Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])#[N:2].[C:24]([CH2:28][O:29][CH2:30][CH2:31]Br)([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([CH:18]1[CH2:23][CH2:22][N:21]([CH:30]([O:29][CH2:28][C:24]([O:26][CH3:27])=[O:25])[CH3:31])[CH2:20][CH2:19]1)=[O:17])#[N:2]
Reactant: N#CCCCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(C)N1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix 1-[(4-cyanobutyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.0 g, 12.91 mmol), carbomethoxy methoxy ethylbromide (3.0 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:15](OC)(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[SH:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][N:11]([CH3:12])[C:10]([NH:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15](=[O:23])[N:2]=2)[N:8]=1)=[O:14]
Reactant: COC(=O)c1ccccc1S
Reactant: CN(C)C(=O)Nc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50 %

Procedure:
N′-(6-Cyano-2-pyridyl)-N,N-dimethylurea (0.72 g, 3.8 mmol) and methyl thiosalicylate (0.89 g, 5.2 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected and recrystallized from diisopropyl ether-methanol to give the titled compound (0.62 g, 50%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]4=[N:22][CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH3:12])=[CH:7][CH:6]=1)=[O:4].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:29][C:28]1[C:23]2[N:24]([C:20]([C:18]3[C:17]([C:30]#[N:31])=[CH:16][N:15]=[C:14]([NH:13][C@H:11]([C:8]4[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:6][CH:7]=4)[CH3:12])[N:19]=3)=[CH:21][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C1CCNC1
Reactant: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(=O)CBr)cc4)ncc3C#N)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(=O)CN5CCCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg of the compound [3-2] was dissolved in 0.4 mL of N,N-dimethylformamide, and 7 μL of pyrrolidine was added thereto. The reaction mixture was stirred for 30 minutes at room temperature, and then thereto was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography, to obtain 3 mg of 4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-({(1S)-1-[4-(pyrrolidin-1-ylacetyl) phenyl]ethyl}amino)pyrimidine-5-carbonitrile [3-3] (hereinafter, referred to as the compound [3-3]) as a colorless oily product.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH2:19]1[O:21][C@H:20]1[CH2:22]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.O>CN(C)C=O>[S:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH:20]3[CH2:19][O:21]3)=[CH:12][CH:13]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2
Reactant: Oc1ccc(-c2csc3ccccc23)cc1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Cool a mixture of sodium hydride (585 mg, 60% dispersion in mineral oil, 14.6 mmol) in dimethylformamide (20 mL, anhydrous), with an ice bath, under a nitrogen atmosphere. Add a solution of 4-benzo[b]thiophen-3-yl-phenol (3.0 g, 13.3 mmol) in dimethylformamide (20 mL) over a period of 5 minutes. Reaction mixture has noticeable gas evolution and is a yellow mixture. Stir at room temperature for 0.5 hours and cool via an ice bath to give a yellow solution. Rapidly, add a solution of (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (3.78 g, 14.6 mmol) in dimethylformamide (20 mL) and stir at 0° C. for 35 minutes. The reaction mixture is a red-orange color. Stir reaction mixture at room temperature overnight. Pour the reaction mixture into cold (0° C.) water (300 mL) and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with water (100 mL), saturated sodium chloride (100 mL), dry (MgSO4) and concentrate (in vacuo) to give a brown oil. The brown oil is purified by column chromatography (dichloromethane) to give a light green/clear, viscous oil. The oil is dried (0.5 mm Hg) at room temperature for 3 hours to give the title compound as a solid (3.19 g, 85% Yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH2:39][OH:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:8][S:9]([O:40][CH2:39][C:34]1[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([CH2:31][O:30][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(CO)c1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (7.8 mL, 56 mmol) and methanesulfonyl chloride (2.9 mL, 37 mmol) were added to a solution of [3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorophenyl]methanol (7.65 g, 18.6 mmol, from Step 2) in DCM (50 mL) at 0° C. The cooling bath was removed and after reaction