Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[C:17]([CH:28]=O)=[N:18][CH:19]=[C:20]([N:22]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH3:23])[N:21]=1.[CH2:30]([NH:37][CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:30]([N:37]([CH2:28][C:17]1[C:16]([Cl:15])=[N:21][C:20]([N:22]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[CH3:23])=[CH:19][N:18]=1)[CH2:38][CH2:39][OH:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCNCc1ccccc1
Reactant: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(CC1CC1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
Sodium triacetoxyborohydride (0.51 g) was added to a solution of 3-chloro-5-[(cyclopropylmethyl)(methyl)amino]pyrazine-2-carbaldehyde (0.37 g), N-benzylethanolamine (0.29 g) and acetic acid (0.28 mL) in acetonitrile (5 mL), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→40% ethyl acetate/hexane) to give the title compound (0.5 g, 86%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH2:19][CH3:20])[CH3:18])[C:12]=1[N:21]=[C:22]=[S:23])([CH2:9][CH3:10])[CH3:8].Cl>>[CH:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:7]([CH2:9][CH3:10])[CH3:8])[C:12]=1[NH:21][C:22]([NH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:23])([CH2:19][CH3:20])[CH3:18]
Reactant: NC1CCCC1
Reactant: CCC(C)c1cccc(C(C)CC)c1N=C=S
Agent: Cl
Product: CCC(C)c1cccc(C(C)CC)c1NC(=S)NC1CCCC1
Reaction time: 12 h

Procedure:
20.0 g of cyclopentylamine are taken and 15.0 g of 2,6-di-sec.-butyl-phenyl isothiocyanate are introduced whilst stirring. The reaction takes place exothermically. The batch is left to stand for 12 hours and is then stirred with dilute hydrochloric acid and filtered. The filter cake is triturated with dilute methanol, filtered off, washed and dried. For further purification, the product can be recrystallised from petroleum ether. Yield 18 g; melting point 107°-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([N:1]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C=Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Temperature: -5 °C

Procedure:
Sixty-three and one half grams of m-amino pentafluoropropionanilide is dissolved in 150 ml of tetrahydrofuran containing 65 g. of triethylamine. This mixture is added dropwise with coolng to 37 g. of phosgene dissolved in 150 ml of tetrahydrofuran cooled to -5° C. When addition is complete the mixture is allowed to warm up to room temperature. The triethylamine hydrochloride is filtered off and the solvent is removed under vacuum. The product, 70 g., was not isolated but diluted to 140 ml with tetrahydrofuran and used in subsequent reactions.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH2:69]>CN(C=O)C>[CH3:63][N:64]([CH3:70])[CH2:65][CH2:66][CH2:67][CH2:68][NH:69][C:43]([C:40]1[S:39][C:35]2[N:36]=[CH:37][N:38]=[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=3[O:47][CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:34]=2[C:41]=1[CH3:42])=[O:44]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Reactant: CN(C)CCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NCCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
HATU (0.073 g, 0.193 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.07 g, 0.175 mmol) and Hünig's base (30 μL, 0.175 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. N1,N1-dimethylbutane-1,4-diamine (0.177 g, 0.875 mmol) was added, the coolant removed and the reaction stirred at ambient temperature overnight. The crude reaction mixture was applied to an SCX cartridge and eluted with MeOH (30 mL) followed by ammonia in MeOH. The product was purified by flash column chromatography (10% MeOH/DCM→15% MeOH/DCM/0.5% NH4OH) to give the title compound as a waxy colourless solid (0.012 g, 37%).
Reaction SMILES: [CH3:1][C:2]12[CH:12]3[CH2:13][CH2:14][C:15]4([CH3:25])[C:19]5([O:24][C:22](=[O:23])[CH2:21][CH2:20]5)[CH2:18][CH2:17][CH:16]4[CH:11]3[CH:10]=[CH:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.CN1CCCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:45]([OH:48])(=[S:47])[CH3:46]>O.C(O)(=O)C>[CH3:46][C:45]([S:47][C@H:10]1[C@H:11]2[C@H:16]3[C@:15]([CH3:25])([CH2:14][CH2:13][C@@H:12]2[C@:2]2([CH3:1])[C:8](=[CH:7][C:5]([CH2:4][CH2:3]2)=[O:6])[CH2:9]1)[C@@:19]1([O:24][C:22](=[O:23])[CH2:21][CH2:20]1)[CH2:18][CH2:17]3)=[O:48]
Reactant: CC(O)=S
Reactant: CC12CCC(=O)C=C1C=CC1C2CCC2(C)C1CCC21CCC(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC[C@@]34CCC(=O)O4)[C@H]12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 5.00 g of 17-hydroxy-3-oxo-17α-pregna-4,6-diene- 21-carboxylic acid γ-lactone (99.5% purity, 14.6 mmole), 15 ml of N-methyl-2-pyrrolidone and 228 mg of p-toluene-sulfonic acid monohydrate was heated to 80° C. in a nitrogen atmosphere. Then 3.0 ml of thioacetic acid was added and the mixture was stirred for 2 hours. At a temperature of 80° C., 5 ml of acetic acid was added followed by dropwise addition of 15 ml of water over 5 minutes. After completion of the dropwise addition, the resulting mixture was gradually cooled to 30° C. over an hour and twenty minutes. During the cooling, the acetylthio derivative was precipitated from the solution. Subsequently a mixture of 16.5 ml of methanol and 15 ml of water was added dropwise over 12 minutes. After completion of the dropwise addition, the mixture was stirred at 30° C. for another hour and filtered. The collected cyrstals were washed twice each with 25 ml of an equal volume mixture of methanol and water, and dried at a reduced pressure at 70° C. Thus, 4.7951 g of dried pure spironolactone was obtained as crystals, m.p. 204.4°-206.3° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[NH2:16][NH2:17]>>[CH:10]1([NH:9][C:8]([NH:16][NH:17][C:8](=[N:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)[NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NN
Product: C1CCC(N=C(NNC(=NC2CCCCC2)NC2CCCCC2)NC2CCCCC2)CC1

