Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[C:31]([O:33][Si](C(C)(C)C)(C)C)[CH:30]=[CH:29][C:28]=1[CH:41]1[CH2:46][CH2:45][CH:44]([C:47]([OH:49])=[O:48])[CH2:43][CH2:42]1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[C@H:41]1[CH2:42][CH2:43][C@H:44]([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(C(=O)O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Reaction time: 24 h

Procedure:
Tetrabutylammonium fluoride (0.12 ml) was added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanecarboxylic acid (22 mg) in tetrahydrofuran (1 ml) at room temperature under argon. After 24 hr, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:1 v/v, <1% acetic acid) to give the title compound as an orange solid (10 mg, 89%). δH (CD3OD) 1.40-1.65 (4H, m), 1.88-1.95 (2H, m), 2.06-2.14 (2H, m), 2.35 (1H, tt), 2.82 (1H, tt), 6.25-6.30 (2H, m), 6.90 (1H, m), 6.90 (1H, d); m/z (ES−) 235 (M−H)−.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:40][CH2:41][CH2:42][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[CH:35]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:37]([NH:36][C:34]1[CH:35]=[C:30]([NH:29][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:14]([C:26]([NH2:28])=[O:27])=[CH:13][N:12]=2)[CH:31]=[CH:32][C:33]=1[O:40][CH2:41][CH2:42][N:43]1[CH2:44][CH2:45][CH2:46][CH2:47]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1cc(N)ccc1OCCN1CCCC1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc(Nc2ncc(C(N)=O)c(NCc3cccc(F)c3)n2)ccc1OCCN1CCCC1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (57 mg, 0.15 mmol) in NMP (0.6 mL) was added N-(5-amino-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (47 mg, 0.18 mmol) and pTsOH*H2O (28 mg, 0.15 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamido-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (46 mg). MS found for C26H30FN7O3 as (M+H)+ 508.5. λ 248.5.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[CH2:36][OH:37])[CH2:27][CH2:26]1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH2:35][CH2:34][CH2:33][C@@H:32]4[CH2:36][OH:37])[CH2:29][CH2:30]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Reactant: OC[C@H]1CCCN1C1CCNCC1
Agent: Cl
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCC[C@@H]4CO)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 2, 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) and ((R)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 2) gave the title compound as light red amorphous solid. MS: 579.3 (MH+).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc3ccccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 2-bromomethyl-naphthalene (88 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and then the solvent was evaporated. The residue was purified by flash chromatography to give 12.8 mg of the desired product N-cyclopropyl-N-[1-(naphth-2-ylmethyl)-piperidin-4-yl]benzenesulfonamide (15). 1H NMR (CDCl3): δ 8.06-7.71 (m, 7H), 7.61-7.44 (m, 5H), 3.94-3.84 (m, 1H), 3.68 (S, 2H), 3.01-2.94 (m, 2H), 2.18-1.94 (m, 5H), 1.58-1.49 (m, 2H), 1.02-0.96 (m, 2H), 0.81-0.74 (m, 2H). MS (EI): m/z 421 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[OH-].[Li+].O.Cl>C1COCC1.CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Ethyl 5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.143 g, 0.362 mmol) was dissolved in a mixture of THF (4 mL) and methanol (1 mL) and to the solution was added 1.0 M of lithium hydroxide in water (1.5 mL, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was dissolved in water (5 mL) and neutralized with 1.0 M hydrochloric acid in water (1.5 mL, 1.5 mmol). The resulting precipitate was collected via vacuum filtration to afford Intermediate 20 as a white solid (0.1166 g, 88%). LC-MS: (FA) ES+395.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[Mn]([O-])(=O)(=O)=[O:17].[K+]>[OH-].[Na+]>[CH3:9][O:8][C:6]1[C:5]([O:10][CH3:11])=[CH:4][C:3]2[S:12](=[O:14])(=[O:13])[NH:15][C:1](=[O:17])[C:2]=2[CH:7]=1
Reactant: COc1cc(C)c(S(N)(=O)=O)cc1OC
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(cc1OC)S(=O)(=O)NC2=O

Procedure:
16 gm (0.08 mol) of 2-methyl-4,5-dimethoxy-benzene sulfonamide were dissolved in 500 ml of an aqueous 5% sodium hydroxide solution, and the solution was heated at its boiling point for 2 hours after addition of 39.6 gm (0.25 mol) of potassium permanganate. After cooling, the reaction mixture was suction-filtered through celite, and the desired product was precipitated by addition of concentrated hydrochloric acid. Rf -value (benzene/acetone = 3/1): 0.2-0.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([NH:23]C(OCC2C=CC=CC=2)=O)[C:19]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)=O.CO.O.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[C:19]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NC(=O)OCc3ccccc3)C2=O)cc2cnccc21
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21