mixture warmed to room temperature, the reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with two further portions of DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-40% EtOAc/hexanes. Yield: (6.8 g, 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:19](Cl)=[O:20]>ClCCl.Cl>[F:17][C:18]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 4-aminobenzonitrile (1.58 g), triethylamine (1.36 g), and dichloromethane (20 mL) was cooled in ice under a nitrogen atmosphere. To this mixture was added perfluorobutyryl chloride (3.11 g) in dichloromethane (10 mL) and the resulting mixture was allowed to warm to room temperature and was then stirred for three hours. The reaction mixture was diluted with HCl solution (1N, 50 mL) and the layers were partitioned in a separatory funnel. The organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated with a rotary evaporator. The residue was dissolved in dichloromethane. Upon dilution with hexane the product precipitated to give 1.55 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide, m.p. 116°-118° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:16]=[CH:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[CH:5][CH:4]=1)[CH3:12]
Reactant: C#Cc1ccc(C#C)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(C#CC=CC(=O)OCC)cc1

Procedure:
The general procedure was used to convert 1,4-Diethynyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product in 12 hours. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow solid (560 mg, 87% yield). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 4H), 6.37-6.34 (d, J=11.4, 2H), 6.17-6.14 (d, J=11.4, 2H), 4.28-4.23 (q, J=7.1, 4H), 1.34-1.30 (t, J=7.1, 6H). 13C NMR (100 MHz, CDCl3) δ 164.57, 131.88, 128.72, 123.31, 122.34, 100.27, 88.36, 60.39, 14.21. Anal. Calcd. for C20H18O4: C, 74.52; H, 5.63; Found C, 74.33; H, 5.71. m.p.: 73.0°-74.0° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N([CH2:17][CH3:18])CC)C.[NH2:19][CH2:20][CH:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:19][CH2:20][CH:21]([NH:29][S:7]([C:4]2[CH:5]=[CH:6][C:17]([CH3:18])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NCC(N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCC(Cc2ccccc2)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (92.0 g, 0.482 mole) and triethylamine (48.8 g, 0.482 mole) in CH2Cl2 (350 ml) at 0° C. under a dry argon atmosphere was added a solution of 1,2-diamino-3-phenylpropane prepared as in Example 6A (34.5 g, 0.230 mole) in CH2Cl2 (100 ml), maintaining the temperature <10° C. The addition required 1 h. The mixture was allowed to warm to room temperature and was stirred an additional 15 h. The mixture was then poured onto ice (500 g) and the CH2Cl2 layer was separated. The CH2Cl2 layer was washed with 1N HCl, H2O and saturated NaCl solution and was dried (MgSO4). The solvent was removed in vacuo and the resulting yellow oil washed with hexane. The crude product was purified by recrystallization from CH2Cl2 -hexane to give 71.4 g (68% yield) of the product as a crystalline solid: mp 128°-31° C.; 1H NMR (CDCl3) δ 2.42 (s, 3 H), 2.43 (s, 3 H), 2.69 (ABq of dd, γν=44.0 Hz, J=14.0, 6.6 Hz, 2 H), 3.02 (m, 2 H), 3.36 (hex, J=6.6 Hz, 2 H), 4.85 (d, J=6.6 Hz, 1 H), 5.16 (t, J=6.5 Hz, 1 H), 6.87 (m, 2 H), 7.15 (m, 5 H), 7.29 (m, 2 H), 7.50 (m, 2 H), 7.70 (m, 2 H).
Reaction SMILES: [C:1](=[S:3])=[S:2].[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([CH3:22])[CH:16]=1.[OH-].[K+].[CH3:25]I>CN(C)C=O.O>[S:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:1](=[S:3])[S:2][CH3:25])=[C:17]([CH3:22])[CH:16]=1
Reactant: CI
Reactant: S=C=S
Reactant: Cc1cc(OCc2nc3ccccc3s2)ccc1N
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=S)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
0.13 ml of carbon disulfide were added to a stirred solution of 500 mg of 4-(benzothiazol-2-yl)methoxy-2-methylaniline [prepared as described in Example 21(b) below] and 114.5 mg of potassium hydroxide in 6 ml of dimethylformamide and 6 ml of water with cooling in an ice-water bath, and the resulting mixture was stirred for 10 minutes. The temperature of the mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes at this temperature. The reaction mixture was again cooled in an ice-water bath and 0.15 ml of methyl iodide were added thereto and the resulting mixture stirred at this temperature for 10 minutes. The temperature of the reaction mixture was then elevated to room temperature and the mixture was stirred at this temperature for 2.5 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate to give 458.2 mg (yield 68%) of the title compound as a solid having a melting point of 133°-135° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([O:22]C)=O)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].O.[NH4+:25]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[O:12][C:13]3[C:19]([C:20]([NH2:25])=[O:22])=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN(C)C)c3)oc12
