Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].O=[O+][O-].[C:17]([OH:36])(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=C\CCCCCCCC>>[C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:17]([OH:36])(=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=C(O)CCCCCCCC(=O)O
Agent: O=[O+][O-]
Product: CCCCCCCCC(=O)O

Procedure:
The azelaic acid component of the present invention may be obtained via any number of methods. One method involves the ozone oxidation of oleic acid. According to this method, oleic acid is oxidized using ozone to form azelaic acid and pelargonic acid. The preparation of azelaic acid is disclosed in U.S. Pat. No. 2,813,113, the entire contents of which are incorporated herein by reference. The azelaic acid produced is di-basic and has a melting point of about 102° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=C)[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].I([O-])(=O)(=O)=[O:38].[Na+]>O1CCOCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:38])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: C=Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C=O)c2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (240 mg, 0.420 mmol) and sodium periodate (270 mg, 1.261 mmol) in dioxane (5 mL) and water (3 ml) was added osmium tetroxide (2.5% solution in t-butanol) (0.106 ml, 8.44 μmol) and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with EtOAc, washed with water and the solvent was removed. The crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (189 mg, 0.330 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.92 (s, 1H), 8.79 (t, 1H), 8.00 (s, 1H), 7.65-7.82 (m, 1H), 7.48-7.57 (m, 1H), 7.37-7.49 (m, 2H), 7.28 (d, 1H), 5.51 (s, 2H), 4.51 (d, 2H), 3.21-3.60 (m, 2H), 0.77 (t, 2H), −0.07 (s, 9H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:12][N:13](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.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>[OH:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH:3]=1)[C:12]#[N:13]
Reactant: COc1ccc(CO)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Product: COc1ccc(CO)cc1C#N
Temperature: 80 °C
Reaction time: 48 h
Yield: 51 %

Procedure:
To a solution of (3-bromo-4-methoxy-phenyl)-methanol (1 g, 4.607 mmol) in dimethylformamide (10 mL) at room temperature was added zinc cyanide (324.5 mg, 2.764 mmol). The reaction mixture was degassed by passing argon through for 30 min before tetrakis(triphenylphosphine)palladium (319 mg, 0.276 mmol) was added. The reaction mixture was heated at 80° C. for 12 h and stirred at room temperature for 2 d. It was diluted with diethyl ether (50 mL) and washed with sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 40% ethyl acetate in hexanes yielded 5-hydroxymethyl-2-methoxy-benzonitrile (385 mg, 51%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.C[N:37](C=O)C>ClCCCl.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH2:37])=[O:28])=[N:25][CH:26]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)nc3)n2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(N)=O)nc3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylic acid (Intermediate 124, 50 mg, 128 μmol) in DCE (10 mL) and DMF (100 μL) was added oxalyl chloride (22 μL, 256 μmol). The resulting solution was stirred at room temperature for 2 h, evaporated to dryness and re-suspended in a solution of ammonia in dioxane (7N, 10 mL). The reaction mixture was stirred overnight at room temperature and then poured into water (50 mL). The mixture was extracted with DCM (3×50 mL) and the combined organics were dried and concentrated under vacuum to afford a crude yellow solid. The crude material was suspended in MeOH, filtered and washed with further MeOH. The resulting solid was recrystallised in dioxane and water to afford the title compound as a white solid (15 mg, 30%).
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][O:12][CH3:13].[Br:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][OH:25])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27].O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:14][C:15]1[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]2[O:22][C:21]([CH2:24][O:25][CH2:11][O:12][CH3:13])([CH3:23])[CH2:20][C:19]=2[C:26]=1[CH3:27]
Reactant: COCCl
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOCC1(C)Cc2c(C)c(Br)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
Ethyldiisopropylamine (1.26 g, 9.74 mmol) and chloromethylmethylether (627 mg, 7.79 mmol) were serially added to a solution of THF (15 mL) containing (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.85 g, 6.49 mmol) synthesized in Reference Example 123 under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 15 hours. Ethyldiisopropylamine (1.26 g, 9.74 mmol) and chloromethylmethylether (523 mg, 6.49 mmol) were further added serially to the reaction solution under ice-cooling condition, and the mixture was warmed to room temperature and stirred for 15 hours. The reaction solution was poured into saturated sodium bicarbonate water, and THF was removed under reduced pressure, followed by extraction using ethyl acetate. The extract was washed with saturated saline and dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 96:4-80:20) to give 1.62 g of the title compound as an oily product (yield: 76%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:33])[C:31]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:31]3[C:30]([Cl:33])=[CH:29][N:28]=[CH:27][C:26]=3[Cl:25])[CH2:2][CH2:3]2)=[O:8])[CH2:14][CH2:13]1)=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCNCC2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCN(C(=O)C2CCN(c3c(Cl)cncc3Cl)CC2)CC1
Yield: 36.8 %