Procedure:
DCC (1.03 g, 4.97 mmol) was dissolved in tetrahydrofuran (15 mL). Hydrazine (135 mg, 4.22 mmol) was added via syringe. Stirring 30 hours at room temperature produced a clear yellow mixture which was evaporated to a white powder (922 mg). Solution of this powder in diethyl ether, filtration and acidification with HCl (60 mL of saturated Et2O) gave a yellow white precipitate (856 mg). Two recrystallizations (EtOH in an Et2O chamber) gave white prisms (133 mg, 18%, M.P. 288°-290° C.). The low percentage of nitrogen in the elemental analysis of this compound indicates that two equivalents of DCC have reacted to hydrazine, forming the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(O)nc1
Reaction time: 6.5 h
Yield: 89 %

Procedure:
To a solution of 6-hydroxynicotinic acid (5.0 g, 35.9 mmol) in ethanol (180 mL), sulfuric acid (1.0 mL) was added. The resultant mixture was stirred at 60° C. for 20 minutes, then added with surfuric acid (33.0 mL), and stirred for 6.5 hours while heated to reflux. The reaction solution was then added with a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions and ethanol was concentrated in vacuo. After extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Ethyl 6-hydroxynicotinate (5.33 g, yield 89%) was obtained as a white crystal.
Reaction SMILES: [CH3:1][C:2](=O)[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(O)C.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>ClCCl.O>[CH3:1][C:2](=[N:26][OH:27])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(=NO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
3α-fluor, 5α-pregnan-20-one (10 mmol) is dissolved in dichloromethane 5 mL and ethanol 50 mL at rt and air atmosphere, in a 250 mL round bottom flask. 4 equiv. of NH2OH chlorhydrate and 4 equiv. of sodium acetate are dissolved in 5 mL H2O and then added to the steroid solution. 20 mL of ethanol are added and the mixture put on reflux overnight. The mixture is then cooled and the solvent removed under reduced pressure. The white residue is then treated with 50 mL H2O and 50 mL dichloromethane, the aqueous phase extracted with 3×30 mL dichloromethane. The collected organic phases are then dried over MgSO4, filtrated and the solvent removed under reduced pressure. The final residue is purified by silica flash column chromatography (dichloromethane:diethyl ether 4:1). Quantitative yield.
Reaction SMILES: C1[CH2:11][CH2:10][N:9]2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)CC1.[CH3:12][C:13]([CH3:17])([OH:16])[C:14]#N.C(OCC)(=[O:20])C>C(#N)C>[C:13]([O:16][C:4]([N:9]1[CH2:10][CH2:11][C@@H:7]([C:6]#[N:5])[CH2:8]1)=[O:20])([CH3:17])([CH3:14])[CH3:12]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Reactant: CC(C)(O)C#N
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1

Procedure:
The compound (12.2 g) obtained in (7) was dissolved in anhydrous acetonitrile (122 ml). To the solution, 1,8-diazabicyclo[5,4,0]-7-undecene (8.02 ml) and acetone cyanohydrin (6.53 ml) were added, followed by heating under reflux for 10 hours. The reaction mixture was diluted with ethyl acetate (1 liter) and washed five times with water (200 ml) and once with a saturated aqueous solution of ammonium chloride (200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, whereby the crude product (9.10 g) was obtained. The resulting crude product was purified by column chromatography (eluent: benzene/ethyl acetate=17/1), whereby (3R)-1-tert-butoxycarbonyl-3-cyanopyrrolidine (4.41 g) was obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH3:29])=[CH:26][CH:25]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: CN(CCn1cnc(-c2cc(C(=O)O)ccn2)c1)c1ccc(Cl)cc1
Yield: 19 %

