Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([N:23]1[C:27]([NH2:28])=[CH:26][C:25]([CH3:29])=[N:24]1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:28][C:27]2[N:23]([CH2:21][CH3:22])[N:24]=[C:25]([CH3:29])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CCn1nc(C)cc1N
Reactant: CCNC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2CC)ncc1Cl
Temperature: 160 °C
Yield: 35 %

Procedure:
A vessel was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-ethylbenzamide (100 mg, 0.322 mmol), 1-ethyl-3-methyl-1H-pyrazol-5-amine (60.5 mg, 0.484 mmol), cesium carbonate (315 mg, 0.967 mmol), 1,4-dioxane (5.0 mL), and THF (1.0 mL). The reaction mixture was degassed by nitrogen for 10 min at which time (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (40.1 mg, 0.064 mmol) and palladium (II) acetate (7.24 mg, 0.032 mmol) in a minimum amount of 1,4-dioxane were added. The vessel was sealed and the reaction mixture was heated in microwave oven 160° C. for 40 min. The resulting suspension was cooled to room temperature and filtered through celite. The filtrate was evaporated to dryness and the crude reaction mixture was purified by reverse-phase HPLC to give the title compound as a solid (45 mg, 30% yield); MS: M(C20H23ClN6O)=398.89, (M+H)+=399, 401; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.34 (s, 1 H) 7.94 (s, 1 H) 7.66 (br. s., 1 H) 7.51 (d, J=7.8 Hz, 1 H) 7.31-7.47 (m, 2 H) 6.96-7.17 (m, 1 H) 6.58 (s, 1 H) 6.19 (t, J=5.2 Hz, 1 H) 5.86 (s, 1H) 4.01 (q, J=7.3 Hz, 2 H) 3.42-3.62 (m, 2 H) 2.24 (s, 3 H) 1.37 (t, J=7.3 Hz, 3 H) 1.26 (t, J=7.3 Hz, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>C(#N)C>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[N:8]([CH3:7])[S:9]([CH3:12])(=[O:11])=[O:10])#[N:17]
Reactant: N#Cc1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN(c1ccccc1C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.5 %

Procedure:
To a solution of cesium carbonate (55.78 g, 171 mmol) in acetonitrile (500 mL) at room temperature was added N-methylmethane-sulfonamide (14.0 g, 0.128 mol). 2-Fluoro-benzonitrile (10.37 g, 86 mmol) was then added in portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 12 hours. Upon completion, the mixture was filtered and then concentrated. The residue diluted with water and extracted by dichloromethane. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate and evaporated to afford the product N-(2-cyanophenyl)-N-methylmethane-sulfonamide (16.0 g, yield 88.9%). 1H NMR (400 MHz, CDCl3) δ ppm 7.62-7.73 (m, 2H), 7.54-7.56 (m, 1H), 7.45-7.50 (m, 1H), 3.40 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[NH:14][C:20](=[O:21])[NH:19][S:16](=[O:18])(=[O:17])[C:12]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: O=C1Nc2ccc(Oc3ccccc3)cc2S(=O)(=O)N1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
4-Phenoxybenzenamine (18.4 g, 101.1 mmol) dissolved in nitromethane (30 mL) was added slowly over 25 minutes to a solution of chlorosulfonyl isocyanate (16.4 g, 115.8 mmol) in nitromethane (100 mL) at −5° C. The suspension was stirred at −5° C. for an additional 15 minutes and AlCl3 (16.8 g, 125.9 mmol) was added portionwise. The reaction mixture was then heated at 105° C. for 30 minutes. The hot solution was poured onto ice (1 L) and the resulting precipitate was filtered off and washed with water (300 mL). The solid was then dissolved in hot aqueous sodium bicarbonate solution (10 g/200 mL), treated with charcoal, and filtered. The cooled solution was neutralized using 6N HCl and the resulting white precipitate was filtered off, washed with water and dried to afford the title compound (18 g, 62%).
Reaction SMILES: C([N:8]1[C@@H:12]([C@@H:13]([C:17](OC(C)(C)C)=[O:18])[C@H:14]([OH:16])[CH3:15])[CH2:11][CH2:10][C@H:9]1[C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.C(N1[C@@H]([C@H](C(OC(C)(C)C)=O)[C@H](O)C)CC[C@H]1C(OC(C)C)=O)C1C=CC=CC=1.C1[C@@H]2CC(=O)N2CC1.C(N1[C@@H]([C@H](C(OC(C)(C)C)=O)[C@@H](O)C)CC[C@H]1C(OC(C)C)=O)C1C=CC=CC=1>>[OH:16][C@@H:14]([C@H:13]1[C:17](=[O:18])[N:8]2[C@H:9]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:10][CH2:11][C@H:12]12)[CH3:15]
Reactant: CC(C)OC(=O)[C@@H]1CC[C@H]([C@@H](C(=O)OC(C)(C)C)[C@@H](C)O)N1Cc1ccccc1
Agent: CC(C)OC(=O)[C@@H]1CC[C@H]([C@H](C(=O)OC(C)(C)C)[C@@H](C)O)N1Cc1ccccc1
Agent: CC(C)OC(=O)[C@@H]1CC[C@H]([C@H](C(=O)OC(C)(C)C)[C@H](C)O)N1Cc1ccccc1
Agent: O=C1C[C@H]2CCCN12
Product: CC(C)OC(=O)[C@@H]1CC[C@@H]2[C@@H]([C@@H](C)O)C(=O)N21