Procedure:
General procedure C (See Example 1) was followed using benzyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate 12 (0.11 g, 0.33 mmol), 3,4,5-trichloropyridine (61 mg, 0.33 mmol), NMP (2.5 mL) and triethylamine (93 μL, 0.66 mmol). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 1:1) to furnish the title compound 13 as a white solid (58 mg, 36%), umax (CHCl3)/cm−1 3023, 1699, 1635, 1559, 1432, 1285, 1232, 1015; m/z (ESI) C23H27Cl2N4O3 requires 477.1455, found [M+H]+ 477.1457.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:41]1[N:46]=[CH:45][CH:44]=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: Clc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2c1ncccn1)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A solution of amine 84 (325 mg, 0.59 mmol) in DMF (8 mL) was treated with 2-chloropyrimidine (88 mg, 0.76 mmol) and DIPEA (0.15 mL, 0.88 mmol) and heated to 80° C. in an oil bath. After 18 h, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with Et2O (3×). The combined organic extracts were washed successively with water (3×), and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 89 (341 mg, 92%) as an orange-colored solid that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ8.67 (d, J=4.8 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.30 (t, J=4.8 Hz, 1H), 7.08-6.87 (m, 1H), 6.86 (br s, 1H), 6.79-6.72 (m, 1H), 6.67-6.49 (m, 2H), 4.74-4.53 (m, 3H), 4.40-4.36 (m, 0.5H), 4.19-4.17 (m, 0.5H), 4.08-3.93 (m, 3H), 3.86-3.80 (m, 1H), 3.68-3.54 (m, 1H), 3.49-3.99 (m, 1H), 3.27-2.89 (m, 2H), 2.79 (s, 3H), 2.48-2.44 (m, 1.5H), 2.21-2.11 (m, 0.5H), 2.01-1.84 (m, 2H), 1.50-1.48 (m, 9H), 1.34-1.30 (m, 3H), 1.03-0.95 (m, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[CH:29][C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 50%).
Reaction SMILES: [N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[CH:17][C:16]=3[N:15]=[C:14]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:1]1([C:7](=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[C:17]([NH2:42])[C:16]=3[N:15]=[C:14]2[CH2:26][CH2:27][CH3:28])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinoline (3.6 g, 9.1 mmol) in chloroform (100 mL) was treated with mCPBA (6.29 g, 36.5 mmol). The reaction was stirred for two hours, washed sequentially with saturated aqueous sodium bicarbonate (3×) and brine, dried over magnesium sulfate, and filtered. Concentrated ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.60 g, 13.7 mmol) were added sequentially to the filtrate. The reaction was stirred vigorously for two hours, and then the organic layer was separated and washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) followed by recrystallization from ethyl acetate:hexane to provide 0.84 g of 1-(6-morpholin-4-yl-6-oxohexyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 149-151° C.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 53 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-pentyl chloroformate. Yield: 53% of theory, C35H42N6O6 (642.7) Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1 ##EQU140##
Reaction SMILES: [N:1]1[N:9]2[C:4]([CH2:5][CH2:6][S:7][CH2:8]2)=[CH:3][C:2]=1[CH2:10][OH:11]>C(Cl)(Cl)Cl.O=[Mn]=O>[N:1]1[N:9]2[C:4]([CH2:5][CH2:6][S:7][CH2:8]2)=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CSCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CSCC2

Procedure:
To a 17.2 gram of the crude (4,5-dihydro-6-thia-1,7a-diazainden-2-yl)methanol in 520 mL of CHCl3 was added activated MnO2 (88.0 g) under a nitrogen atmosphere at room temperature, and then refluxed for 2 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was applied to silicagel column chromatography, and then the column was eluted with hexane-AcOEt (2:1). The titled compound was obtained as yellow crystals (13.0 g, 74.5%)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].O1CCCC1.[OH-].[Na+].Cl>CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:4])=[O:2])=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a mixture of the compound obtained in Example 22 (3) (0.26,g), tetrahydrofuran (5 ml) and methanol (10 ml), a 1N aqueous sodium hydroxide solution (5 ml) was added at 15 to 30° C. and the mixture was stirred for 2 hours. 1N hydrochloric acid was added thereto and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 0.25 g of the desired product as a white crystal.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O.C(OCC)(=O)C.S(=O)(=O)(O)O>O1CCCC1.O>[C:17]1([CH:14]2[CH2:15][CH2:16][CH:11]([CH2:9][OH:8])[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCC(c2ccccc2)CC1
Temperature: 55 °C
Yield: 92.2 %

