Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:18])[C:14]([O:16]C)=[O:15].[OH-].[K+].Cl>O>[Br:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH:13]([CH3:18])[C:14]([OH:16])=[O:15]
Reactant: COC(=O)C(C)c1cn(C)c2c(F)cc(Br)c(OC)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(Br)cc(F)c2c1c(C(C)C(=O)O)cn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 9-2 (0.5 g, 1.5 mmol) in water (10 mL) was added 2N KOH (10 mL). The mixture was stirred at room temperature for 1 h. The mixture was neutralized with HCl to pH:5. The precipitate was filtered and dried. 9-3 (210 mg, crude) was obtained as a yellow solid.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH:14]([C:17]1[CH:18]=[C:19]([CH:23]([CH3:27])[CH2:24][CH:25]=[O:26])[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]>C(O)(C)C.CCOCC>[CH:14]([C:17]1[CH:18]=[C:19]([CH:23]([CH3:27])[CH2:24][CH2:25][OH:26])[CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)CCO)c1
Yield: 73.7 %

Procedure:
To a refluxing solution of 132.8 g aluminum isopropoxide in 800 ml of isopropanol, a solution of 300 g of 3-(3-isopropylphenyl)butanal in 200 ml of isopropanol was dropped in. The resulting solution was refluxed for 1.5 hours, then cooled and diluted with ether. Then, the organic phase was washed with brine, dried, and evaporated to dryness. The resulting oil was distilled to yield 223.5 g of a colorless oil.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccccc2)CC1
Yield: 83.5 %

Procedure:
To a stirred solution of 1-(2-tert-butylphenyl)piperazine dihydrochloride (0.150 g, 0.52 mmol) and pyridine (0.166 g, 2.13 mmol) in dichloromethane (5 mL) was added benzoyl chloride (0.079 g, 0.56 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 90:10 to 70:30 heptanes/ethyl acetate, gradient elution) to provide [4-(2-tert-butylphenyl)piperazin-1-yl](phenyl)methanone (0.140 g, 83%) as a white powder, mp 104-106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1>ClCCl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: Nc1cccc(Br)n1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(Br)n1)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3-fluorobenzenesulfonyl chloride (684 mg, 370 μl, 2.5 mmol) in dichloromethane (2 ml) was added slowly at room temperature to a solution of 2-amino-6-bromopyridine (346 mg, 2.0 mmol) in pyridine (2 ml). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase washed with water (×2), separated, dried and evaporated. Purification by column chromatography eluting with 20-60% ethyl acetate in hexanes afforded the title compound (D1), MS (ES+) m/e 409, 411, 413 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[F:43][C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[N:48][CH:49]=1>>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]2[CH:3]=[C:2]([C:46]3[CH:47]=[N:48][CH:49]=[C:44]([F:43])[CH:45]=3)[CH:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[N:18]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Product: COc1ccc(Nc2ncc(-c3cncc(F)c3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoropyridin-3-ylboronic acid (Combi-Blocks Inc.), and was isolated as an orange crystalline solid (22%). m/z (ESI, +ve ion) 405.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.90 (1H, s); 9.09 (1H, d, J=2.7 Hz); 8.80 (1H, s); 8.75 (1H, d, J=2.7 Hz); 8.56 (2H, t, J=2.5 Hz); 8.19 (1H, dd, J=8.9, 2.8 Hz); 8.10 (1H, br. s.); 7.92 (1H, br. s.); 7.77 (1H, br. s.); 6.86 (1H, d, J=9.0 Hz); 3.86 (3H, s), 2.47 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])(=O)=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]([C:16]1[CH:17]=[C:18]([OH:23])[C:19]([OH:22])=[CH:20][C:21]=1[Cl:27])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN(C(=O)OCc1ccccc1)c1ccc(O)c(O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1cc(O)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Benzyloxycarbonyl 3,4-dihydroxyphenylglycine (0.79 g, 2.5 mmole) in acetic acid (10 ml) was treated with sulphuryl chloride (0.2 ml), stirred at room temperature for two hours then diluted with ethyl acetate (50 ml), washed with water (2×3 ml) and brine (20 ml), dried and evaporated to a gum which was crystallized from chloroform, 0.36 g, 41%, mp 141°-143°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](Br)=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[N:22]([C:24](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1Br
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn2c1/C=C/C(N)=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
200 mg (0.375 mmol) {1-[4-(3-Bromo-2-methyl-7-phenyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutyl}-carbamic acid tert.-butyl ester, (intermediate example Int-2-3), 53.3 mg (0.75 mmol) acrylamide, 19.4 mg (0.064 mmol) tri-2-tolylphosphane, 16.8 mg (0.075 mmol) palladium(II) acetate and 0.06 mL (0.427 mmol) triethylamine in 2.6 mL degassed acetonitrile were heated in the microwave at 110° C. for three hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated, washed with brine, dried, and the solvent was removed. The crude product (247 mg) was used in the next step without further purification.
Reaction SMILES: C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)OC1O)(=[O:3])C.[C:25]1([P:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:38]1([P:31](=[O:3])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 15 h