Procedure:
The residue was divided into three portions, and each portion was purified by a medium pressure silica gel column chromatography (Lobar size B, ethyl acetate-hexane 7:5→2:1). There were obtained a carbapenam ((6R,8R)-isomer, pale yellowish viscous liquid, 319 mg, 9.4%) derived from Compound 8a, and a mixture (76:24, pale yellowish viscous liquid, 2.06 g (containing about 5% of impurities), yield 58%. Yield of Compound S10 from Compound 8b was 75%) of Compound S10 and a carbapenam ((6S,8S)-isomer) derived from Compound 8c.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[C:25](=[O:32])[N:24]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[OH:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:29]([C:26]4[C:25](=[O:32])[N:24]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:23]([CH3:22])[C:27]=4[CH3:28])=[O:30])=[CH:3][CH:4]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1O
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 10 h
Yield: 93.6 %

Procedure:
To a solution of 4-(4-aminophenoxy)-6-methoxyquinolin-7-ol (3.61 g, 12.8 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.85 g, 12.27 mmol) in DMF (50 mL) was added EDCI (2.81 g, 14.66 mmol) and HOAT (0.33 g, 2.4 mmol). The reaction was stirred at 60° C. for 10 hours, cooled to room temperature and diluted with H2O (200 mL). The solid was collected by filtration and dried in vacuo at 60° C. overnight to give the title compound as a white solid (5.7 g, 89.9%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=2)[O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)=[CH:2]1.ClC(OC)=O.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>O1CCCC1.O.C(OCC)C>[CH:32]1([NH:35][C:14](=[O:16])[CH2:13][O:12][CH2:11][CH2:10][O:9][C:8]2[CH:17]=[CH:18][CH:19]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[CH2:34][CH2:33]1
Reactant: O=C(O)COCCOc1cccc(-c2ccsc2)c1
Reactant: NC1CC1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(COCCOc1cccc(-c2ccsc2)c1)NC1CC1

Procedure:
0.36 g of 2-[3-(3-thienyl)phenoxy]ethoxyacetic acid was dissolved in 7 ml of tetrahydrofuran, and under ice cooling, 110 μl of methyl chloroformate and 200 μl of triethylamine were added. After the mixture was stirred with cooling for 30 minutes, 178 μl of cyclopropylamine was added. The mixture was stirred at room temperature for 1 hour, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner to give 0.31 g of N-cyclopropyl-2-[3-(3-thienyl)phenoxy]ethoxyacetamide as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>C(OC(=O)C)(=O)C>[F:1][C:2]1[N:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([NH:8][C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)nc1)C1CCC1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C(Nc1ccc(F)nc1[N+](=O)[O-])C1CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
[step 2] N-(6-fluoropyridin-3-yl)cyclobutanecarboxamide (800 mg, 4.12 mmol) obtained in step 1 was dissolved in acetic anhydride (4 mL), fuming nitric acid (0.7 mL, 15.7 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Under ice-cooling, 5 mol/L aqueous sodium hydroxide solution was added dropwise to the mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give N-(6-fluoro-2-nitropyridin-3-yl)cyclobutanecarboxamide (348 mg, 35%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[S:20])[NH2:19]>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[S:20][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: NC(=S)c1ccccn1
Product: Cc1ccncc1-c1csc(-c2ccccn2)n1
Yield: 23.3 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (446 mg) and pyridine-2-carbothioamide (157 mg), the title compound (67 mg) was obtained as pale-red powder crystals.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:17]=[C:18]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)[C:19](F)=[N:20][CH:21]=1.[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1.C1COCC1>[NH4+].[Cl-].O.C(OCC)(=O)C>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[C:16]1[CH:17]=[C:18]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)[C:19]([NH:32][C:33]2[CH:38]=[N:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[N:20][CH:21]=1
Reactant: COc1ccc(N)cn1
Reactant: CSc1nc(C)nc(-c2cc(C3OCCO3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncc(C3OCCO3)cc2-c2nc(C)nc(SC)n2)cn1
Reaction time: 1 h
Yield: 6.2 %