Procedure:
Dry tetrahydrofuran (THF) (420 ml) was added to lithium aluminum hydride (11.1 g, 0.293 mol), and while the mixture was vigorously agitated, there was dropwise added a solution obtained by dissolving trans-4-phenylcyclohexanecarboxylic acid methyl ester (II) (64.0 g, 0.293 mol) in THF (70 ml), at a reaction temperature kept at 20° C. or lower. After completion of the addition, the reaction mixture was warmed up to 55° C., followed by reacting it for 2 hours and cooling. Ethyl acetate (12 ml) and water (100 ml) were then added, followed by adding a 1N aqueous solution of sulfuric acid (350 ml) to dissolve inorganic matter, separating the resulting organic layer and aqueous layer from one another, adding n-heptane (200 ml) to extract the organic layer, washing the extract solution with water (500 ml), then washing with a 2% aqueous solution of Na2CO3, further washing with water until the aqueous layer became neutral, distilling off n-heptane and THF, recrystallizing the resulting solid as residue from n-heptane (20 ml), filtering off crystals and drying to obtain 4-phenylcyclohexylmethanol (III) (51.4 g). M.P. 47.3°~48.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:54][NH:55][O:56][CH3:57].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:15]([N:55]([CH3:54])[O:56][CH3:57])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CNOC
Reactant: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)OC
Reaction time: 0.05 h

Procedure:
To 400 μL CH2Cl2 was added 47.4 mg (200 μmole) of EtOCO-Phe, 34.8 mL (200 μmole) DIEA, and 88.4 mg (200 μmole) BOP. After 3 min, 19.4 mg (200 μmole) N,O-dimethyl-hydroxylamine.HCl and 34.8 mL (200 μmole) DIEA were added. The reaction was monitored by TLC, and after 45 min it was diluted with CH2Cl2, washed 2× with dilute HCl and 2× with saturated NaHCO3. The organic layer was dried with Na2SO4, filtered, and the filtrate evaporated by rotary evaporation to give the title compound. NMR (300 MHz, CDCl3): δ 7.20 (m, Ph, 5H), 4.82 (br m, Phe-α, 1H), 4.00 (q, CH3 CH2OCO, 2H), 3.62 (s, N(CH3)OCH3, 3H), 3.11 (s, N(CH3)OCH3, 3H), 3.00 (dd, Phe-b, 1H), 2.85 (dd, Phe-b, 1H), 1.17 (t, CH3CH2OCO, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)=N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)N2
Yield: 92.7 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-3,4-dihydroquinoline-6-carboxylate (152 mg, 0.33 mmol) and 10% Pd/C (100 mg) in methanol (3 mL) and tetrahydrofuran (3 mL) was hydrogenated by a H2 balloon at 30° C. After filtration, the filtrated was concentrated and purified on preparative Thin layer chromatography to afford 140 mg of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. (Yield: 92%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:20]=[C:21]5[CH:27]=[N:26][N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]5=[N:23][CH:24]=4)[CH:15]=[C:14]([NH2:37])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51](Cl)=[O:52])[N:50]=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:44][CH2:45][C:46]1[S:47][CH:48]=[C:49]([C:51]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:20]=[C:21]4[CH:27]=[N:26][N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[C:22]4=[N:23][CH:24]=3)[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:52])[N:50]=1
Reactant: Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2cnc3c(cnn3S(=O)(=O)c3ccccc3)c2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-1H-indazol-4-amine (185 mg, 0.349 mmol) was dissolved in DCM (3 ml) and pyridine (0.034 mL, 0.418 mmol) was added. The mixture was cooled to 0° C. in an ice bath and 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (77 mg, 0.349 mmol) in DCM (3 ml) was added dropwise over 5 mins. The mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added. The mixture was stirred for 2 hours, letting the ice melt over this time. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (38.4 mg, 0.174 mmol) in DCM (1.5 ml) was added and stirring continued with monitoring by LCMS. The mixture was diluted with DCM (10 ml), saturated aqueous sodium bicarbonate (10 ml) was added and the mixture stirred vigorously for 10 mins. The organic layer was separated, washed with water (10 ml), passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in DMSO and loaded onto a 43 g C18 Reverse Phase RediSep column that was then eluted with 30-85% acetonitrile (+0.1% TFA)/H2O (+0.1% TFA) over 30 mins. The product-containing fractions were combined and concentrated in vacuo to give a cream solid which was then dried on the vacuum line for 1 hour to give the title compound (54 mg).