Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:51])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH2:23][CH2:24][N:25]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:26]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][C:27]=3[CH:28]=2)=[O:21])=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[NH2:1][C:2](=[O:51])[CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][S:12]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH2:23][CH2:24][N:25]([CH2:47][CH:48]([CH3:50])[CH3:49])[C:26]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:35][CH:34]=4)=[CH:29][C:27]=3[CH:28]=2)=[O:21])=[CH:15][CH:14]=1)=[O:60]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(N)=O)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(N)=O)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of N-[4-[[[1-(4-amino-4-oxobutyl)-1H-imidazol-2-yl]methyl]thio]phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (350 mg) in dichloromethane (30 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.18 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:19→1:9), to give N-[4-[[[1-(4-amino-4-oxobutyl)-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 416) (259.9 mg) as yellow amorphous.
Reaction SMILES: Br[CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5].[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2>>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:2][CH:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH:13]=[CH:12]2
Reactant: CCC(CC)CBr
Reactant: Brc1ccc2[nH]ccc2c1
Product: CCC(CC)Cn1ccc2cc(Br)ccc21

Procedure:
The title compound was prepared from 1-bromo-2-ethylbutane (14.14 mL, 101 mmol) and 5-bromoindole (20 g, 101 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product (17.78 g, 62%) was obtained as a colorless oil. Mass spectrum (ESI, [M+H]+) m/z 280. 1 HNMR (400 MHz, DMSO-d6): δ 7.71 (d, 1H, J=1.83 Hz), 7.43-7.39 (m, 2H), 7.21 (dd, 2H, J=8.72 and 1.99 Hz), 6.41 (d, 1H, J=2.90 Hz), 4.04 (d, 2H, J=7.48 Hz), 1.76 (hep, 1H), 1.21 (p, 4H), and 0.82 ppm (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][OH:11])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1.N.C(O)(=[O:37])C>Cl.O.CO>[OH:11][CH2:10][C@@H:9]([NH:8][C:4]1[N:5]=[CH:6][NH:7][C:2](=[O:37])[C:3]=1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:26]=[C:27]([CH3:28])[C:21]=2[N:20]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Reactant: CC(=O)O
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)nc[nH]c3=O)nc12
Temperature: 100 °C
Yield: 37 %

Procedure:
To a solution of (S)-2-[6-chloro-5-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-pyrimidin-4-ylamino]-3-phenyl-propan-1-ol in 4 N HCl (0.5 mL) and acetic acid (0.5 mL) was added two drops of water. The reaction mixture was heated to 100° C. for 8 h, cooled to room temperature, and neutralized with ammonia in methanol. After concentration, the residue was purified by prep. HPLC to yield the title compound (26 mg, 37% for two steps). 1H NMR (400 MHz, CD3OD) δ 9.41 (1H, narrow t, J=1.5 Hz), 8.06 (1H, narrow dd, J=1.6, 1.9 Hz), 7.93 91H, s), 7.77 (1H, narrow dd, J=1.6, 1.8 Hz), 7.73 (1H, narrow d, J=1.9 Hz), 7.11–7.21 (6H, m), 4.70–4.74 (1H, m), 3.74 (2H, d, J=4.7 Hz), 3.11 (1H, dd, J=6.1, 13.5 Hz), 3.00 (1H, dd, J=7.8, 13.5 Hz), 2.70 (3H, s). LCMS (M+H)+ m/z 442 (t=2.17 min.).
Reaction SMILES: [CH:1]([C:3]1[S:7]/[C:6](=[N:8]\[CH3:9])/[N:5]([CH3:10])[C:4]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>ClCCCl.C(O)(=O)C>[CH3:10][N:5]1[C:4]([CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]2)=[C:3]([CH2:1][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[S:7]/[C:6]/1=[N:8]\[CH3:9]
Reactant: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C/N=c1\sc(CN2CCOCC2)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 35a) and morpholine (0.36 mL) were dissolved in a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C., and the mixture was mixed at room temperature overnight. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.2 g) as pale brown crystals.
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20][C:21]4[NH:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[N:22]=4)[C:13]=3[CH3:30])[CH2:6][O:5]2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH2:3]1[C:4]2([O:5][CH2:6][CH:7]([CH2:10][O:11][C:12]3[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([CH2:19][S:20]([C:21]4[NH:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[O:39])[C:13]=3[CH3:30])[CH2:8][O:9]2)[CH2:1][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC2(CCC2)OC1
Reaction time: 0.92 h
Yield: 86.1 %

