Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH-:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: [NH-]S(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(CS(N)(=O)=O)c1
Reaction time: 4 h
Yield: 93.4 %

Procedure:
(3-Nitrophenyl)methanesulfonyl amide (3.5 g, 16 mM) was hydrogenated over Raney-Ni (0.5 g) in methanol at 50° C. and 70 psi for 4 hours. Then the catalyst was filtered off and washed with warm methanol. The combined filtrates were evaporated to give 2.83 g (95%) of (3-amino-phenyl)-methanesulfonamide.
Reaction SMILES: Cl.[CH:2]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>CN(C=O)C.N1C=CC=CC=1.C(OCC)(=O)C.O.Cl.CCOCC>[CH:2]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:9]([NH:38][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][N:29]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1nccc2ccccc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)O)cc2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nccc4ccccc34)cc2)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid hydrochloride (150 mg, 0.346 mmol) is slurried in DMF (3 mL) with TEA (97 μL, 0.692 mmol) and cooled to 0° C. After 45 min, isoquinolin-1-ylamine (50 mg, 0.346 mmol) in pyridine (1 mL) is added dropwise. The reaction is allowed to stir and warm to RT overnight. The reaction is diluted with ethyl acetate and water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown oil. Purification via flash chromatography using 0→2% methanol in ethyl acetate affords the pure product. This is dissolved in 1 M hydrochloric acid in ether and stirred at RT for 30 min, then concentrated. Dissolution in water followed by lyophilization affords 3-cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide, hydrochloric salt as a yellow solid: LC/MS 507.4 (M+1), 505.5 (M−1); 1H NMR (400 MHz, DMSO-D6) δ 1.2 (m, 2 H) 1.5 (m, 2 H) 1.6 (m, 2 H) 1.7 (m, 2 H) 1.8 (dd, J=13.3, 6.9 Hz, 2 H) 2.2 (dd, J=13.0, 7.5 Hz, 1 H) 2.7 (m, 5 H) 2.9 (s, 1 H) 3.1 (s, 1 H) 3.4 (d, J=11.9 Hz, 2 H) 3.8 (d, J=12.4 Hz, 2 H) 5.0 (s, 1 H) 7.8 (m, 2 H) 7.9 (m, 2 H) 8.0 (m, 2 H) 8.1 (t, J=7.6 Hz, 1 H) 8.2 (d, J=8.1 Hz, 1 H) 8.2 (d, J=6.6 Hz, 1 H) 9.0 (s, 1 H) 11.1 (s, 1 H). EC50 in primary enzyme assay 50 μM
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].Cl.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=2[O:30][CH3:31])[CH2:19][CH2:18]1>CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:28][C:24]3[C:23]([O:30][CH3:31])=[C:22]([O:21][CH2:20][CH:17]4[CH2:19][CH2:18]4)[CH:27]=[CH:26][N:25]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Reactant: COc1c(OCC2CC2)ccnc1CCl
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2nc(SCc3nccc(OCC4CC4)c3OC)[nH]c2cc1C
Yield: 100.8 %

Procedure:
To a solution of 5-carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.58 g, 2.6 mmol) in methanol (25 ml) aqueous NaOH (1.0 ml 5M, 5.0 mmol) and 4-cyclopropylmethoxy-3-methoxy-2-chloromethyl pyridine hydrochloride (prepared according to processes known per se.) (0.63 g, 2.4 mmol) dissolved in methanol (25 ml were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over Na2SO4 and evaporated giving a yellow syrup (1.0 g, 100%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40].[C:41]([O:46]CC)(=[O:45])[CH:42]([CH3:44])[OH:43].C(=O)(O)[O-].[Na+]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40].[C:41]([O-:46])(=[O:45])[CH:42]([CH3:44])[OH:43]
Reactant: CCOC(=O)C(C)O
Agent: CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(O)C(=O)[O-]
Reaction time: 8 h

