Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.Br[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=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>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[C:22]([NH:33][C:34]([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:41]=2)=[O:35])[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: COc1ccccc1B(O)O
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: O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
Water (0.6 mL), sodium carbonate (70 mg), 2-methoxyphenylboronic acid (40 mg), and tetrakis(triphenylphosphine)palladium(0) (13 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) suspension of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain 61 mg of tert-butyl 4-(2-methoxyphenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH2:28])[CH2:12][CH2:11]2)=[N:2]1.[CH3:29][C:30]([CH3:35])=[CH:31][C:32](Cl)=[O:33]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH:28][C:32](=[O:33])[CH:31]=[C:30]([CH3:35])[CH3:29])[CH2:14][CH2:15]2)=[N:2]1
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1cc(N)c(CCN2CCN(c3nsc4ccccc34)CC2)cc1OC
Product: COc1cc(CCN2CCN(c3nsc4ccccc34)CC2)c(NC(=O)C=C(C)C)cc1OC
Yield: 68.2 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy phenylamine (300 mg, 0.75 mmol) and 3,3 dimethyl acryloyl chloride (87.7 μL, 0.79 mmol) and following the procedure as outlined in Example 1, 246 mg of 3-methyl-but-2-enoic acid {2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenyl}-amide was isolated as a white foam in 100% purity @ 254 nm; LCMS (APCI): 481 [M+H]+; mp 58° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[N:14][OH:15])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(C=NO)c[nH]c2c1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of 6-methyl-1H-indole-3-carbaldehyde (0.96 g, Lit. 20) in ethanol (30 ml) was added at 22° C. hydroxylamine hydrochloride (0.46 g) and sodium acetate (0.54 g) and the mixture was stirred for 3 h. The mixture was evaporated and the residue triturated with water and dichloromethane/n-heptane (1:1) and dried to give the title compound (0.96 g) as a pink solid. MS: 175.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4](F)[N:3]=1.[CH3:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([F:12])[N:5]=[C:4]([NH:15][CH3:14])[N:3]=1
Reactant: CN
Reactant: Fc1nc(F)c(OC(F)F)c(Cl)n1
Solvent: C1CCOC1
Product: CNc1nc(F)c(OC(F)F)c(Cl)n1
Reaction time: 1 h

Procedure:
20.3 g (0.0938 mol) of 4-chlorodifluoromethoxy-2,6-difluoropyrimidine in 150 ml of tetrahydrofuran were initially taken, and 5.8 g (0.188 mol) of gaseous methylamine were added at from -70° to -60° C. in the course of 30 minutes while stirring. Stirring was continued for 1 hour in each case at -70° C., 0° C. and 25° C. The reaction mixture was evaporated down under reduced pressure, after which the residue was stirred with water, the solution was extracted twice with ethyl acetate and the extract was dried over magnesium sulfate. It was partially evaporated down under reduced pressure and then subjected to fractional chromatography over silica gel using 1:5 ether/petroleum ether. The first fractions contained the title compound of melting point 57°-61° C. in a yield of 12.5 g (58.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20]([Cl:26])(=O)[CH2:21][C:22]([Cl:24])=O.O=P(Cl)(Cl)Cl>C(#N)C>[Cl:24][C:22]1[CH:21]=[C:20]([Cl:26])[N:16]2[N:15]=[C:14]([S:11]([NH:10][C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[Cl:1])(=[O:13])=[O:12])[N:18]=[C:17]2[N:19]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(Cl)cc(Cl)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred solution of 6.44 g (0.02 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine in 100 mL of dry acetonitrile was added 2.82 g (0.02 moles) of freshly distilled malonyl chloride. The mixture was stirred at room temperature overnight after which time some starting material remained. Additional malonyl chloride (0.56 g) was added and stirring was continued for 4 hrs. The reaction mixture was concentrated to dryness and the residue was slurried with POCl3 (122 g; 0.8 moles) and heated at 90° C. for 9 hrs. The reaction mixture was cooled and concentrated under reduced pressure and the residue was poured into ice-water. The resulting precipitate was filtered and dried to give 8.35 g of product having a purity of 75 percent (73 percent yield).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:49])[CH2:47][NH2:48]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:48][CH2:47][C:46]([OH:45])=[O:49])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: COC(=O)CN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)NCC(=O)O)cc2)cc1