Procedure:
2-[3-(S)-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (2.8 g, 6.0 mmol) in HCO2H/MeOH (30 mL, 4.4% solution) is quickly added via cannula to a solution of palladium black (2.0 g, 18.8 mmol) in water (1 ml,). After ca. 40 min the catalyst is filtered through Celite and basified with saturated sodium bicarbonate solution. The filtrate is concentrated in vacuo to remove methanol then the resulting solution is extracted with methylene chloride. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated to dryness. The resulting white solid can be used in the subsequent step without further purification. The title compound was purified in the following manner to prepare a focused sulfonamide library. The crude solid was purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate fractions are combined and neutralized with saturated sodium bicarbonate solution then concentrated to remove CH3CN. The aqueous layer is extracted with methylene chloride (×4) and the organic layers are washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:3])[CH3:2].[H-].[Na+].Cl[S:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[C:16]([O:15][C:14]([N:13]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[C:4]=1[CH:1]([CH3:3])[CH3:2])[S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1)(=[O:26])=[O:25])=[O:20])([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)c1c(NC(=O)OC(C)(C)C)nc2ccccn12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.2 %

Procedure:
To a suspension of compound 4-E (0.267 g, 0.97 mmol) in DMF (10 mL), cooled to 0° C., was added 60% NaH (0.043 g, 1.08 mmol) and the reaction mixture was stirred at 0° C. for 40 min. Methyl 4-(chlorosulfonyl)benzoate (0.341 g, 1.46 mmol) was added in one-portion and the reaction mixture was stirred at ambient temperature for 2 h. Ice water was added to the reaction solution and the product was extracted into EtOAc, washed with H2O (2×), then brine, and dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude product. The crude material was purified by flash column chromatography (SiO2) eluting with a gradient of EtOAc (20-60%) in heptanes to afford compound 4-F as a colorless glass (0.235 g, 51%). 1H-NMR (CDCl3): δ 8.4 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H), 8.05 (d, J=7.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.19-7.24 (m, 1H), 6.86-6.90 (m, 1H), 3.98 (s, 3H), 3.37-3.50 (m, 2H), 1.50-1.59 (m, 6H under H2O peak), 1.32 (s, 9H); MS: m/z 474.1 (MH+).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(SC2C=CC=CC=2C(O)=O)C=CC=CC=1.S(Cl)(Cl)=O.[CH3:37][NH:38][CH3:39]>C1C=CC=CC=1>[CH3:37][N:38]([CH3:39])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1Sc1ccccc1
Reactant: CNC
Agent: O=C(O)c1ccccc1Sc1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1ccccc1Sc1ccccc1

Procedure:
Following the procedure described in Example 1, 2-(phenylthio)benzoyl chloride is prepared from 0.065 mole of 2-(phenylthio)benzoic acid and excess thionyl chloride. A solution of the oily acid chloride in 50 ml. of benzene is added dropwise with stirring to a solution of 7 g. of dimethylamine in 50 ml. of benzene. The mixture is heated briefly to refluxing. Evaporation of the solvent under reduced pressure leaves N,N-dimethyl-2(phenylthio)benzamide as the residue.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][C:3]1([NH:8][C:9]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:27][C@H:15]3[C:16]=2[N:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:18]=1)=[O:10])[CH3:7].[CH3:28][NH:29][CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C.C1COCC1>[CH3:28][N:29]([CH2:7][C:3]1([NH:8][C:9]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:27][C@H:15]4[C:16]=3[N:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:18]=2)=[O:10])[CH2:2][CH2:6][CH2:5][CH2:4]1)[CH3:30]
Reactant: CC1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CCCC1=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CC1(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)CCCC1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To a solution of (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-oxo-methyl-cyclopentyl)-amide (26 mg, 0.070 mmol) in methanol (0.5 mL) was added a 2.0 M THF solution of dimethylamine (0.088 mL, 0.175 mmol) and acetic acid (0.681 μL, 0.012 mmol). The mixture was stirred at 23° C. for 15 min, added sodium triacetoxyborohydride (16.3 mg, 0.077 mmol), and stirred for another 1.5 h. One drop of acetic acid was added and the stirring was continued at room temperature for 3 h. Additional sodium triacetoxyborohydride (20 mg) and 2 M dimethylamine (200 μL) was added and the stirring was continued for 3 days. The mixture was purified by preparative TLC to provide the title compound (5.7 mg) as a colorless solid. LCMS m/z=401.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.48 (td, J=4.8, 3.3 Hz, 1H), 1.13 (td, J=7.8, 4.9 Hz, 1H), 1.58-1.68 (m, 2H), 1.76-1.83 (m, 4H), 2.09-2.18 (m, 3H), 2.22-2.28 (m, 1H), 2.39 (s, 6H), 2.76-2.85 (m, 2H), 2.94 (d, J=16.4 Hz, 1H), 3.04 (dd, J=16.4, 6.3 Hz, 1H), 6.97-7.04 (m, 2H), 7.12 (s, 1H), 7.62-7.68 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:31][CH3:32])[CH2:34][CH2:35]1
Reactant: OCC1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-piperidine methanol (38 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (31 mg, yield 54%).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].O[C:74]1[CH:86]=[CH:85][C:77]([C:78]([O:80]C(C)(C)C)=[O:79])=[CH:76][CH:75]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][C:74]3[CH:86]=[CH:85][C:77]([C:78]([OH:80])=[O:79])=[CH:76][CH:75]=3)=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Product: CCn1c(C)c(C(=O)Oc2ccc(C(=O)O)cc2)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1