Procedure:
Polidocanol 41.32 g (70.9 mmol) Polidocanol, 21.07 g (178.4 mmol) ethyl lactate, 4.64 g Novozyme 435 and 1.00 g (11.9 mmol) sodium bicarbonate were added to a 100 mL 1-neck round bottom flask. The flask was then fitted to a rotary evaporator with the bath temperature set at 62° C. The pressure was slowly reduced to 15 mmHg under moderate rotation and the reaction mixture was held for 8 hours. Ethyl lactate (5.79 g, 49.0 mmol) was added to replenish the amount removed by distillation and the mixture was held an additional 16 hours at 62° C. and 15 mmHg. The round bottom flask was removed from the evaporator and the mixture was diluted with 20 mL petroleum ether. The solids were separated by vacuum filtration on a Buchner funnel with a #1 Whatman filter paper. The filtered solids were washed with 16 mL petroleum ether and the wash liquors were combined with the mother liquors. The combined filtrates were added to a 100 mL 1-neck round bottom flask and the flask was affixed to a rotary evaporator. The petroleum ether and excess ethyl lactate were distilled @15 mmHg with a bath temperature of 75-80° C. Upon completion of the distillation the pot was cooled and 38.19 g of Polidocanol lactate was obtained as a lightly colored waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8]([OH:10])=[O:9])=[O:4].CN(C1C=CC=CN=1)C.[C:28](O)([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>C(Cl)Cl>[CH3:18][S:15]([O:14][C:12]1[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[C:7]([CH:11]=1)[C:8]([O:10][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:9])(=[O:17])=[O:16]
Reactant: CC(C)(C)O
Reactant: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)O)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-[(methylsulfonyl)oxy]benzoic acid (0.74 g, 2.7 mmol) in DCM (25 mL) was added dimethylaminopyridine (0.165 g, 1.35 mmol) and tert-butanol (0.226 g, 3.05 mmol). The reaction mixture was cooled to 0° C. To the reaction was added EDC (0.569 g, 2.97 mmol). The reaction stirred at 0° C. for 2 h and then warmed to room temp over 16 h. The reaction mixture was washed with 1N HCl, H2O, dried with MgSO4, filtered, concentrated and purified by flash chromatography (25 g silica, 10-30% EtOAc/hexanes) to give 0.74 g (83%) of tert-butyl methyl 5-[(methylsulfonyl)oxy]isophthalate. 1H NMR (400 MHz, CDCl3) δ 8.58 (m, 1H), 8.09 (m, 1H), 8.05 (m, 1H), 3.96 (s, 3H), 3.23 (s, 3H) 1.61 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[C:11]([O:14][C:15](=O)[CH3:16])(=O)[CH3:12].C(OCC)(OCC)(OCC)C>C(OCC)(=O)C.O>[CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([C:5](=[C:11]([O:14][CH2:15][CH3:16])[CH3:12])[C:6]#[N:7])=[O:8])[CH3:2]
Reactant: CCC(CC)C(=O)CC#N
Reactant: CC(=O)OC(C)=O
Agent: CCOC(C)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(C)=C(C#N)C(=O)C(CC)CC

Procedure:
A mixture of 4-ethyl-3-oxo-hexanenitrile (1.013 g, 7.28 mmol), acetic anhydride (1.5 ml) and triethyl orthoacetate (1.240 g, 7.64 mmol) was heated to reflux overnight. The reaction mixture was taken up in ethyl acetate and water. The brine and the ethyl acetate layer were separated. The organic layer was dried and concentrated to give 1.262 g of dry oil which was used directly for the next reaction. 1H NMR (CDCl3): 0.8-1.0(m,6H), 1.44(t,3H), 1.4-1.8(m,4H), 2.61(s,3H), 3.03(m,1H), 4.28(q, 2H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][OH:15]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[CH:5]=[N:14][OH:15]
Reactant: NO
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C=NO)c(OC)c1

Procedure:
2,4-Dimethoxybenzoic acid is reacted with hydroxylamine to form 2,4-dimethoxybenzaldoxime. 2,4-Dimethoxybenzaldoxime is reacted with diphosphorus pentoxide to form 2,4-dimethoxybenzonitrile. 2,4-Dimethoxybenzonitrile is reacted with boron trichloride to form 2,4-dihydroxybenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:19])([C:15](OC)=[O:16])[C:3]=1[C:4]=23.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C:14]([OH:19])([CH2:15][OH:16])[C:3]=1[C:4]=23
Reactant: COC(=O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CNc2ccc(F)c3c2N1CC3(O)CO
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A solution of methyl 7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxaline-6-carboxylate (0.558 g, 0.002 mol) in methanol (40 mL) was cooled to 0° C. and treated with sodium borohydride (0.080 g, 0.002 mol). After 2 hours and again after a further 2 hours, further portions of sodium borohydride (0.04 g, 0.5 equivalent each time) were added at 0° C. After 5 hours in total, the reaction mixture was quenched by addition of water (2 mL) and the solvent was removed. The residue was placed directly onto the top of a 20 g silica gel column and chromatographed, eluting with a 0-100% ethyl acetate in hexane gradient, then with a 0-50% methanol in ethyl acetate gradient to afford the product (0.331 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C[Al](C)C.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]([NH:12][C:10]2[N:11]=[C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]3[N:9]=2)=[O:24])=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Reactant: COC(=O)c1ccc(Br)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3ccc(Br)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of 24 mg (0.1 mmol) 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine in 1 ml dioxane was added 0.4 ml (0.4 mmol) of a 1 M solution of AlMe3 in toluene and allowed to stir for 1 h at room temperature. 86 mg (0.4 mmol) 4-bromo-phenyl carboxylic acid methyl ester in I ml dioxane was added and the mixture was stirred for 48 h at 90° C. 0.5 ml 1N HCl aq. was added and the mixture was evaporated to dryness. The residue was taken up in 1.5 ml formic acid and 0.5 ml methanol and subjected to reversed phase HPLC chromatography eluting with a water/acetonitrile gradient. Evaporation of the eluents yielded 6 mg (15%) of the title compound. MS m/e (%): 423.3 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)Cc1cccc(N)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1cccc(NC(C)=O)n1
Reaction time: 1 h