Procedure:
To a toluene (20 ml)-methanol (2 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-ylmethoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (499 mg, 1.17 mmol) obtained in the step (13d), a toluene (1 ml)-methanol (1 ml) solution of 3-chloroperbenzoic acid (280 mg, 1.05 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred in the same conditions for 55 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 20 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected with ethyl acetate, and concentrated. To the residue, diethyl ether was added and then the mixture was concentrated to obtain the title compound (445 mg, yield: 86.1%) as a colorless foam.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:11]=[C:12]([F:20])[C:13]2[S:17][C:16](N)=[N:15][C:14]=2[CH:19]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:16]1[S:17][C:13]2[C:12]([F:20])=[CH:11][C:10]([F:9])=[CH:19][C:14]=2[N:15]=1
Reactant: Nc1nc2cc(F)cc(F)c2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution containing copper chloride (II) (0.89 g, 6.64 mmol) and tri(ethylene glycol) dimethyl ether (6 mL) in acetonitrile (60 mL) was added isoamyl nitrite (0.97 g, 8.30 mmol) and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 5,7-difluoro-1,3-benzothiazol-2-amine (1.03 g, 5.53 mmol) in tri(ethylene glycol) dimethyl ether (20 mL) and acetonitrile (30 mL). The reaction mixture was stirred at rt for 10 minutes and heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (400 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered, and concentrated. The residue was purified by flash chromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane to afford 2-chloro-5,7-difluoro-1,3-benzothiazole (0.55 g, 48%). 1H NMR (400 MHz, CD2Cl2) 7.02 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH:8]2[C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[C:2]1([CH3:1])[CH:20]=[CH:19][C:5]([C:6]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1ccc(C(=O)C2C(=O)c3ccccc3C2=O)cc1
Solvent: O
Product: Cc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 0 °C

Procedure:
A mixture of 2-(4-methylbenzoyl)indan-1,3-dione (1.32 g, prepared in a similar manner to the starting material in Example 6) and hydrazine hydrate (15 ml) was boiled under reflux for 24 hours. The mixture was cooled, poured into ice-water and the solid was collected by filtration, washed with absolute ethanol and dried to give 3-(p-tolyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 267-269° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH:7]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(CC(C)C)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(CC(C)C)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step A of Example 1 from 3-{3-[(4-isobutyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, 2H), 7.57 (m, 1H), 7.52 (m, 2H), 7.11 (m, 1H), 7.03-6.86 (m, 6H), 6.79 (s, 1H), 4.29 (s, 2H), 4.28 (s, 2H), 3.67 (s, 3H), 2.80 (t, 2H), 2.50 (t, 2H), 2.40 (d, 2H), 1.80 (m, 1H), 0.86 (m, 6H); MS 480 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33](=[O:42])[N:34]([CH3:41])[CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[CH:35]1([N:34]([CH3:41])[C:33]([CH:29]2[CH2:30][CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[C:20]([CH:21]=[C:4]4[NH:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])[CH:23]=3)[CH2:28]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: CN(C(=O)C1CCCN(c2ccc([N+](=O)[O-])c(C=O)c2)C1)C1CCCCC1
Product: CN(C(=O)C1CCCN(c2ccc([N+](=O)[O-])c(C=C3NC(=O)NC3=O)c2)C1)C1CCCCC1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-[3-(N-methyl-N-cyclohexylcarbamoyl)-1-piperidinyl]benzaldehyde analogous to the procedure of Example (2-1), m.p. 153°-162° C., crystallized from MeOH-H2O.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([SH:22])=[N:7][C:8]([C:12]([F:21])([F:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:26]>C(O)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([S:22][CH3:26])=[N:7][C:8]([C:12]([F:20])([F:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1ccc(C(F)(F)c2nc(S)c3ccc(Br)cc3n2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline-4-thiol (500 mg, 1.29 mmol) in isopropanol (10 mL) were added 1N NaOH (1.94 mL, 1.94 mmol) and iodomethane (0.097 mL, 1.55 mmol) and the mixture was stirred at rt for 30 min. A brown solid formed, which was collected by filtration and washed with MeOH to afford 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (0.373 g, 72%). 1H NMR (300 MHz, CDCl3) δ 8.45-8.51 (m, 1H), 8.26-8.32 (m, 1H), 7.93-8.03 (m, 2H), 7.74 (dd, J=1.9, 8.9 Hz, 1H), 7.54-7.65 (m, 1H), 2.61 (s, 3H); LC-MS (ESI) m/z 400/402 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:6][CH2:5][CH2:4]1.[CH2:7]1[O:11][C:10]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=2[O:8]1>>[CH:3]1([CH2:2][O:16][C:13]2[CH:14]=[CH:15][C:9]3[O:8][CH2:7][O:11][C:10]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrCC1CCC1
Product: c1cc2c(cc1OCC1CCC1)OCO2