Procedure:
6 was prepared from BM-957 and tert-butyl 4-hydroxybenzoate according general procedure IV. MS (ESI): m/z 1186.00 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.[BrH:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl>CO.C(Cl)(Cl)Cl>[BrH:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=2)=[O:35])[CH2:27][CH2:26]1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Reactant: O=C(O)CCCN1CCOCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
3.54 g. (11.27 mmole) of 1-Hydroxy-3-n-pentyl-6,6,9-trimethyl-10a,6a ,7,8-tetrahydrodibenzo[ b,d] pyran, 2.86 g. (11.27 mmole) of γ-morpholinobutyric acid hydrobromide and 2.50 g. (12.12 mole) of dicyclohexylcarbodiimide were combined in 200 ml. of methylene chloride and stirred at room temperature for 24 hours. The reaction mixture was cooled and the by-product of dicyclohexylurea was removed by filtration. The volume of methylene chloride was reduced and 25 ml. of cyclohexane was added. The mixture was cooled and the small amount of solid which formed was removed by filtration. All solvents were removed on a rotary evaporation and the residue was dried in vacuo. The resulting foamy material was dissolved in a mixture of benzene and ether and placed in cold storage to yield 3.0 g. (50%) of product as colorless crystals, m.p. 103°-105°C. The compound gave a Rf 0.5 in 5% MeOH/CHCl3. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:24]4[CH2:28][CH2:27][CH2:26][CH:25]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.C([SiH](CC)CC)C>[Pd]>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(C4=CCCC4)ccc23)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(C4CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-cyclopent-1-enyl-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. 1H NMR (400 MHz, DMSO-d6): δ 8.59 (t, J=6.01 Hz, 1H), 8.10 (d, J=8.82 Hz, 1H), 7.96 (d, J=9.22 Hz, 1H), 7.75 (d, J=9.23 Hz, 1H), 7.59 (d, J=8.81 Hz, 1H), 3.35-3.39 (m, 1H), 3.29 (s, 2H), 2.06-2.09 (m, 2H), 1.78-1.87 (m, 4H), 1.69-1.75 (m, 3H), 1.47-1.61 (m, 4H), 1.47-1.48 (m, 1H), 1.23-1.29 (m, 1H), 1.03 (t, J=12.81 Hz, 1H), 0.83-0.84 (m, 3H), 0.73-0.76 (m, 1H). m/z: 401.2 [M+H]+
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4](F)=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7]=2[CH:18]=1.[O:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH3-]C#N.[Na+]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:10][C:9](=[O:11])[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([CH:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:14][CH2:13]3)[C:7]=2[CH:18]=1
Reactant: O=C1CCOCC1
Reactant: O=c1[nH]c2cc(F)c(Cl)cc2n1C1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.0 g), Ti(iPrO)4 (4.2 mL), and tetrahydro-4H-pyran-4-one (1.4 g) were stirred together at room temperature for 1 h; dry methanol (30 mL) followed by NaBH3CN (0.8 g) were added and the mixture was stirred at room temperature for 1 h. The crude mixture was then quenched with methanol and it was purified first by SCX column chromatography followed by filtration and silica gel chromatography (methanol-NH3-dichloromethane). Conversion to the hydrochloride gave the title compound, 950 mg, MH+=336 and 338, 1H NMR (HCl salt) (DMSO-d6) 1.72 (2H, m), 1.94 (2H, m), 2.03 (2H, m), 2.81 (2H, m), 3.20 (2H, m), 3.33 (2H, m), 3.44 (1H, m), 4.01 (2H, m), 4.61 (1H, m), 7.02 (2H, m), 7.66 (1H, s), 10.52 (1H, bs) and 11.12 (1H, s).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([NH2:11])[N:8]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[C:16]([O:32][CH3:33])[CH:15]=3)[CH3:13])[C:5]2=[N:6][CH:7]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:33][O:32][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:3]=[C:4]3[N:10]=[C:9]2[NH2:11])[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(C(C)n2c(N)nc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(C)n2c(N)nc3cc(-c4cnn(C)c4)cnc32)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 4 h
Yield: 136.1 %

Procedure:
To a stirred mixture of 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine (0.253 g, 0.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.158 g, 0.76 mmol), potassium phosphate tribasic (0.495 g, 2.29 mmol) in tetrahydrofuran (5 mL)/water (4 mL) was added 2nd generation XPhos precatalyst (0.032 g, 0.041 mmol). The yellow solution was degassed under vacuum/backfilled with nitrogen (×3). The mixture heated to 75° C. After 4 h, the mixture was allowed to cool to room temperature and was diluted with water (40 mL). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.320 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded 0.178 g (77%) of the product as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1.9 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.66-7.62 (m, 3H), 7.57-7.53 (m, 2H), 6.96-6.92 (m, 1H), 6.89-6.84 (m, 2H), 6.11 (q, J=7.1 Hz, 1H), 5.21 (s, 2H), 4.46 (br s, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 1.87 (d, J=7.1 Hz, 3H) ppm; (M+1)=523.