Procedure:
LiHMDS (1.0 M in THF, 4.14 mL, 4.14 mmol) was added to a stirred solution of 2-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (0.425 g, 1.379 mmol) and 5-amino-2-methoxypyridine (0.257 g, 2.068 mmol) in THF (3.00 mL, 36.6 mmol) at 0° C. and the mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with NH4Cl (aq) and water (10 mL each) and diluted with ethyl acetate (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and the residue was purified by flash column chromatography (ISCO CombiFlash®, Teledyne ISCO, Lincoln, Nebr., hexanes to 50% ethyl acetates in hexanes) to give 5-(1,3-dioxolan-2-yl)-N-(6-methoxypyridin-3-yl)-3-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyridin-2-amine (35 mg, 0.085 mmol, 6.15% yield) as a yellow solid. LCMS (API-ES) m/z 413 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 2 h

Procedure:
To a solution of 100 milligrams (0.6 millimole) of 2-thiopheneacetyl chloride in 5 milliliters of absolute methylene chloride was added slowly a slurry of 137 milligrams (0.5 millimole) of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 86 milligrams (0.9 millimole) of triethylamine in 10 milliliters of absolute methylene chloride. The addition was carried out at -15° C., with stirring. After the addition, stirring was continued for two hours at -15° C. and for one and one-half hours at room temperature. The reaction mixture was then cooled and filtered to separate the precipitated solid. The solid, 80 milligrams, was analyzed on bioautogram. Bioautogram showed that approximately 50 percent of the sample was 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and another 50 percent was the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH2:21]([C:24]1[CH:29]=[C:28]([CH:30]=[CH:31][C:32]#[N:33])[CH:27]=[CH:26][N:25]=1)[CH2:22][CH3:23]>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:30]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([CH2:21][CH2:22][CH3:23])[CH:29]=3)[CH:31]=[C:32]([NH2:33])[N:12]2[N:13]=1
Reactant: CCCc1cc(C=CC#N)ccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: CCCc1cc(-c2cc(N)n3nc(-c4ccco4)nc3c2)ccn1

Procedure:
The title compound, MS m/e (%): 319 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(2-propyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: COc1cccc(CO)c1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(CCl)c1OC
Yield: 99.4 %