Procedure:
The title compound was prepared in 19% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-chloro-N-methylaniline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.77 (3H, s), 3.71 (2H, t, J=6.4 Hz), 4.17 (2H, t, J=6.4 Hz), 6.71 (1H, d, J=9.0 Hz), 6.99 (1H, m), 7.15 (1H, s), 7.17 (1H, s), 7.57 (1H, m), 7.65 (1H, s), 7.78 (1H, s), 8.24 (1H, s), 8.41 (1H, d, J=5.2 Hz). [M+H] Calc'd for C18H17ClN4O2, 358. Found, 358.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[N:32](CCC(C)(C)C([O-])=O)[CH:33]=[CH:34][N:35]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCN1C=CN=C1C1C2CCN(C([C@H]3CCCC[C@H]3NC(=O)C3C=CC=CC=3)=O)C=2C2C=CC=CC=2N=1)(=O)C(C)(C)C>>[NH:35]1[CH:34]=[CH:33][N:32]=[C:31]1[C:22]1[C:21]2[CH2:20][CH2:19][N:18]([C:16]([C@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:17])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CC(C)(CCn1ccnc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1)C(=O)[O-]
Agent: CC(C)(C)C(=O)OCn1ccnc1-c1nc2ccccc2c2c1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CCc2c(-c3ncc[nH]3)nc3ccccc3c21)c1ccccc1

Procedure:
In the same manner as in Example 325, [2-((3aR*,4R*,9bR*)-1-{[(1S,2R)-2-(benzoylamino)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-4-yl)-1H-imidazol-1-yl]methylpivalate was subjected to the oxidization reaction to synthesize [2-(1-{[(1S,2R)-2-(benzoylamino)cyclohexyl]carbonyl}-2,3-dihydro-1H-pyrrolo[3,2-c]quinolin-4-yl)-1H-imidazol-1-yl]methyl pivalate, and then the title compound was synthesized in the same manner as in Example 81 by removing the pivaloyloxymethyl group.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][NH:14][CH2:13]3)=[CH:4][CH:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]23[CH2:17][CH:16]2[CH2:15][N:14]([CH3:20])[CH2:13]3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C23CNCC2C3)c2ccccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CC2CC2(c2ccc(F)c3ccccc23)C1

Procedure:
A stirred solution/suspension of 1-(4-fluoronaphthalen-1-yl)-3-azabicyclo[3.1.0]hexane (215 mg, 0.95 mmol) in 1,2-dichloromethane (12 mL) was treated with 37% aqueous formaldehyde (0.5 mL, 9.5 mmol), then with sodium triacetoxyborohydride (1.25 g, 4.75 mmol), stirred for 3 h, then treated with 1N sodium hydroxide (5 mL). The organic layer was separated and the aqueous solution was extracted with methylene chloride containing a little 2-propanol (2×10 mL). The combined organic solution was dried (MgSO4) and concentrated in vacuo to afford 1-(4-fluoronaphthalen-1-yl)-3-methyl-3-azabicyclo[3.1.0]hexane (150 mg, 65%, essentially pure without chromatography). This was dissolved in anhydrous ether (5 mL) and treated with 2N HCl/ether (0.35 mL, 0.7 mmol), stirred a few minutes, filtered, rinsed with ether, collected, and dried in vacuo to afford 3-methyl-1-(4-fluoronaphthalen-1-yl)-3-aza-bicyclo[3.1.0]hexane, hydrochloride (150 mg, 82%) as a white solid. MS (M+1) 242.1. 1H NMR (DMSO-d6) δ 0.91-1.01 (m, 1 H) 2.01-2.09 (m, 1 H) 2.13-2.24 (m, 1 H) 2.72-2.84 (m, J=4.69 Hz, 3 H) 3.16-3.30 (m, 1 H) 3.72 (q, J=5.60 Hz, 2 H) 3.93 (dd, J=11.23, 5.17 Hz, 1 H) 7.31 (dd, J=10.74, 8.01 Hz, 1 H) 7.48-7.79 (m, 3 H) 8.07 (d, J=8.20 Hz, 1 H) 8.20 (d, J=8.40 Hz, 1 H). 13C (DMSO-d6) δ 14.51, 22.36, 29.97, 56.72, 60.47, 109.90, 121.34, 123.61, 125.04, 127.43, 128.50, 131.39, 134.24 157.08.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10](=[O:23])[N:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH:44](=O)[CH2:45][CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:7](=[O:30])[N:8]([CH:9]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:10](=[O:23])[N:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][N:20]([CH2:44][CH2:45][CH3:46])[CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: CCC=O
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCNCC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Solvent: C1CCOC1
Product: CCCN1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)n(S(=O)(=O)c4ccc(OC)cc4)c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 52 mg (0.08 mmol) of 5-chloro-1-(4-methoxybenzenesulfonyl)-3-[2-oxo-1-phenyl-2-(4-piperidin-4-ylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzimidazol-2-one (Example 128) in 3 ml of THF was mixed with 5.32 mg (0.09 mmol) of propionaldehyde and 70 mg of MP-triacetoxyborohydrde resin (Argonaut, 2.55 mmol/g, 0.17 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 8-11% methanol in dichloromethane). Yield: 33.2 mg (60%) of colorless solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([CH3:14])=[N:5]2.S(=O)(=O)(O)O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([CH:14]=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=1)=[N:5]2
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1C=Cc1ccc(F)cc1
Temperature: 85 °C
Yield: 97.6 %

