Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH:27]([Si:30]([CH:50]([CH3:52])[CH3:51])([CH:47]([CH3:49])[CH3:48])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[CH:39]=2)=[CH:34][CH:33]=1)([CH3:29])[CH3:28].C1COCC1>ClC(Cl)C.CN(C=O)C.Cl[Ti](Cl)(Cl)Cl>[CH:50]([Si:30]([CH:27]([CH3:29])[CH3:28])([CH:47]([CH3:49])[CH3:48])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:4]([O:3][CH3:2])[CH:5]=2)=[O:9])=[CH:34][CH:33]=1)([CH3:52])[CH3:51]
Reactant: COc1cc(C(=O)O)ccc1OCCN1CCCC1
Reactant: CC(C)[Si](Oc1ccc(-c2cc3ccccc3s2)cc1)(C(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3)sc3ccccc23)ccc1OCCN1CCCC1
Temperature: 25 °C

Procedure:
A slurry of 4.34 g (14.4 mmol) of 3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride (Part G, below) in 75 mL of dichloroethane was treated with 2 drops of DMF followed by 5.00 mL (57.3 mmol; 4 eq) of oxalyl chloride. The reaction was stirred at ambient temperature until gas evolution ceased and was concentrated in vacuo. The solid was reconstituted in 75 mL dichloroethane. The mixture was cooled to 0° C., treated with 5.00 g (13.0 mmol; 0.9 eq) of 2-(4-triisopropylsilyloxyphenyl)benzo[b]thiophene (Part B) and 6.40 mL (58.4 mmol; 4 eq) of TiCl4, and stirred at ambient temperature for 5 h. The reaction was quenched by the addition of 50 mL of sat'd aq NaHCO3. The two layers were separated and the aqueous layer was extracted with EtOAc (4×25 mL). The combined organic layers were washed with H2O (50 mL), dried over K2CO3, filtered, and concentrated in vacuo to give an oil. Flash chromatography (SiO2; 15% THF and 5% TEA in hexanes) afforded 5.60 g (8.90 mmol; 62%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1C(C)=[CH:6][S:5][C:4]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[CH2:15]([Cl:17])[Cl:16].C(=O)(O)[O-].[Na+]>O>[ClH:16].[NH2:2][C:3]1[C:15]([Cl:17])=[CH:6][S:5][C:4]=1[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: ClCCl
Reactant: Cc1csc(C(=O)OC(C)C)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)c1scc(Cl)c1N
Reaction time: 8 h

Procedure:
11.75 g (50 mmol) of i-propyl 3-amino-4-methyl-thiophene-2-carboxylate hydrochloride are dissolved in 100 ml of water. 150 ml of methylene chloride are added to this solution, and sodium bicarbonate is then added a little at a time until a pH of 7 has been exceeded. The mixture is stirred for 8 hours and the organic phase is separated off, washed with water, dried with magnesium sulphate and filtered. The filtrate is concentrated using water pump vacuum and the amorphous residue is crystallized from petroleum ether.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([NH:11][C:12](=[O:37])[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][C:5]=1[CH3:38].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:3][C:4]1[C:5]([CH3:38])=[CH:6][C:7]([NH:11][C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22](=[O:36])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:19][CH2:20]2)=[O:37])=[C:8]([CH3:10])[CH:9]=1
Reactant: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoic acid methyl ester (49.8 g, 93.9 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C. and lithium aluminum hydride (10.7 g, 281.7 mmol) added portion-wise (10×1.07 g). The resulting mixture was stirred for 3 hours and then water (10.7 mL) was added, followed by 1N aqueous sodium hydroxide (10.7 mL) and additional water (32.1 mL). This mixture was stirred overnight and then filtered. The organic layer was concentrated under vacuum and the residue was mixed with ethyl acetate (about 5:1 v/w ethyl acetate to residue). This mixture was heated until all the solid material dissolved and then the solution was allowed to cool to room temperature. The resulting precipitate was filtered and dried to afford biphenyl-2-ylcarbamic acid 1-[2-(4-hydroxymethyl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (24.6 g, 95% purity, 47.5% yield). This material was used without further purification. m/z: [M+H+] calcd for C30H35N3O4 502.62; found 502.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (3.0 g, 12.5 mmole) and N-(benzyloxycarbonyloxy)-succinimide (3.42 g, 13.7 mmole) were mixed in 15 ml of dichloromethane. The mixture was stirred at room temperature overnight and then concentrated under vacuum to provide the crude product. The residue was purified by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.29-7.43 (m, 5H) 5.13 (s, 2H) 4.15-4.33 (m, 1H) 3.39-3.74 (m, 5H) 3.20-3.37 (m, 1H) 2.84-2.96 (m, 1H) 1.92-2.03 (m, 1H) 1.66-1.82 (m, 1H) 1.46 (s, 9H). MS: (M+H)+=347.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][NH2:17]>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:17][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CN
Reactant: O=C1CCC(c2ccc(CO)cc2)CC1
Product: CN[C@H]1CC[C@H](c2ccc(CO)cc2)CC1

Procedure:
from 4-(4-hydroxymethylphenyl)cyclohexanone and methylamine. Melting point: 131°-134° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[N:5]2[N:9]=[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:11]([C:12]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])=[C:4]2[CH:3]=1.[CH3:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[C:17]([O:16][C:15]([N:14]([CH3:22])[C:12]([C:11]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:9][N:5]2[C:6]([F:8])=[CH:7][C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][C:31]=3[CH3:30])[C:35]([OH:37])=[O:36])=[CH:3][C:4]=12)=[O:13])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a degassed mixture containing tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate (0.060 g, 0.14 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.047 g, 0.18 mmol), sodium carbonate (0.043 g, 0.43 mmol), dioxane (1.2 mL) and water (0.24 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.005 g, 0.004 mmol). The mixture was stirred at 95° C. for 18 h. The mixture was cooled to room temperature, filtered to remove solids and adjusted to below pH 4 with 1N aqueous hydrochloric acid (2.0 mL). Water was added (10 mL) and the aqueous portion was extracted with ethyl acetate (2×15 mL). The combined organic portions were washed with brine (20 mL) and dried over magnesium sulfate. The mixture was filtered and concentrated to afford 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid as a residue which was used without further purification. LCMS retention time: 2.725 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 522 (MH+).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]([F:37])([F:39])[F:38])=[C:29]([CH:33]=1)[C:30]([NH:2][CH2:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][CH:5]=1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Reactant: NCc1cccc(=O)[nH]1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NCc1cccc(=O)[nH]1)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of the crude product from Example 3, 20 ml of acetone and 4.7 g of sodium carbonate was added dropwise 2.8 g (8.21 mmole) of 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoyl chloride in 10 ml of acetone. The mixture was stirred at about 20° C. for about 16 hours. To the mixture was added 50 ml of acetone, and the resulting inorganic residue was separated by filtration and washed with acetone. The filtrate and washings were combined and evaporated. This residue was dissolved in benzene, and the solution was washed sequentially with 10% aqueous sodium carbonate solution, 2% acetic acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, and then filtered and evaporated. The residue was boiled in carbon tetrachloride, and the mixture was cooled and the solid was separated by filtration. The solid was purified by chromatography on 30 g of silica gel. The column was eluted sequentially with 5% ethyl acetate in dichloromethane and 2% methanol in dichloromethane. The product was obtained as a white solid, 6-[5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzamidomethyl]-2(1H)-pyridone. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [N:1]([C:4]1[N:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)([CH3:11])[CH3:10])=[CH:7][N:8]=1)=[N+]=[N-]>CO.C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([C:6]2[N:5]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:4]([NH2:1])=[N:8][CH:7]=2)([CH3:11])[CH3:10])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(C)(C)c2cnc(N=[N+]=[N-])n2-c2ccc(F)cc2)ccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)c2cnc(N)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A solution of 2-azido-5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (0.126 g, 0.33 mmol) was added MeOH-THF (3 mL, 1:1, v/v) was sparged with argon briefly. Next 5% Pd on CaCO3 poisoned with lead was added to the flask, which then was purged with hydrogen and stirred under 1 atm hydrogen. After 3 h, when the reaction was shown to be complete by LCMS, the mixture was filtered through Celite™ and concentrated in vacuo to afford 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-amine (93 mg) as a beige solid. MS (EI) m/z 360 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH2:26][OH:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([N:8]([CH3:23])[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:27][CH2:26][CH2:25][CH2:24][O:22]1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of N-benzyl-N-methyl-2,3-dioxoindoline-5-sulfonamide (2.88 g, 7.8 mmol), 1,3-propane-diol (1.43 mL, 19.5 mmol, 2.5 eq) and para toluene-sulfonic acid hydrate (0.296 g, 1.56 mmol, 0.2 eq) in benzene (135 mL) was refluxed with a Dean Stark Trap for 3.5 hours and stirred at room temperature overnight. The reaction was washed with NaHCO3 (2×), water (2×) and brine (2×) and concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient of 35/65 to 45/55 Pet. ether/EtOAc to give the title compound as a bright yellow solid (1.33 g, 44% yield). NMR (300 MHz, DMSO-d6): consistent.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.CN1CC(=O)OB(/[CH:20]=[CH:21]/[CH3:22])OC(=O)C1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O.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>[CH3:9][C:4]1[CH:3]=[C:2](/[CH:20]=[CH:21]/[CH3:22])[N:7]=[C:6]([NH2:8])[CH:5]=1
Reactant: Cc1cc(N)nc(Br)c1
Reactant: C/C=C/B1OC(=O)CN(C)CC(=O)O1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C/C=C/c1cc(C)cc(N)n1
Temperature: 150 °C
Yield: 59.6 %

Procedure:
6-bromo-4-methylpyridin-2-amine (500 mg, 2.67 mmol), (E)-6-methyl-2-(prop-1-enyl)-1,3,6,2-dioxazaborocane-4,8-dione (1.05 g, 5.35 mmol), cesium carbonate (2.61 g, 8.02 mmol) and tetrakis(triphenylphosphine)palladium (0) (309 mg, 267 μmol) were combined with dioxane (7.4 mL and water (1.5 mL) and the mixture was heated to 150° C. for 60 min in the microwave. The reaction mixture was cooled and then diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with water and brine. The organic phase was concentrated in vacuo and then purified by chromatography (silica, 20% to 60% ethyl acetate in hexanes) to give a residue that was triturated with methanol to obtain a yellow precipitate. This precipitate was collected by filtration and dried to give (E)-4-methyl-6-(prop-1-enyl)pyridin-2-amine (235 mg, 1.59 mmol, 59%) as a yellow oil. MS (EI/CI) m/z: 148.8 [M+H].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH:12]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
To a mixture of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.52 g, 4.93 mmol), 2-bromo-5-nitropyridine (1.00 g, 4.93 mmol) and PdCl2(PPh3)2 (173 mg, 0.246 mmol) under nitrogen was added 1,4-dioxane (30 mL) followed by 3 M aqueous sodium carbonate (4.93 mL, 14.8 mmol). The resulting mixture was degassed with nitrogen for 10 minutes then heated at reflux for 16 hours. On cooling EtOAc (150 mL) was added and the resulting solution was washed with water (3×50 mL), brine (50 mL) then dried (Na2SO4). The volatiles were evaporated under reduced pressure to give a brown solid that was purified using silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound I8 as a yellow solid (1.43 g, 95%); 1H NMR (400 MHz, CDCl3) δ 9.37 (dd, J=2.6, 0.5 Hz, 1H), 8.43 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.95-6.83 (m, 1H), 4.20 (d, J=3.0 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H), 2.70-2.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.140 min; m/z 304 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[C:5]([S:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[N:16]=2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=2[Cl:23])(=[O:36])=[O:35])[CH:3]=[C:4]([Cl:22])[C:5]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=2[N:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a 1M solution of 1-[5-Amino-3-chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone, (265) (4.12 g, 11.19 mmol) in pyridine, obtained from Aldrich, was added 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride (3.75 g, 13.43 mmol) and heated to 90° C. for 1.5 hours. The crude reaction mixture was concentrated under vacuum, partitioned between 2M aqueous HCl (100 mL) and EtOAc (100 mL), and extracted 3 times with EtOAc (100 mL). The combined organic layers were washed twice with saturated aqueous brine (100 mL), dried over Na2SO4, concentrated under vacuum, purified by column chromatography (0–5% Et2O in CH2Cl2), and triturated with CH2Cl2/hexane mixture with 0.5 mL of MeOH added to yield compound 277 (4.9 g, 72%) as an off white solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>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.COCCOC>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
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: O=C1Nc2cccc(-c3ccc(Cl)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.119 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (119 μL , 0.238 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 4-chlorophenylboronic acid (21 mg, 0.134 mmol) (Aldrich) in 4 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by column chromatography. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes elution) provided a crude yellow solid. Recrystallization from chloroform-pentane yielded pure (Z)-4-(4-chlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (34 mg, 89%) as a yellow solid (mp 188-190° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[CH2:20][NH:19][C:18](=[O:21])[C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC(Cl)(Cl)C(O)=[O:27].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[CH:20]([OH:27])[NH:19][C:18](=[O:21])[C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: O=C1NCC2=C1CN=C(c1ccccc1Cl)c1cc(Cl)ccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(O)C2=C1CN=C(c1ccccc1Cl)c1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In one portion, 0.35 g (1 mmol) of 8-chloro-6-(2-chlorophenyl)-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one was added to an ice-cooled solution of 1.3 g (7.9 mmol) of trichloroacetic acid and 1.0 g (2.2 mmol) of lead tetraacetate in 15 ml of methylene chloride. After stirring for 4 hours, the mixture was neutralized with saturated aqueous sodium bicarbonate solution. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 5% methanol in methylene chloride) followed by crystallization from ether gave 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-hydroxypyrrolo[3,4-d][2]benzazepin-3(2H)-one as pale yellow prisms, mp 247°-249° C.
Reaction SMILES: C1(C(Cl)=O)CC1.[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[F:37].C1(C)C=CC=CC=1>C(O)C>[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[CH:7]1([C:10]([NH:12][C:13]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([O:29][C:20]3[C:19]4[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)=[C:31]([F:37])[CH:32]=2)=[S:14])=[O:11])[CH2:9][CH2:8]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)C1CC1
Agent: O=C(N=C=S)C1CC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
1-Cyclopropanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (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 (46 mg, yield 66%).