Procedure:
The product from Example 234B and glycine methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.13-12.77 (br.s, 1 H), 8.94 (s, 1 H), 8.12 (t, 1 H), 7.24 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 3.73 (d, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.19 (t, 2 H), 1.55-1.79 (m, 4 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C(C)=CC=CC=1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Temperature: 85 °C
Yield: 98.7 %

Procedure:
69.1 g (0.5 mole) of p-hydroxybenzoic acid, 216.2 g (2 moles) of benzyl alcohol, 0.7 g of tetraisopropyl titanate and 30 g of xylene were fed into a fournecked glass flask, and refluxed for 3 hours with stirring in an atmosphere of nitrogen. During this time, the temperature of the reaction mixture was maintained at 85° C. Water formed by the reaction was removed out of the reaction system by the Dien-Stark's device. The presence of xylene simplified temperature control and promoted removal of water. Benzyl p-hydroxybenzoate was obtained in a yield of 98.7%.
Reaction SMILES: [CH:1](=O)[CH3:2].C=O.[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:1][CH3:2])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:13])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CC=O
Agent: C=O
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
Following the procedure of Example 104 but substituting acetaldehyde for aqueous formaldehyde, 1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg, 0.08 mmol) was converted to the title product (45 mg) as a white glassy solid. MS found: (M+H)+=563.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:11][NH2:12]>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][N:11]=[C:7]2[NH2:8]
Reactant: NN
Reactant: N#Cc1cc(Br)ccc1F
Product: Nc1n[nH]c2ccc(Br)cc12
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 250 mL round-bottom flask was added 5-bromo-2-fluorobenzonitrile (15.54 g, 77.7 mmol) and hydrazine (124 g, 3885 mmol). The reaction mixture was heated to 100° C. for 5 minutes. The hydrazine was then removed under reduced pressure to give 5-bromo-1H-indazol-3-amine (16.4 g, 99.5% yield). MS m/z: 213 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][OH:21].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:21][CH2:20][CH2:19][O:18][CH3:17]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: COCCO
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-methoxyethanol and DBU in dioxane. ES-MS m/e (%): 316 (M{81Br}+H+, 96), 314 (M{79Br}+H+, 100), 258 ([M{81Br}+H-MeOCH═CH2]+, 70), 256 ([M{81Br}+H-MeOCH═CH2]+, 75).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH:17]=[C:13]([CH3:12])[N:14]=[CH:15]1
Reactant: Cc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2Cl)cn1

Procedure:
The title compound was prepared from 3,4-dichloronitrobenzene and 4-methylimidazole using in analogous manner the procedure described in example 4a). Chromatography on silica gel using ethyl acetate as eluent gave the title compound as a slightly greenish solid in 64% yield. MS ISP (m/e): 238.0/240.2 (100/40) [(M+H)+].
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([N:7]1[C:13](=[O:14])[CH:12]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH2:25][CH:26]=[CH2:27])=[C:19]([Cl:28])[CH:18]=2)[CH2:11][CH2:10][C:9](=[O:30])[N:8]1[CH3:31])[CH3:6])C.CO>[OH-].[Na+].O>[CH2:25]([O:24][C:20]1[C:19]([Cl:28])=[CH:18][C:17]([C:16]([NH:15][CH:12]2[C:13](=[O:14])[N:7]([CH:5]([CH3:6])[C:4]([OH:32])=[O:3])[N:8]([CH3:31])[C:9](=[O:30])[CH2:10][CH2:11]2)=[O:29])=[CH:22][C:21]=1[Cl:23])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(C)N(C(C)C(=O)OCC)C2=O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1c(Cl)cc(C(=O)NC2CCC(=O)N(C)N(C(C)C(=O)O)C2=O)cc1Cl
Yield: 99.7 %