Procedure:
To a solution of the compound of Preparation A (0.927 mmol), dissolved in 40 ml of dry tetrahydrofuran, there are added 2,3,4,6-tetra-O-acetylglucopyranose (1.95 mmol) and triphenylphosphine (1.95 mmol). The reaction mixture is cooled to −78° C., and then DEAD (1.95 mmol) is added dropwise. The temperature is slowly raised to ambient temperature, and the reaction mixture is then stirred for a further 15 hours. After hydrolysis, the organic product is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and filtered, and the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 65/35, and then toluene/ethyl acetate 3/2), the β-glycosylated compound is obtained in the form of yellow crystals and the α-glycosylated compound is obtained in admixture with triphenylphosphine oxide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=[N:18][OH:19])=[CH:7][C:6]=1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: NO
Reactant: COc1cc(C=CC=O)ccc1OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=CC=NO)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
4-Acetoxy-3-methoxycinnamaldehyde (2.0 g, 9.1×10-3M) is dissolved in methanol (100 ml) and cooled to 0° C. with an ice/water bath. Hydroxylamine hydrochloride (0.8 g, 1.2×10-2M) is added with sodium acetate (0.97 g, 1.2×10-2M) and stirred for one hour. The reaction mixture is concentrated to near dryness, and redissolved in ethyl acetate (150 ml). The residual organics are washed twice with water dried over sodium sulfate, filtered, evaporated to dryness, and chromatographed on flash silica using hexane:ethyl acetate 3:1 to afford 1.45 g of 4-acetoxy-3-methoxycinnamaldehyde oxime in 68% yield; mp=72°-74° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[Cl-].[OH:13][NH3+:14].N1C=CC=CC=1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[N:14][OH:13]
Reactant: O=Cc1cc2ccccc2o1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Product: ON=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.9 %

Procedure:
To a solution of 2-benzofuran carbaldehyde (1.00 g, 6.85 mmol) in methanol (20 ml) were added hydroxylammonium chloride (530 mg, 7.63 mmol) and pyridine (2.8 ml), followed by stirring at room temperature for 6.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing sequentially with a 5% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (1.07 g) as a white solid. (Yield: 97%)
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].N[CH2:22][CH2:23][SH:24].C(O)C>O>[S:24]1[CH2:23][CH2:22][N:2]=[C:1]1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: NCCS
Solvent: O
Solvent: CCO
Product: O=S(=O)(Nc1cccc2cc(C3=NCCS3)[nH]c12)c1cccs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.54 g), 2-aminoethanethiol (0.14 g) and ethanol (20 mL) was stirred at 60° C. overnight. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography, and eluted with ethyl acetate. The eluate was treated with activated carbon and concentrated to give the title compound (0.19 g, yield 29%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 189-190° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=12.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=1>>[CH:14]1([CH2:13][N:8]2[C:7]3=[C:2]([O:26][CH2:25][C:24]4[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=4)[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]2[CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1c(C)n(CC2CCCCC2)c2c(Cl)nncc12
Reactant: OCc1ccc(F)cc1
Product: Cc1c(C)n(CC2CCCCC2)c2c(OCc3ccc(F)cc3)nncc12
Yield: 45.6 %

Procedure:
The title compound was prepared as a white powder in 45.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-1-cyclohexylmethyl-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4-fluorobenzyl alcohol.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]([NH2:37])=[S:36])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:45][C:46](=O)[CH3:47].O>C(O)C>[CH2:39]([N:20]1[C:19]([CH2:18][NH:17][C:16](=[O:43])[O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]3[S:36][CH:45]=[C:46]([CH3:47])[N:37]=3)[CH:26]=2)[C:21]1=[O:38])[CH:40]([CH3:41])[CH3:42]
Reactant: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Reactant: CC(=O)CBr
Solvent: CCO
Solvent: O
Product: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Yield: 81.9 %

Procedure:
A suspension of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.47 g, 0.8 mmol) and bromoacetone (0.22 g, 1.6 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl. acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl [2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.41 g, 82.0%) as an amorphous.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1)=O)(C)(C)C>O1CCCC1.[OH-].[K+]>[C:18]1([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26]4[S:39][CH:38]=[CH:37][C:27]=4[NH:28][N:29]=2)=[CH:10]3)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(=O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy-phenyl-methyl)-indole-1-carboxylic acid tert-butyl ester [640 mg, 1.17 mmol, Intermediate (12)] in Dichloromethane (25 mL) is added Dess-Martin Periodinane (677 mg, 1.69 mmol) and stirred at room temperature. After 30 minutes water (5 mL) is added and stirred for 10 minutes. The reaction mixture is diluted with dichloromethane (50 mL) and washed twice with a mixture of 10% Na2S2O3/saturated NaHCO3 (5 mL), NaHCO3 (10 mL), water (10 mL), brine and dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge, eluting with 30% ethyl acetate/Heptane to afford 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [440 mg, 69%, Intermediate (13)] as a white solid; LC/MS: 544 (M+H). Step 2. A mixture of 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [122 mg, 0.224 mmol, Intermediate (13)] in tetrahydrofuran (9 mL) and 1M KOH(aqueous, 2 mL) is heated at 60° C. oil bath overnight. The solvent is removed and added water (5 mL). The water layer is neutralized with 3N hydrochloric acid and extracted three times with ethyl acetate (20 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel cartridge, eluting with 50 to 100% ethyl acetate gradient in heptane to afford phenyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-methanone (58 mg, 75%, Example 25) as a pale yellow solid; 1H NMR [(CD3)2SO)]: δ 13.38 (1H, s), 12.09 (1H, s), 8.05 (1H), 7.78 (8H, m), 7.23 (1H, d, J=5.2 Hz), 6.87 (1H); LC/MS: 344 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH:8]([CH2:10][CH3:11])[CH3:9])=[CH:4][CH:3]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]([CH2:10][CH3:11])[CH3:9])[C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:22])=[CH:12][CH:13]=1
Reactant: CCC(C)NCc1ccc(Br)cc1
Reactant: O=C=Nc1ccccc1
Product: CCC(C)N(Cc1ccc(Br)cc1)C(=O)Nc1ccccc1
Yield: 90.7 %

