol).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:11][C:12]1[C:17]2[CH:18]=[C:19]([C:21]([C:23]3[O:24][C:25]4[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[C:26]=4[CH:27]=3)=O)[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.Cl>C(OCC)C>[Br:32][C:28]1[C:26]2[CH:27]=[C:23]([CH2:21][C:19]3[O:20][C:16]4[CH:15]=[CH:14][CH:13]=[C:12]([Br:11])[C:17]=4[CH:18]=3)[O:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(c1cc2c(Br)cccc2o1)c1cc2c(Br)cccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Brc1cccc2oc(Cc3cc4c(Br)cccc4o3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aluminum chloride (4.8 g, 11.43 mmol) in dry diethyl ether (70 mL) was added dropwise under Ar to a stirred suspension of lithium aluminum hydride (0.98 g, 25.78 mmol) in dry diethyl ether (100 mL). Pre-dried under high vacuum 82 (4.8 g, 11.43 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 1 hour followed by careful addition of 2 M HCl (100 mL) and extraction with diethyl ether (2×100 mL). The ether solution was dried over CaCl2 and concentrated to provide 84 product as white crystals (3.84 g, 83%): mp 142-143° C. (diethyl ether). 1H NMR (DMSO-d6) δ7.60 (d, J=8.2 Hz, 2H), 7.47 (d, J=7.7 Hz, 2H), 7.24 (dd, J=8.2, 7.7 Hz, 2H), 6.80 (s, 2H), 4.52 (s, 2H). HPLC (method B) tR 10.67 min (100.00 area %). Anal. (C17H10Br2O3) C, H, Br.
Reaction SMILES: [C:1]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[SH:19][CH2:20][C:21]([OH:23])=[O:22]>>[C:21]([CH2:20][S:19][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])([OH:23])=[O:22]
Reactant: C=CCCCCCCCCC(=O)N1CCOCC1
Reactant: O=C(O)CS
Product: O=C(O)CSCCCCCCCCCCC(=O)N1CCOCC1
Temperature: 60 °C

Procedure:
5 g (.02 mole) of 10-undecenoylmorpholine and 2.3 g (.025 mole) of mercaptoacetic acid were placed in a flask equipped with stirring bar. The temperature was raised to 60° C and maintained there for two hours with stirring. The excess mercaptoacetic acid was removed by distillation at reduced pressure and water washings.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:44])[C:39](I)=[CH:40][O:41][CH3:42].[O-]P([O-])([O-])=O.[K+].[K+].[K+].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.O>[CH3:36][O:37][C:38](=[O:44])[C:39]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:10][CH:11]=1)=[CH:40][O:41][CH3:42]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC(C)(C)C
Reactant: COC=C(I)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC=C(C(=O)OC)c1ccc(CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
A mixture of (3-tert-butoxycarbonylamino-propyl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (6.00 g, 12.25 mmol), 2-iodo-3-methoxy-acrylic acid methyl ester (4.45 g, 18.38 mmol), K3PO4 (7.79 g, 36.75 mmol), Pd(PPh3)4 (0) (0.68 g, 0.61 mmol), dioxane (60 mL) and water (12 mL) was degassed and heated at 80° C. for 20 h under argon atmosphere. The reaction mixture was diluted with EtOAc (500 mL), washed with water (300 mL) and brine (300 mL). The organic solution was concentrated and purified by flash chromatography (0%-30% EtOAc in heptane) to give desired product (5.35 g, 91%) as brown oil. 1NMR (300 MHz, CDCl3): δ 7.56 (s, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.20 (br.d, 2H), 5.20 (br.s, 0.5H), 4.62 (br.s, 0.5H), 4.39 (br, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.27 (m, 2H), 3.08 (m, 2H), 1.62 (m, 2H), 1.50 (br.d, 9H), 1.43 (s, 9H). LCMS (EI) m/z: 501 (M+Na+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([CH3:13])[CH:7]=[CH:6][N:5]=1)[CH3:2].C(=O)(O)[O-].[Na+]>Cl>[NH2:10][C:9]1[C:4]([S:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][C:8]=1[CH3:13]
Reactant: CCSc1nccc(C)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCSc1nccc(C)c1N
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
2-Ethylthio-4-methyl-3-nitropyridine (10.0 g, 50.4 mmol) was added slowly with stirring to a solution of 57 g (0.25 mole) of stannous chloride in 250 mL of concentrated aqueous hydrochloric acid. An exothermic reaction took place. The solution was held at 70° C. for 30 min, cooled, and then poured slowly into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ether and the extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.8 g (68 percent of theory) of a light yellow oil that solidified upon standing. This solid was recrystallized from hexane to obtain 3.2 g of the title compound as a white solid melting at 37°-38° C.
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:41])=[CH:19][CH:18]=1.CN(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[Br:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH:35]([CH3:2])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:41])=[CH:19][CH:18]=1
Reactant: [Li]CCCC
Reactant: CCOC(=O)CCCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
n-BuLi (1.6M in hexane, 6.4 mL, 10.3 mmol) was added slowly to 2,2,6,6-tetramethylpiperidine at -10° C. and the slurry was stirred 30 min, then cooled to -78° C. and diluted with 25 mL degassed THF. This solution was transferred via cannula into a 50 mL (degassed) THF solution of ester from Step 1 (4.15 g, 9.3 mmol) at -78° C. After stirring 1-- h, HMPA (1.6 mL, 9.3 mmol) was added and 30 min later CH3I (5.8 mL, 93 mmol) was added. The reaction mixture was stirred 12 h at -78° C., then quenched with saturated NH4Cl and extracted with Et2O and ethyl acetate. The organic phase was washed with aqueous Na2S2O5, water, brine and dried over MgSO4. Purification by flash chromatography (15% ethyl acetate in hexane) provided 2.5 g of the title compound.
Reaction SMILES: C([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)CC1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:20]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:43])=[O:44])[CH:15]=2)[CH:11]=[N:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 205 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.290 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (85.7% yield) of the titled compound. MS: m/z=589.2 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C([O-])(O)=O.[Na+]>[N:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=[CH:18][C:10]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)SCCN2CCCN1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)SCCN2CCCN1CCCC1)c1cccs1
Reaction time: 18 h
Yield: 85.1 %

