Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:22]([F:25])([F:24])[F:23])[N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH:8]=[CH:7][C:6]=12.[C-]#N.[Na+].[CH3:29][NH:30]CCNC>C1(C)C=CC=CC=1.[Cu]I>[F:19][C:18]([F:21])([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:5]([C:4]([C:22]([F:24])([F:23])[F:25])=[N:3][C:2]=3[C:29]#[N:30])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: CNCCNC
Reactant: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1nc(C(F)(F)F)n2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 130 °C

Procedure:
1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (50.0 mg, 0.118 mmol), NaCN (7.0 mg, 0.142 mmol, 1.2 equiv.), CuI (2.2 mg, 0.0118 mmol, 0.1 equiv.) and KI (3.9 mg, 0.0236 mmol, 0.2 equiv.) were successively placed in a 5 mL Samith vial. To the vial was added a solution of N,N′-dimethylethylenediamine (10.4 mg, 0.118 mmol, 1.0 equiv.) in toluene (5 mL). The suspension was heated by the microwave reactor (Biotage, Personal Chemistry) at 130° C. for 60 min. The suspension was filtered through Celite (3 g) using EtOAc (70 mL). The solvent was removed from the filtrate under a reduced pressure to give a crude mixture. The crude mixture was purified by a preparative TLC (SiO2=1 plate, EtOAc/hexane=1:7 Rf=0.1) to give 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carbonitrile as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:14]=[C:13]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:39]3[CH:38]=[CH:37][C:36]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:41][CH:40]=3)=[CH:30][CH:29]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenyl-amino}-acetic acid methyl ester (1.4 g, 2.5 mmol) was coupled with 4-cyclohexyl-phenyl boronic acid (615 mg, 3.0 mmol) according to general procedure G to give {4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(4-methanesulfonyl-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([NH2:24])(=[O:23])[CH2:19]C(O)=O.N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:12]=1[OH:13])[CH:8]=[CH:19][C:18]([NH2:24])=[O:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)CC(=O)O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=CC(N)=O)cc(C(C)(C)C)c1O

Procedure:
3.5-di tert.butyl-4-hydroxycinnamamide was prepared by heating a mixture of 23.4 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 31 grams of malonic acid monoamide, 75 milliliters of pyridine, and 3 milliliters of piperidine at 90° to 100° C. for 101/2 hours. The reaction mixture was poured into a solution of 75 milliliters of concentrated hydrochloric acid and 100 milliliters of water. The solid which precipitated was filtered off, dried, and recrystallized from benzene. Ten grams of product was obtained which melted at 217° to 219° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]1[C:8](=[CH:9][C:10](=[O:22])[C:11]3[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=31)[O:7]2)[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26].[C:32](OCC)(=[O:34])[CH3:33].C1(C)C=CC=CC=1>[Zn]>[CH3:26][C:25]([O:22][C:10]1[CH:9]=[C:8]2[C:13]([N:14]([C:32](=[O:34])[CH3:33])[C:15]3[C:6]([O:7]2)=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:23][CH3:24])=[CH:17][CH:16]=3)=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12)=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: CCN(CC)c1ccc2nc3c4ccccc4c(=O)cc-3oc2c1
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc2c(c1)Oc1cc(OC(C)=O)c3ccccc3c1N2C(C)=O
Temperature: 80 °C

Procedure:
A mixture of 10.0 g of 9-diethylaminobenzo[a]phenoxazin-5-one, 75.0 ml of acetic anhydride and 10.0 g of zinc dust was maintained at approximately 80° C. for approximately thirty minutes. After the reaction mixture was cooled to room temperature, the solid present was collected by filtration and it was washed twice, each time with 25.0 ml of acetone. The filtrate and the acetone washes were combined and added slowly to approximately 400.0 ml of water. An oily liquid separated from the water and was extracted from the water with toluene. Subsequently, the toluene solution was washed with water and saturated sodium chloride solution, treated with activated carbon and clarified. The resulting toluene solution was evaporated to dryness. The residue obtained was dissolved in a mixture of ethyl acetate:toluene (2:23::V:V) and purified by passing the solution through a chromatography column packed with silica gel. Fractions 7 through 11 were combined, evaporated to dryness and the residue triturated with hexane to obtain 0.26 g of 5-methylcarbonyloxy-9-diethylamino-12-acetylbenzo[a]phenoxazine (Formula III: R=CH3 ; R2 =R3 =C2H5), a pale brown-colored solid which melted at 64° to 72° C. Significant infrared maxima appeared at 1772 cm-1 (C=O;m) and 1680 cm-1 (C=O;s). Paper treated with an ink formulation of the product produced a strong purple-colored image when traced with an applied voltage stylus.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[O:11]1CCC[CH2:12]1.[H][H].FC1C=CC=CC=1N>[Pd].C1(C)C=CC=CC=1.O.C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:12]=[O:11]
Reactant: [H][H]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Pd]
Agent: Nc1ccccc1F
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=CNc1ccccc1F