Procedure:
Starting from commercially available bromomethyl-cyclobutane and sesamol the title compound is obtained as colorless solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:25])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])([O-:35])=[O:34].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:25][C:4]([F:3])([F:24])[C:5]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:42]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N+:33]([O-:35])=[O:34])(=[O:43])=[O:44])[CH2:19][C@@H:18]2[CH3:23])=[N:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@H]1CNCCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a 15 mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydrochloride (0.28 g, 0.66 mmol, Example 89, Step 2), triethylamine (0.28 mL, 2.0 mmol) and CH2Cl2 (6 mL). To this solution at room temperature was added 2-nitrobenzenesulfonyl chloride (0.15 g, 0.66 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred at room temperature for 3 h and then saturated aqueous sodium bicarbonate was added. This was stirred for an additional 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected. The collected solution was purified by silica gel chromatography (0 to 75% EtOAc in hexanes) to afford (S)-1,1,1,3,3,3-hexafluoro-2-(2-(2-methyl-4-(2-nitrophenylsulfonyl)piperazin-1-yl)pyrimidin-5-yl)-2-propanol (0.24 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CS(C)=O>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:33][CH2:32][C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:31][CH:30]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccc(OCCN2CCOCC2)cc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccc(OCCN4CCOCC4)cc3)c3ccccc3nc21
Temperature: 25 °C
Yield: 77.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol), 4-[2-(4-morpholinyl)ethoxy]phenylmethylamine (0.75 g, 3.2 mmol) and DMSO (3 mL) was heated on a steam bath for 8 hours. Additional 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (0.7 g, 3 mmol) was then added and the reaction mixture was heated on a steam bath for another 4 hours. The reaction mixture was cooled to room temperature and then was poured into water. The mixture was extracted with CH2Cl2 (3×100 mL) and then CH2Cl2 layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (95/5), followed by recrystallization from ethyl acetate, to afford 1.0 g of 1-ethyl-N-[4-[2-(4-morpholinyl)ethoxy]phenylmethyl]-1H-pyrazolo[3,4-b]quinolin-4amine, as a yellow solid, m.p. 170°-172° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 24.2 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.1 mmol) was reacted with benzenesulfonyl chloride (0.51 mL, 4.0 mmol) to provide 0.35 g of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as a yellow crystalline solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[CH3:33][C:34]1[N:35]=[C:36]([CH2:39][NH2:40])[NH:37][CH:38]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH2:39][C:36]1[NH:37][CH:38]=[C:34]([CH3:33])[N:35]=1)=[O:5]
Reactant: Cc1c[nH]c(CN)n1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), C-(4-methyl-1H-imidazol-2-yl)-methylamine hydrochloride (5.15 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((4-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (5.5 mg, 10.07 μmol, 21.71% yield): LCMS=525.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (2 H, d, J=8.53 Hz), 7.48-7.72 (8 H, m), 6.64 (1 H, d, J=1.00 Hz), 5.17 (1 H, s), 4.28-4.53 (2 H, m), 2.18 (3H, d, J=1.00 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[NH:13][N:12]=[CH:11][CH:10]=1)=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[Cl:1][CH2:2][C:3]1[S:23][C:7]([C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)=[N:6][N:5]=1
Reactant: O=C(CCl)NNC(=O)c1ccn[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: ClCc1nnc(-c2ccn[nH]2)s1
Yield: 55.8 %

Procedure:
N′-(2-chloroacetyl)-1H-pyrazole-5-carbohydrazide (110 mg, 0.54 mmol) and Lawesson's reagent (220 mg, 0.54 mmol) were suspended in THF 5.5 mL and then heated to reflux for 3 hr. The reaction mixture was concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt and hexanes to give the title compound as white solid (60.5 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: COc1cc(Cl)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Cl)ccc1Cc1ccncc1
Yield: 34.6 %

Procedure:
A mixture of 1-bromomethyl-4-chloro-2-methoxy-benzene (50 mg, 0.21 mmol), 4-pyridyl boronic acid (39 mg, 0.32 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol) and 2M Na2CO3 were combined in DME (2 mL), purged with N2, and heated to reflux for 3 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 17 mg (33%) of the title compound. MS (ESI) m/e 234 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Oc1cccnc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (250 mg) was reacted with 3-hydroxypyridine to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide (112.6 mg).