Procedure:
A solution of 4-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.43 g, 1.550 mmol) in dry ethanol (15 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.884 g, 3.10 mmol) at room temperature, and the resulting mixture was stirred overnight (18 hours). The reaction was diluted with saturated NaHCO3 solution (30 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (20 mL) and then dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2 M NH3 in MeOH):CH2Cl2), to obtain the title product 21 (0.51 g, 85%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=4.5 Hz), 7.55 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=3.6, 4.9 Hz), 6.70 (d, 1H, J=8.7 Hz), 6.52-6.44 (m, 2H), 6.32 (brs, 2H), 3.51-3.48 (m, 2H), 3.27 (t, 2H, J=7.2 Hz), 3.04-3.00 (m, 2H), 2.48-2.40 (m, 6H), 1.80-1.60 (m, 6H); ESI-MS (m/z, %): 387 (MH+, 68), 276 (100), 194 (75); HPLC purity: 98.32% by area.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:34][C:35]#[N:36].O>C1COCC1>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:34][C:35]#[N:36])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: N#CCBr
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC#N)cc1
Yield: 52.6 %

Procedure:
To the phenol prepared in example 91 (608 mg, 1.5 mmol) in THF (20 mL) at 0° C. was addded sodium hydride (66 mg of a 60% dispersion in oil, 1.66 mmol). After ten minutes bromoacetonitrile (199 mg, 1.66 mmol) was added. The suspension was stirred at room temperature whereupon another portion of bromoacetonitrile (360 mg, 3 mmol) was added and stirring continued until the reaction was complete by TLC. Water (50 mL) was added to the reaction and the two layers separated. The aqueous phase was extracted with ether (2×40 mL) and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 10% MeOH/CHCl3 to provide 350 mg (53%) of product. Anal. Calcd for C27H30N3O3: C, 67.56; H, 6.30; N, 8.75. Found: C, 67.39; H, 6.51; N, 8.49.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][CH2:24][CH3:25])[C:15]2=[O:26])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:23]([N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]1=[O:26])[CH2:24][CH3:25]
Reactant: CCCn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-t-butoxycarbonyl-4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine (540 mg, 1.5 mmol) in chloroform (7 mL) containing trifluoroacetic acid (1 mL) was allowed to stir at ambient temperature for 15-25 hours. The solvent was removed on a rotary evaporator, the residue dissolved in chloroform and washed with aq. Na2CO3. The dried (Na2SO4) chloroform extract was evaporated to give 4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine as an oil which was used as is.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([O:26]C)=[O:25])=[CH:23][C:17]=4[N:16]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:17]=4[N:16]=3)[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(C3CCN(C(=O)c4ccc(-c5ccccc5)cc4)CC3)nc2c1
Temperature: 80 °C
Yield: 5.6 %

Procedure:
To a stirred solution of methyl 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-1H-benzimidazole-5-carboxylate (74 mg, 0.168 mmol) in THF (2 mL) is added 5M aqueous HCl (3 mL). The reaction is heated at 80° C. for 6 h. The mixture is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC to give 4 mg of 2-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-1H-benzimidazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)[CH2:14][CH2:13]2)[N:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[NH2:26])[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc([N+](=O)[O-])c4)CC3)cccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Yield: 84 %

Procedure:
A solution of 2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (D5) (0.14 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of iron powder (0.07 g; 3.2 eq) and ammonium chloride (0.1 g; 5.3 eq) in water (3 mL). The reactants were heated at reflux for 8 hours, adding additional amounts of iron powder (total 0.07 g; 3.2 eq) and ammonium chloride (total 0.1 g; 5.03 eq) in 3 portions during the reaction. The reaction mixture was filtered using a Millipore filter. The filtrate was concentrated under reduced pressure, diluted with water (5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2 mL), extracted into ethyl acetate (3×5 mL), dried over Na2SO4 and concentrated under reduced pressure obtaining the title compound in 84% yield (0.11 g).