Procedure:
A mixture of 25 g of 2-fluoronitrobenzene, 250 ml of tetrahydrofuran and 0.5 of a commercial palladium catalyst (5% on charcoal) was hydrogenated (50 psig hydrogen pressure) in a Parr shaker at room temperature. A mixture of the 2-fluoroaniline thus formed and a ten percent molar excess of formic acid in toluene was refluxed for 2 hours, water of reaction being removed as formed. The resulting mixture was distilled to 90°-95° C., 0.05 Torr. On cooling, the product crystallized to give N-(2-fluorophenyl)formamide (1B), as a solid, m.p.: 47°-48° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]([Cl:27])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CC(C)=O>[CH3:12][N:7]1[CH:6]([CH2:5][CH2:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:27]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1
Product: Cl
Reaction time: 16 h
Yield: 60.4 %

Procedure:
Unpurified 2-(2-aminophenethyl)-1-methylpiperidine (II; 14.3 g, 0.066 moles) was dissolved in 100 mL dry acetone and p-anisoyl chloride (12.1 g, 0.071 mole) was added. The reaction mixture was stirred for 16 hours, cooled to 5o, and filtered. The solid material was washed with 25 mL of cold acetone and dried in vacuo at 25o for 6 hours. The dried solid was recrystallized from isopropanol-methanol to give 15.5 g of encainide hydrochloride, m.p. 183°-185°.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][Cl:25]>CCO>[ClH:25].[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: FC(F)(F)c1cccc(CCl)c1
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1cccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)c1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-trifluoromethylbenzyl chloride (0.243 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 196 mg of the product 202. 1H NMR (DMSO-d6) δ 11.32 (s, 2H), 8.10-7.65 (m, 4H), 7.15-6.95 (m, 6H), 6.90-6.60 (m, 4H), 5.78 (s, 2H), 4.93 (s, 2H); MS: m/z 413 (M++1).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:16]S(O)(=O)=O>CO>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([O:8][CH3:16])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1ccc(O)cc1)C1CC1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(c1ccc(O)cc1)C1CC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer and reflux condenser was charged with 5 mL of Methanol. To the stirred solvent was added 3-cyclopropyl-3-(4-hydroxyphenyl)propanoic acid (160 mg, 0.7759 mmol) followed by the addition of Methane sulfonic acid (74.56 mg, 0.7759 mmol). The resulting mixture was stirred at 65° C. for 2 h. After completion of the reaction (reaction monitored by TLC), solvent from the reaction mass was removed under reduced pressure and the resulting crude mass was taken in ethyl acetate (50 mL) and was washed with water (100 mL×3), sodium bicarbonate solution (100 mL×3), saturated brine solution (100 mL). Then the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The product was obtained as brown syrup. yield: 98.0% (0.23 g, crude) (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 7.01-7.04 (d, 2H), 6.64-6.67 (d, 2H), 3.49 (s, 3H), 2.63-2.68 (m, 2H), 2.14-2.22 (m, 1H), 0.93-0.97 (m, 1H), 0.45-0.49 (m, 1H), 0.26-0.33 (m, 1H), 0.13-0.17 (m, 1H), 0.04-0.07 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1.CCOC(C)=O.O.[NH2:22][NH2:23]>CCO>[NH:22]([C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[O:12])[N:5]([CH3:13])[C:4](=[O:14])[CH:3]=1)[NH2:23]
Reactant: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Yield: 100 %