Procedure:
The following procedure described in Example 1, process variant (a), 48 g (0.2 mole) of N-(4-bromobenzyl)-N-sec.-butylamine were reacted with 24 g (0.2 mole) of phenyl isocyanate. 65.5 g of N-(4-bromobenzyl)-N-sec.-butyl-N'-phenylurea were obtained. Yield: 91%. Melting point: 86°-88° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2ccccc2n1

Procedure:
29.89 g of quinoline-2-carboxylic acid were heated under reflux for 51/2 hours in 450 ml of ethanol with the addition of 3.5 ml of sulfuric acid. The reaction mixture was worked up by evaporating it, taking up the residue in water and extracting the mixture with dichloromethane. The organic phase was washed with aqueous sodium bicarbonate solution and then with water until neutral, dried and evaporated. 32.23 g of crude ethyl quinoline-2-carboxylate were obtained as a green oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1F.[CH2:32]([NH2:34])[CH3:33].O>C(#N)C>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]([F:17])([C:9]([F:11])([F:10])[F:12])[C:13]([F:16])([F:15])[F:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[NH:34][CH2:32][CH3:33]
Reactant: CCN
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc([N+](=O)[O-])ccc1F
Solvent: CC#N
Solvent: O
Product: CCNc1ccc([N+](=O)[O-])cc1C(=O)Nc1c(C)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-fluoro-5-nitrobenzamide (5.0 g, 11 mmol) (see Example I4) in acetonitrile (100 ml) was added a solution of N-ethylamine in water (70% by weight) (2.23 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-2-ethylamino-5-nitrobenzamide (4.8 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]2)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=1[OH:44]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc(Cl)c1O

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.055 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 1.0 mmol) followed by formation of the dihydrochloride salt to afford the desired product (18 mg, 59%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.49 (d, J=8.9 Hz, 1H), 8.32 (d, J=9.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 5.80-5.70 (m, 1H), 4.03 (s, 3H), 3.08 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.76 (s, 3H), 2.49-2.39 (m, 2H), 2.08-1.96 (m, 3H), 1.72-1.62 (m, 2H), 1.47-1.35 (m, 2H). ESI MS m/z 483 [M+H]+; HPLC>99% (AUC), tR=9.62 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.N1C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)Nc1cccc(O)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2cccc(NC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Hydroxyphenyl)urea (2.00 g), p-tolylboronic acid (3.57 g), and Cu(OAc)2 (2.63 g) were dissolved in 150 mL of THF, and 5.32 mL of pyridine was added. The reaction was stirred at room temperature overnight, then filtered through Celite with the aid of 200 mL EtOAc. The filtrate was washed with water, 0.2N CuSO4, 0.5N NaOH, and brine, and dried over Na2SO4 The solution was concentrated to a solid that was taken up in 200 mL of dichloromethane and stirred at room temperature for about 1 hour, after which time it was filtered to give 1-(3-(p-tolyloxy)phenyl)urea as white solid. The material was used in Step B without further purification.
Reaction SMILES: [CH:1]([NH:3][NH:4][S:5]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:6])=O.O.[C:17]([OH:21])(=[O:20])C=O>Cl.O>[CH:8]([S:5]([NH:4][N:3]=[CH:1][C:17]([OH:21])=[O:20])(=[O:7])=[O:6])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC(=O)O
Reactant: O=CNNS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)C=NNS(=O)(=O)C=Cc1ccccc1
Reaction time: 4.5 h
Yield: 53.6 %

Procedure:
In this operation a suspension of 1-formyl-2-(β-styrenesulfonyl)hydrazine (4.98 g, 22 mmol) in 6 N HCl (44 cc) was stirred for 4.5 hr at 50°-55° C. After cooling a small amount of insoluble material was removed by filtration. The filtrate was added all at once to a stirred solution of glyoxylic acid monohydrate (2.4 g, 26 mmol) in water (180 cc), and stirring was continued for 3 hr. The white crystalline solid which had precipitated was collected by filtration and air dried to give 3.0 g of the product compound, m.p. 141° (dec.).