Procedure:
6,7-Dichloro-3-methyl-1H-quinoxalin-2-one (5 g, 22 mmol) (prepared as described in: Collins, J. L.; Dambek, P. J.; Goldstein, S. W.; Faraci, W. S. Bioorg. Med. Chem. Lett. 1992, 2, 915-8) was dissolved in a mixture of glacial acetic add (100 ml) and 98% sulfuric acid (10 ml). 4-Fluorobenzaldehyde (2.3 ml, 22 mmol) was added and the resulting mixture was stirred at reflux temperature for 3.5 hours. The mixture was allowed to cool to 85° C. and then poured onto ice (500 ml). The solid was filtered, washed with water and ethyl acetate and dried in vacuo at 30° C. overnight to afford 7.2 g (99%) of 6,7-dichloro-3-[2-(4-fluorophenyl)vinyl]-1H-quinoxalin-2-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][CH2:30][CH2:31][CH3:32].ClCCl>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[C:16]([CH2:29][CH2:30][CH2:31][CH3:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][S:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)(=[O:8])=[O:7])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
2-Thiophenesulfonyl chloride (0.3 g in 10 ml dichloromethane, 1.6 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.5 g, 1.6 mmol), dichloromethane (40 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for a few hours and then an additional portion of 2-thiophenesulfonyl chloride (0.1 g, 0.6 mmol) was added. The reaction was maintained overnight and then concentrated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethanemethanol) and the fractions containing product were washed with saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated to provide 0.2 g of N2-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-thiophenesulfonamide as an off white powder, m.p. 137.5-141.5° C. 1H NMR (300 MHz, DMSO-d6) δ8.00 (d, J=8.0 Hz, 1H), 7.89 (dd, J=5.0, 1.3 Hz, 1H), 7.83 (broad s, 1H), 7.61 (dd, J=8.3, 1.1 Hz, 1H), 7.54 (dd, J=3.7, 1.3 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.44 (broad s, 2H), 4.47 (t, J=7.4 Hz, 2H), 2.87 (m, 4H), 1.80 (m, 4H), 1.58-1.38 (m, 4H), 0.96 (t, J=7.4 Hz, 3H); IR (KBr) 3467, 3361, 3167, 3091, 2957, 2933, 2870, 1644, 1617, 1585, 1533, 1478, 1405, 1336, 1154, 1095, 1014, 854, 761, 733 cm−1; MS (EI) m/e 457.1606 (457.1606 calcd for C22H27N5O2S2); Anal calcd for C22H27N5O2S2: C, 57.74; H, 5.95; N, 15.30. Found: C, 57.50; H, 5.98; N, 15.15.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(COC)OC.CO.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[C:39]([F:50])([F:49])[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)c1c(-c2ccccc2C(F)(F)F)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 135B (30 mg), 2-(trifluoromethyl)phenylboronic acid (15.3 mg), tetrakis(triphenylphosphine)palladium(0) (3.1 mg) and cesium fluoride (16.3 mg) in dimethoxyethane (1.4 ml) and methanol (0.7 ml) was heated at 100° C. in a microwave reactor (CEM Discover) for 30 minutes and was concentrated. The residue was purified by flash chromatography, eluting with 0%-100% dichloromethane in hexane, to provide ethyl 5-(benzyloxy)-1-(3-(naphthalen-1-yloxy)propyl)-3-(2-(trifluoromethyl)phenyl)-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ 12.67 (s, 1H), 8.04-8.40 (m, 1H), 7.87 (d, J=7.32 Hz, 1H), 7.82 (d, J=7.63 Hz, 1H), 7.69 (t, J=7.32 Hz, 1H), 7.57-7.65 (m, 2H), 7.44-7.56 (m, 3H), 7.26-7.41 (m, 7H), 6.97 (dd, J=9.00, 2.29 Hz, 1H), 6.85 (d, J=7.93 Hz, 1H), 6.55 (d, J=2.14 Hz, 1H), 4.83-4.98 (m, 4H), 4.05-4.24 (m, 2H), 2.28-2.40 (m, 2H).