Procedure:
2-[6-(4-Allyloxy-3,5-dichloro-benzoylamino)-2-methyl-3,7-dioxo-[1,2]diazepan-1-yl]-propionic acid ethyl ester (17) (216 mg, 0.44 mmol) was stirred in 1N NaOH (2 mL) and MeOH (2 mL) at room temperature for 45 min. The mixture was diluted with water (30 mL), extracted with dichloromethane three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to dryness to afford 201 mg (99% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.58-1.68 (m, 3H), 1.88-2.00 (m, 1H), 2.40-2.48 (m, 1H), 2.80-3.18 (m, 2H), 3.25-3.48 (d, 3H), 4.47-4.65 (m, 2.5H), 4.74-4.81 (m, 0.5H), 4.90-5.05 (m, 1H), 5.27-5.31 (d, 1H), 5.38-5.43 (d, 1H), 6.08-61.8 (m, 1H), 7.07-7.22 (m, 2H), 7.71 (d, 2H). Analytical HPLC: 5.85 min. LC-MS (ES+): m/e=458, 460 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 5.5 g. portion of 3-(4-phenoxyphenylaminomethyl)pyridine was dissolved in dichloromethane, and reacted with 1.7 ml. of methanesulfonyl chloride in the presence of 3 g. of potassium carbonate. The mixture was stirred at ambient temperature for several days. It was diluted with dichloromethane, extracted with water, dried over magnesium sulfate, and evaporated under vacuum. The residue was triturated in diethyl ether and petroleum ether, filtered and dried to obtain 6.4 g. of the desired product, m.p. 139°-140°.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:10]([C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)=[O:11])[C:20]1=[O:21])[CH2:24][CH2:25][CH3:26]
Reactant: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCS(=O)c2cccc3nccn23)C1=O

Procedure:
To a solution of 0.33 g (0.98 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)butyl]thiazolidine-2,4-dione and 0.10 ml (1.1 mmol) of n-butyraldehyde in 5 ml of ethanol, 0.01 ml (0.1 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 0.287 g (74.8%, yellow oily substance) of the desired product.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH3:26])[NH:11][CH:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH2:24]([O:23][C:21]([CH:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH3:26])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])[CH3:25]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)O

Procedure:
N-(1-Ethoxycarbonyl-3-Phenylpropyl)-L-Alanine Benzylester (4.2 g) is dissolved in 40 ml ethanol, to which is added 630 mg 10% Pd-C and a few drops of acetic acid. Hydrogenation occurs under a 30 psi hydrogen atmosphere at room temperature overnight. The resulting mixture is filtered through celite and dried under vacuum to remove the solvent, yielding a residue. The residue is partitioned between chloroform and aqueous 5% NaHCO3, separated, and the chloroform layer further washed with aqueous 5% NaHCO3. The aqueous layers are combined, acidified to pH 3.5 with dilute HCl, extracted with chloroform or ethylacetate several times, dried over MgSO4, and placed under vacuum to evaporate the solvent and yield 2.5 g of the diastereoisomeric product, a brown sticky solid [TLC (Silica gel; CHCl3 /MeOH/HOAC=9:1:0.5); Rf=0.4].
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:20]=[CH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[C:26](=[O:29])[CH2:27]Cl>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:27][C:26]([N:25]([CH3:30])[CH3:24])=[O:29])[C:8]=2[CH:20]=[CH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=Cc1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=O)N(C)C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-vinyl-1H-indole-6-carboxylate (from Step 1) in DMF, NaH (1.2 eq.; 60% in mineral oil) was added. After evolution of gas had ceased, N,N-dimethyl chloroacetamide (1.3 eq.) was added dropwise. The mixture was stirred overnight, then all volatiles were evaporated and the residual material was taken up in DCM. The solution was washed with 1N HCl (1×), brine (2×) and then dried over Na2SO4. The solvent was evaporated and the residual material crystallised from DCM with PE. The product was obtained as a yellow solid (68%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.36-1.38 (m, 3H); 1.69-1.96 (3m, 7H); 2.85 (s, 3H); 2.91-2.95 (m, 1H); 3.13 (s, 3H); 3.85 (s, 3H); 5.15 (s, 2H); 5.41 (d, J 17.8, 1H); 5.61 (d, J 11.6, 1H); 6.71-6.78 (dd, Ja 11.6, Jb 17.8, 1H); 7.61 (d, J 78.3, 1H); 7.81 (d, J 8.5, 1H); 7.94 (s, 1H). MS (ES+) m/z 369.6 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8](=O)([O-])[NH2:9].Cl[CH2:13][CH2:14]Cl>>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:9]1[CH2:8][CH2:14][CH2:13][CH2:1]1
Reactant: ClCCCl
Reactant: NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: C1CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (3 mL, 38.9 mmol) was added to a stirred solution of carbamate J1c (238 mg, 0.367 mmol) in DCE (7 mL) and the reaction was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum to yield a TFA salt of pyrrolidine J1d (260 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10]1[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1.CC(C)([O-])C.[K+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:11]2[C:10]3[CH:9]([CH2:16][C:17]([OH:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]=3[C:4]3[C:12]2=[C:13]([F:15])[CH:14]=[C:2]([F:1])[CH:3]=3)=[CH:29][CH:28]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)CC1CCCc2c1[nH]c1c(F)cc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 639.6 %