Procedure:
To the solution of ethyl 2-(6-aminopyridin-2-yl)acetate (50 mg, 0.28 mmol) and N-ethyl-N-isopropylpropan-2-amine (71.0 mg, 0.55 mmol) in DCM was added acetyl chloride (43.2 mg, 0.55 mmol) dropwise at room temperature. The mixture was continued to stir for 1 h, washed with brine and evaporated in vacuum to dryness. The residue was purified by a standard method to afford desired compound. LC-MS: m/z (M+H)=222.4
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[OH-].[Na+]>CO>[O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2-[4-(methoxycarbonyl)benzyl]phenyl β-D-glucopyranoside (0.050 g) in methanol (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.26 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on (benzenesulfonylpropyl) silica gel (eluent: methanol) to give 2-(4-carboxybenzyl)phenyl β-D-glucopyranoside (0.038 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:12][CH2:11][CH2:10][S:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCSCCc1ccccc1
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCOCCSCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
A mixture of 2-[(2-phenylethyl)thio]ethanol (1.0 g), 1,4-dibromobutane (3.79 g), TAB (0.6 g) and 50% aqueous sodium hydroxide (12 ml) was stirred at room temperature under nitrogen for 20 h. The mixture was diluted with water (100 ml), extracted with diethyl ether (2×100 ml), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with cyclohexane followed by System B (5:95) gave the title compound (1.34 g) as a colourless oil. T.l.c. (System F 3:1) Rf 0.62.
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[C:51]([F:58])=[CH:50][C:49]=1[C:59]1[S:63][C:62]([CH2:64]O)=[C:61]([CH3:66])[CH:60]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:64][C:62]2[S:63][C:59]([C:49]3[CH:50]=[C:51]([F:58])[C:52]([C:54]([F:55])([F:57])[F:56])=[CH:53][C:48]=3[F:47])=[CH:60][C:61]=2[CH3:66])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3cc(F)c(C(F)(F)F)cc3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 120).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[NH2:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[CH:39]2.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH:41]1[C:42]2[C:38](=[CH:37][C:36]([NH:35][C:1]([C:4]3[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]4[N:18]=[C:17]([N:19]5[C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=6[N:21]=[CH:20]5)[CH:16]=[CH:15][N:14]=4)[CH3:11])[CH:7]=[CH:8][CH:9]=3)=[O:2])=[CH:44][CH:43]=2)[CH:39]=[CH:40]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (19.2 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (37 μL) was added followed by 5-aminoindole (19.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.3 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 30 min then eluted on silica gel column (2-4%MeOH in CH2Cl2) then on one 250 μm silica gel plate (1:1 hexanes:acetone) to yield 3.7 mg of the title compound. 1H NMR (500 MHz, CDCl3,partial): δ 8.50 (br s, 1H); 8.40 (d, J=5.5 Hz, 1H); 8.22 (br s, 1H); 8.03 (s, 1H); 7.96 (br s, 1H); 7.87 (s, 1H); 7.64 (d, J=7.8 Hz, 1H); 7.51 (t, J=7.8 Hz, 1H); 7.25 (m, 1H); 6.81 (d, J=5.5 Hz, 1H); 6.56 (br s, 1H); 5.89 (br s, 1H); 5.29 (br s, 1H); 1.69 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 474.3 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccnc(F)c3)ccn2c1=O
Yield: 89.3 %