Procedure:
To a solution of 6-chloro-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (2.0 g 9.3 mmol) in EtOH (8 mL), hydrazine monohydrate (1.3 mL) in EtOH (3 mL) is added slowly. The reaction mixture is refluxed for 5 hours, and then cooled. A large amount of AcOEt is added into the reaction mixture, and then cooled and filtered to give 1.95 g of product as yellowish solids (Yield: 100%).
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2:5].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[S:13](=[O:15])=[O:14]>O>[OH2:2].[OH2:12].[OH2:14].[OH2:2].[OH2:2].[OH2:2].[OH:12][C:6]1([S:13]([O-:2])(=[O:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Ca+2:5].[OH:12][C:6]1([S:13]([O-:2])(=[O:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: O=S=O
Reactant: O=C1CCCCC1
Agent: [Ca+2]
Solvent: O
Product: O=S(=O)([O-])C1(O)CCCCC1

Procedure:
Pure calcium 1-hydroxy-1-cyclohexanesulfonate hexahydrate was prepared by mixing 15 g of calcium carbonate (0.15 mole) with 100 g of 50 weight percent mixture of cyclohexanone in water. Sulfur dioxide was passed into the mixture until the pH was less than 0.5. The mixture was filtered, the cake washed with 100 g of methanol, then air dried and chemically analyzed. Calculated for Ca[C6H10 (OH)SO3 ]2 ·6H2O: Ca 7.9 percent, S 11.6 percent, C 28.3 percent, H 6.4 percent. Observed: Ca 7.9 percent, S 12.6 percent, C 28.5 percent, H 6.7 percent.
Reaction SMILES: IC.CN([CH:6]=[O:7])C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:14]O)[O:12][CH:13]=1.[H-].[Na+]>O.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH2:14][O:7][CH3:6])[O:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: OCc1cc(Br)co1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Iodomethane (1.6 mL) was added to a DMF (15 mL) solution of (4-bromofuran-2-yl)methanol (3.0 g) as obtained in Example 18-(1). Under ice cooling, 60% sodium hydride (0.82 g) was added in divided portions, and the mixture was stirred for 1 hour and 40 minutes at room temperature. Ethyl acetate and water were added, and the organic layer was isolated. The extract was washed with water and brine sequentially, and dried over anhydrous magnesium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure to obtain partially purified 4-bromo-2-(methoxymethyl)furan (yellow oil) (3.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:6].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].CN(C=O)C>C1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:6]=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C(C)=C(C(=O)OC)C(=O)OC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=CN(C)C)=C(C(=O)OC)C(=O)OC
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of 3-ethoxycarbonyl-2-methoxycarbonyl-but-2-enoic acid methyl ester (10 g, 43.5 mmol), dimethylformamide dimethyl acetal (6.1 mL, 45.7 mmol) and DMF (8 mL) was heated at 80° C. for 3 h. The slightly cooled solution was poured into 100 mL of benzene, and the resulting mixture was washed several times with water. The organic layer was dried over MgSO4 and concentrated to give a dark yellow solid, which was recrystallized from CCl4 to give 10.6 g of the title compound as a bright yellow solid. 1H NMR (CDCl3, 200 MHz): δ=6.77 (d, 1H, J=12.8 Hz), 5.74 (d, 1H, J=13.2 Hz), 4.34 (q, 2H, J=7.0 Hz), 3.80 (s, 3H), 3.71 (s, 3H), 2.97 (br s, 6H), 1.36 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[O:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21](=[O:25])([O:22][CH2:23][CH3:24])[O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCOCCO
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 127.9 %