Procedure:
In 30 ml of methylene chloride was dissolved 3.36 g (20 mmol.) of 2,3-dimethoxybenzyl alcohol. Under chilling with ice, to the solution was dropwise added a solution of 1.6 ml (22 mmol.) of thionyl chloride in 5 ml of methylene chloride for 10 min. The mixture was stirred at the same temperature and then placed under reduced pressure to distill off the solvent, to give 3.71 g of 2,3-dimethoxybenzyl chloride as a brown oil, yield 99.5%.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:17][CH:16]2[CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([O:36]C)[CH:31]=2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl.O1CCOCC1>C([O-])(O)=O.[Na+]>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[S:21]([N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:2]([F:1])([F:38])[F:39])[C:4]([F:5])([F:7])[F:6])=[CH:10][CH:11]=2)[CH:16]([CH2:29][C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)[CH2:17]1)(=[O:22])=[O:23]
Reactant: COc1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1cc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc[nH]1
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a 100-mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(4-(2-((2-methoxy-4-pyridinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (72 mg, 0.12 mmol), 5N hydrochloric acid (0.121 mL, 0.60 mmol), and dioxane (3 mL). The reaction mixture was stirred at 100° C. for 16 h and allowed to cool to room temperature. The reaction mixture was diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white solid. The crude product was purified by silica gel chromatography, eluting with 5% MeOH/EtOAc to give 4-((4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-piperazinyl)methyl)-2(1H)-pyridinone (58 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([Li])CCC.CCCCCC.IC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([CH3:20])[C:4]=1[C:16]([F:18])([F:17])[F:19]
Reactant: [Li]CCCC
Reactant: COc1ccc(NC(=O)C(C)(C)C)cc1C(F)(F)F
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(NC(=O)C(C)(C)C)c(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A solution of N-[4-methoxy-3-(trifluoromethyl)-phenyl]-2,2-dimethylpropanamide (5.90 g, 21.4 mmol) in tetrahydrofuran (70.0 ml) was cooled to −10 to −15° C., and then a 1.57M n-butyllithium/hexane solution (33.5 ml, 52.5 mmol) was added dropwise thereto over a period of 25 minutes while maintaining the internal temperature at 0° C. or lower. The resulting mixture was slowly warmed up to 20° C. and stirred for 3 hours while maintaining the temperature. The resulting suspension was cooled to −35 to −40° C., and then iodomethane (1.53 ml, 24.6 mmol) was added dropwise thereto over a period of 15 minutes. The resulting mixture was slowly warmed up to −5 to 0° C. and stirred for 1.5 hours while maintaining the temperature. The mixture was partitioned and extracted with water and ethyl acetate, and the organic phase was washed with a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (6.23 g). The crude product was purified by a silica gel column chromatography (eluent: hexane/diisopropyl ether=1/1) to obtain N-[4-methoxy-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (3.20 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C:7]1[N:6]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:5]2[CH:19]=[C:20]([Cl:21])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1)[CH3:18])=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl [(5,6-dichloro-1H-benzimidazol-2-yl)methyl]methylcarbamate (400 mg) and DMF (4 mL) were added ethyl bromoacetate (201 μL) and K2CO3 (335 mg), followed by heating and stirring at 70° C. for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=50/50-0/100) to obtain ethyl (2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-5,6-dichloro-1H-benzimidazol-1-yl)acetate (393 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C.C(N(CC)CC)C>[CH2:23]([NH:27][C:28]([O:21][CH:20]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2ncccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNC(=O)OC1c2cccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 0.5 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 3 hours. n-Butyl isocyanate (2.9 cc.) and triethylamine (2 drops) are then added and heating at the reflux temperature is continued for a further 30 minutes. After concentrating the mixture to dryness under reduced pressure (40 mm.Hg), the residue is triturated with diisopropyl ether (10 cc.). The precipitate is filtered off and recrystallised from acetonitrile (41 cc.) to give 5-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.8 g.) melting at 215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][Br:9].BrBr>CO.[C].[Pd].[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][Br:9]
Reactant: CCC(=COCCBr)C(=O)OC
Agent: [Ag+]
Agent: [Pd]
Agent: BrBr
Solvent: CO
Product: CCC(COCCBr)C(=O)OC
Temperature: 50 °C

Procedure:
47.4 g 3-(2-Bromoethoxy)-2-ethyl-acrylic acid methyl ester was hydrogenated in 300 ml methanol in the presence of 8 g 5% moist palladium-carbon catalyst at ambient temperature and pressure. After 75% of the expected amount of hydrogen had been consumed, the hydrogenation mixture was heated at 50° C. while the remaining 25% of the hydrogen was absorbed. When a sample of the filtered reaction mixture was titrated with silver nitrate, only approximately 1.1% of the bromine originally present was found in the form of bromine ions.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].Br[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Brc1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccs2)cc1
Temperature: 0 °C
Yield: 84.8 %

Procedure:
The corresponding Grignard compound is prepared from 16 g of 4-bromotoluene and 2.23 g of magnesium in 150 ml of THF. This is added dropwise at room temperature to a solution of 10 g of 2-bromothiophene, 3 g of palladium acetate and 1.27 g of triphenylphosphine in 150 ml of THF. The mixture is boiled at reflux under argon for 3.5 hrs., then poured on to ice-water and extracted with ethyl acetate. Chromatography on silica gel (toluene) gives 9.06 g of 2-p-tolyl-thiophene.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([I:22])[CH:24]=1
Reactant: O=C(Cl)c1cccc(I)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide was prepared according to method C with triethylamine (2.23 mL; 15.90 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.5 g; 6.36 mmol) and 3-iodobenzoyl chloride (1.82 g; 6.68 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to provide 2.56 g (95%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide as a white solid.