Procedure:
Methyl 8-(2-fluoro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-pyridin-4-yl-boronic acid (72 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (107 mg, 89%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:14]Br.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:14][C:3]1[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=2[O:1][CH:2]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc2occc2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(O)c1ccc2occ(Br)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
Methyl benzofuran-5-carboxylate (667 mg, 3.8 mmol) is dissolved in 20 ml CH2Cl2 in a flask under nitrogen. The solution is treated with Br2 (1.2 ml, 22.8 mmol), is layered with 20 ml saturated NaHCO3, and the reaction is stirred gently for 2 h at RT. The reaction is stirred vigorously for 30 min, the layers are separated, and the organic layer is concentrated in vacuo to an amber oil. The residue is dissolved in 30 ml EtOH, the solution is treated with anhydrous K2CO3 (3.15 g, 22.8 mmol), and the reaction is stirred vigorously overnight. The insoluble material is removed by filtration and the filtrate is diluted with 3 ml 3N NaOH and the mixture is stirred 3 h at RT. The mixture is concentrated in vacuo, the residue is dissolved in 10 ml H2O, and the pH of the solution is adjusted to 2 with 10% aqueous HCl. The precipitate is collected, washed with water, and is dried to afford 880 mg (96%) of 3-bromobenzofuran-5-carboxylic acid as an off-white solid. HRMS (FAB) calcd for C9H5BrO3+H: 240.9501, found 240.9505 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc([Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc([Si](C)(C)C)cc1
Yield: 90.7 %

Procedure:
The product of Step A (59 g, 0.33 mole) was dissolved in carbon tetrachloride (700 mL). To this solution was added N-bromosuccinimide (59 g, 0.33 mole) and benzoyl peroxide (ca. 200 rag) in one portion. The reaction mixture was heated to reflux for 2.5 hours while being irradiated with a 275 watt sunlamp. After cooling, the solid succinimide was removed by filtration and the filtrate was washed with saturated aqueous NaHSO3. Drying (MgSO4) and concentration gave an oil (77 g, 91% yield) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]([CH2:20][CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.CN(C)C=O.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:23][CH2:22][CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cccnc3OC)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cccnc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of 4-{4-chloro-7-(1-ethylpropyl)-2-[(2-methoxypyridin-3-yl)amino]-1H-benzimidazol-1-yl}butan-1-ol (200 mg, 0.480 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (275 mg, 2.40 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo. The residue was dissolved in water and ethyl acetate. The mixture was extracted with ethyl acetate (×2). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mesylate (MS Calcd.: 398; Found: 399 (M+H)) was subjected for the next step without further purification. The crude material in N,N-dimethylformamide (3.0 mL) was added potassium carbonate (663 mg, 4.80 mmol). The reaction mixture was stirred at 80° C. for 12 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound (137 mg, 0.343 mmol, 71.6% yield) as a white amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)[C:21]([CH2:38][OH:39])=[CH:20][CH:19]=1>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22]2[C:21]([CH2:38][OH:39])=[CH:20][CH:19]=[C:18]([N:16]3[C:10]4[CH:9]=[C:8]([C:6]5[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[N:13]=[CH:12][C:11]=4[CH:14]=[N:15]3)[N:23]=2)[CH2:25]1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2nc(Br)ccc2CO)C1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(CO)c(N3CCC[C@H](N)C3)n2)n1
Yield: 68 %

Procedure:
Following the procedures as described in EXAMPLE 86 and starting with 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine and tert-butyl N-[(3S)-1-[6-bromo-3-(hydroxymethyl)-2-pyridyl]-3-piperidyl]carbamate, 218 was obtained as an off-white solid (40.8 mg, 68%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.77-9.73 (s, 1H), 9.49-9.45 (s, 1H), 9.34-9.31 (s, 1H), 8.69-8.67 (s, 1H), 8.64-8.61 (s, 1H), 8.03-7.98 (d, J=8.1 Hz, 1H), 7.65-7.61 (d, J=8.1 Hz, 1H), 4.59-4.52 (d, J=2.9 Hz, 2H), 3.60-3.52 (d, J=12.4 Hz, 1H), 3.51-3.43 (d, J=9.8 Hz, 1H), 3.21-3.15 (d, J=10.4 Hz, 1H), 3.00-2.92 (s, 1H), 2.74-2.68 (d, J=12.0 Hz, 1H), 2.67-2.64 (s, 3H), 1.98-1.89 (d, J=9.4 Hz, 2H), 1.77-1.66 (m, 1H), 1.37-1.26 (d, J=10.0 Hz, 1H); MS (ESI) m/z: 417.1 [M+H]+