Procedure:
To a mixture of tert-butyl[2-(2--hydroxyethoxy)ethyl]carbamate (53.93 g) obtained above and ethyl acetate (350 mL) were added pyridine (53.78 mL) and ethyl chlorocarbonate (70.57 g) under ice-cooling, and the mixture was stirred at room temperature for 96 hrs. Ethyl acetate (500 mL) was added to the reaction mixture, and the mixture was washed with water (500 mL), an aqueous copper sulfate solution (200 mL), water (300 mL) and saturated brine (300 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate (93.19 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:12]([C:16](=[O:18])[NH2:17])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7](C(OCC)=O)=[CH:8][C:9]=1[NH:10]2.[CH3:24][Mg]Cl.[NH4+].[Cl-].[CH2:29]1[CH2:33][O:32]CC1>O>[Br:1][C:2]1[C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:33]([OH:32])([CH3:29])[CH3:24])=[CH:6][CH:5]=3)[NH:10][C:11]=2[C:12]([C:16]([NH2:17])=[O:18])=[CH:13][C:14]=1[F:15]
Reactant: C[Mg]Cl
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(F)c(Br)c12
Temperature: 0 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-6-fluoro-9H-carbazole-2-carboxylate (10 g, 26.4 mmol) in THF (300 mL) was cooled in an ice-water bath and treated dropwise with 3.0 M methylmagnesium chloride in THF (70.3 mL, 211 mmol). The solution was stirred at 0° C. for 18 h. The mixture was poured into 1000 mL of well-stirred saturated aqueous NH4Cl cooled in an ice-water bath. The resulting mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed twice with water, then with brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-DCM (gradient from 20-100%), to give 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (6.36 g, 65% yield).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.C(B(CC)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)C.C(=O)(O)[O-].[Na+].C(O)C>O.C(COC)OC.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>[C:11]1([N:8]2[C:7]3[C:2]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[CH:3][C:4]([C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=3[N:10]=[CH:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCB(CC)c1cccnc1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
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
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(-c2cccnc2)c2c(c1)ncn2-c1ccccc1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (370 mg, 1 mmol), diethyl 3-pyridylborane (220 mg, 1.5 mmol), sodium bicarbonate (420 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) in a mixture of water (5 ml) and dimethoxyethane (10 ml) was stirred at reflux overnight The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic extract was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and acetone (9:1, v/v). The product was isolated by removal of solvent from appropriate eluate fractions followed by trituration of the residue with a mixture of water and ethanol. Yield: 130 mg (38%), m/z, 340.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:15]([C:23](O)=[O:24])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:29][CH:28]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:39]=[C:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]([C:15]2[CH:16]=[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C(O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-furan-2-yl-1H-pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 62 mg 4-(4-Amino-phenyl)-morpholin-3-one and 67 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C@@H:9]([CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:24]([O-])=O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.[H][H]>CO.[Pd]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH2:12][CH:9]2[O:8][C:7]3[C:6](=[CH:5][CH:4]=[C:3]4[NH:24][C:28]([CH2:27][CH3:32])=[N:1][C:2]4=3)[O:11][CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(N)c3O2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1nc2c3c(ccc2[nH]1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
Toluene-4-sulfonic acid (2R)-8-amino-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-yl-methyl ester (1.0 g, 2.6 mmole) was dissolved in 100 mL of methanol to which 0.25 g of 10% palladium on carbon had been added. p-Toluenesulfonic acid (1.0 g, 5.2 mmole) was then added and the mixture treated with 60 psi of hydrogen on a Parr apparatus for 15 hours. The mixture was filtered through celite and concentrated in vacuum. Propionic acid (50 mL) was added and the solution refluxed under nitrogen for 4 hours. The solvent was removed in vacuum and the residue dissolved in 300 mL of methylene chloride, washed with 200 mL each of saturated aqueous sodium bicarbonate, water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 0.84 g of the (R)-enantiomer of the title compound as a white foam. 1H-NMR (CDCl3): doublet 7.8 δ(2H); doublet 7.3 δ(2H); doublet 7.0 δ(1H); doublet 6.75 δ(1H); multiplet 4.5 δ(1H); multiplet 4.25 δ(3H); multiplet 4.05 δ(1H); quartet 2.9 δ(2H); singlet 2.45 δ(3H); triplet 1.4 δ(3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)([Cl:17])=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(CC(=O)Cl)cc1
Temperature: 90 °C
Yield: 101.1 %

Procedure:
First, a mixture of 110 g (0.51 mole) of 4-methylsulfonylphenylacetic acid and 110 ml (1.51 moles) of thionyl chloride was heated at 90° C. for 2 hours. After completion of the reaction, an excess of thionyl chloride was distilled off under reduced pressure, giving about 120 g of 4-methylsulfonylphenylacetyl chloride as a light brown solid. The solid thus obtained was subjected to the subsequent reaction without isolation and purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[Si:19]([O:5][CH2:4][CH2:3][NH:2][CH3:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNCCO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNCCO[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
To a stirred solution of 2-methylamino-ethanol (18-a) (10 g, 133.13 mmol) in dichloromethane (200 mL) were added diisopropylethylamine (30.8 ml, 186.39 mmol) and tert-butyl-chloro-dimethyl-silane (20.06 g, 133.13 mmol) at room temperature. The mixture was stirred for 16 h. After completion of the reaction, water was added and the mixture was extracted with dichloromethane. The separated organic part was washed with water and was dried over sodium sulfate and concentrated under reduced pressure to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) (18 g, 71.39%) as a yellow liquid.