Procedure:
A solution of 11:1 g of acid from Step II in 100 cc of THF was added portionwise 10.3 g of potassium tert-butoxide. The resulting mixture was stirred for 45 min. at room temperature and 10.3 g p-chlorobenzyl bromide was added portionwise. the reaction mixture was stirred 18 hours at room temperature. The resulting mixture was diluted with 100 cc of water and washed with hexane. The aqueous layer was acidified with HCl (1N) and the resulting precipitate filtered washed with water and air-dried to afford 9.4 g of the title compound. m.p. 168.5°-170° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)(=[O:5])=[O:4].C(N(CC)C(C)C)(C)C.C([O:29][C:30]([C:32]1[N:37]2[C:38]([C:41](=[O:46])C(Cl)(Cl)Cl)=[CH:39][N:40]=[C:36]2[CH:35]=[CH:34][CH:33]=1)=O)C>C(#N)C>[F:17][C:2]([F:16])([F:1])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:15]=[CH:14][C:12]([N:13]2[C:30](=[O:29])[C:32]3[N:37]4[C:38](=[CH:39][N:40]=[C:36]4[CH:35]=[CH:34][CH:33]=3)[C:41]2=[O:46])=[CH:11][CH:10]=1)(=[O:4])=[O:5]
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: Nc1ccc(CCNS(=O)(=O)C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc3ncc(c(=O)n1-c1ccc(CCNS(=O)(=O)C(F)(F)F)cc1)n32
Yield: 6.7 %

Procedure:
To a solution of 1.18 g (4.4 mmol) of 4-[2-(trifluoromethanesulfonamido)ethan-1-yl]aniline and 0.68 g (5.3 mmol) of N,N-diisopropylethylamine in 20 ml of acetonitrile was added a solution of 1.53 g (4.4 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine. The mixture was heated for 38 hours under reflux. After cooling, and the solvent was distilled off. To the residue was added chloroform. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 130 mg of the desired compound (6.8%, brown solid).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[CH3:11]
Reactant: C1=COCCC1
Reactant: Cc1c(Br)ccc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Yield: 57.2 %

Procedure:
To a solution of 5-bromo-4-methyl-1H-benzo[d]imidazole (1.0 g, 4.74 mmol, CASRN 952511-48-7) and 3,4-dihydro-2H-pyran (2.0 g, 23.70 mmol) in THF (10 mL) was added p-TsOH.H2O (90 mg, 0.47 mmol). The mixture was heated at 80° C. overnight, cooled and the solvent was removed in vacuo. The residue was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to dryness in vacuo. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (10 to 50% EtOAc) to afford 800 mg (57%) of 5-bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (254) as light yellow solid: MS (ESI) m/z=295.1 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NC(C)(C)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-(1-(4-hydroxymethylphenyl)-1-methylethyl)acetamide (18.24 g) in chloroform (180 ml) was added dropwise thionyl chloride (7.07 ml) over 10 min under ice-cooling and the mixture was stirred at room temperature for 20 hr. The reaction mixture was poured into water (1000 ml) and the organic layer was separated. The organic layer was washed with aqueous sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (19.17 g) as pale-yellow crystals, m.p.=124-125° C.