Reactant: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)Cc1cccc(-c2nc3cccc(C(N)=O)c3o2)c1
Temperature: 30 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
Methyl 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (66 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide (12 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 2.88 (s, 5H), 4.36 (s, 2H), 7.02 (s, 1H), 7.37-7.41 (t, J=8 Hz, 1H), 7.54-7.61 (m, 2H), 7.84-7.86 (d, J=8 Hz, 1H), 7.97-7.99 (d, J=8 Hz, 1H), 8.28-8.29 (d, J=4 Hz, 1H), 8.50 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16]([OH:18])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.ClC(OCC)=O.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1>[OH:35][CH2:34][CH2:36][NH:37][C:16](=[O:18])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1
Reactant: CCCCCCCCCCCCC(C)C1(C(=O)O)CO1
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(C)C1(C(=O)NCCO)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 g of 2-tetradecylglycidic acid (0.0007 mole) in 10 ml of anhydrous THF at 0° C. (ice water bath) with stirring is added 0.070 g of triethylamine (0.0007 mole) in a small amount of THF. The solution is stirred at 0° for 30 minutes and 76 mg of ethyl chloroformate (0.0007 mole) in a small amount of THF is added. The mixture is stirred at about 0° C. (ice water bath) for 3 hours (ppt. of Et3NHCl observed). At the end of 3 hours, 0.042 g (0.0007 mole) of ethanolamine in THF is added. The mixture is stirred at room temperature for 16 hours. The THF solvent is concentrated to about 1/3 its volume, water is added and the mixture extracted with ether. The ether extract is dried over Na2SO4 and the ether solvent removed to give a white solid of N-(2-hydroxyethyl)-2-tetradecylglycidamide which, upon recrystallization from acetone has a m.p. of 80°-82° C.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br-].[C:16]1([C:22]([PH3+])=[C:23](C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:37](=O)C1C=CC=CC=1>C(OCC)C.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:2]([CH3:37])([CH2:1][CH:23]=[CH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:12]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=Cc1ccccc1
Reactant: [PH3+]C(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(CC=Cc1ccccc1)C(=O)OCC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Under cooling (0° C.), diethyl methylmalonate ([609-08-5], 1.175 g, 7 mmol) was added to a suspension of NaH (60% in mineral oil, 325 mg, 8 mmol) in diethyl ether (30 ml). After 3 h at r.t, the solvent was evaporated and the residue was dissolved in DMF (20 ml). To this solution, triphenylvinylphosphonium bromide ([5044-52-0], 3.00 g, 8 mmol) and benzaldehyde ([100-52-7], 860 mg, 8 mmol) were added. The reaction mixture was stirred at 100° C. overnight, and was then taken up in ethyl acetate, washed (H2O), and dried (Na2SO4). The solvent was evaporated, and 2-methyl-2-(3-phenyl-allyl)-malonic acid diethyl ester was isolated from the residue by column chromatography (silica gel, ethyl acetate/heptane). MS: m/e=291.0 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30][CH2:31][CH3:32])[C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CO.[OH:35][O:36][S:37]([O-:39])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[CH3:49][CH2:50]OC(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:30]([CH2:31][CH3:32])=[O:35])[C:24]([C:26]([F:29])([F:27])[F:28])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([S:37]([CH2:49][CH3:50])(=[O:39])=[O:36])[C:24]([C:26]([F:28])([F:29])[F:27])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(SCC)cc3n2COCCOC)c1
Reactant: O=S([O-])OO
Reactant: CCOC(C)=O
Agent: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)(=O)CC)cc3n2COCCOC)c1
Product: CCOC(=O)c1cnn(-c2nc3cc(C(F)(F)F)c(S(=O)CC)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 44 h
Yield: 45 %
Yield: 48 %

Procedure:
To a mixture of 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.501 g, 1.14 mmol) and MeOH (5.7 mL) was added a solution of Oxone®/potassium peroxymonosulfate (1.47 g, 2.40 mmol) in water (5.7 mL). The mixture was stirred for 44 h at 23° C. EtOAc (50 mL) and water (30 mL) were added and the biphasic mixture stirred. The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-80% EtOAc/hex) to yield the titled compound (0.232 g, 45% yield, 2:1 mixture of regioisomers) and 1-[1-(2-methoxy-ethoxymethyl)-6-ethylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.260 g, 48% yield, 5:2 mixture of regioisomers). MS (ESI/CI): mass calcd. for C13H23ClN4O5S, 454.1; m/z found, 455.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.90 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.6 Hz, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 6.25-6.16 (m, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.68-3.62 (m, 2H), 3.46-3.41 (m, 2H), 3.27 (s, 3H), 3.26-3.13 (m, 1H), 2.94-2.83 (m, 1H), 1.39 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(ON=O)(C)(C)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](N)[CH:9]=1.B(F)(F)[F:20].CCOCC>C1C(Cl)=CC=C(Cl)C=1>[F:20][C:10]1[CH:9]=[N:8][C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: FB(F)F
Reactant: Nc1cnc2ccccc2c1
Agent: CC(C)(C)ON=O
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: Fc1cnc2ccccc2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Tert-butylnitrite (4.6 ml, 38.7 mmol) was added dropwise over 15 min to a solution of quinolin-3-amine (4.61 g, 32.0 mmol) and borontrifluoride-etherate (6 ml, 47.3 mmol) in dichlorobenzene (100 ml). The solution was heated to 100° C. After stirring for 1 h, the solution was cooled to ambient temperature and the dichlorobenzene was decanted leaving 3-fluoroquinoline as a black residue. Method [8] retention time 3.28 min by HPLC (M+ 148).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[N:4]=[CH:3]1.[CH3:14][NH:15][CH3:16].C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:14][N:15]([CH3:16])[C:11]([C:10]1[C:5]2[N:4]=[CH:3][NH:2][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:13]
Reactant: CNC
Reactant: O=C(O)c1cccc2[nH]cnc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid hydrochloride (1 g, 5.04 mmol), dimethylamine (2M in THF; 3.78 mL, 7.55 mmol) and ethyldiisopropylamine (3.51 mL, 20.1 mmol) in DMF (5.0 mL) at room temperature was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (1.95 g, 5.14 mmol) in a single portion. The mixture was stirred at room temperature overnight then concentrated in vacuo. The product was purified by SiO2 chromatography followed by trituration with Et2O providing 1H-benzoimidazole-4-carboxylic acid dimethylamide (730 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12].N1C=CC=CC=1.Cl>ClCCCl>[CH3:10][S:11]([O:6][CH2:5][C:3]([C:2](=[O:1])[CH3:9])([CH3:4])[CH2:7][O:8][S:11]([CH3:10])(=[O:13])=[O:12])(=[O:13])=[O:12]
Reactant: CC(=O)C(C)(CO)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)C(C)(COS(C)(=O)=O)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
66 g (0.5 mol) of 3-oxo-2,2-bis-[hydroxymethyl]-butane (for the preparation, see Beilstein H 1, E III 3306, IV 4132 and J. Chem. Soc., London 1932, 2671) were dissolved in 300 ml of 1,2-dichloroethane, 114.5 g (1 mol) of methanesulphonyl chloride were added dropwise and 158 g (2 mol) of pyridine were added dropwise at 0° to 5° C. The reaction mixture was stirred for a further 15 hours at room temperature and the batch was then introduced into 600 ml of ice-water and 100 ml of concentrated hydrochloric acid. A solid precipitated out and this was filtered off. The aqueous phase was extracted with 1 liter of methylene chloride; the solid was dissolved in the methylene chloride phase, the organic phase was dried over sodium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was suspended in 200 ml of ether. 100 g (about 70% of theory) of 2-acetyl-2-methyl-propane-1,3-diol bismethanesulphonate with a melting point of 105° to 108° C. were obtained. ##STR12##
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[C:24]2[C:19]3=[C:20]([CH2:25][CH2:26][C:27](=[O:28])[N:18]3[CH2:17][CH2:16]1)[CH:21]=[CH:22][CH:23]=2>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]([C:22]2[CH:23]=[C:24]3[C:19]4=[C:20]([CH2:25][CH2:26][C:27](=[O:28])[N:18]4[CH2:17][CH2:16][CH2:15]3)[CH:21]=2)=[O:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=C1CCc2cccc3c2N1CCC3
Product: CC(=O)N1CCC(CCC(=O)c2cc3c4c(c2)CCC(=O)N4CCC3)CC1

Procedure:
Using 3-(1-acetyl-4-piperidinyl)propanoic acid (13.8 g) and 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one (10.8 g) according to the same method as that of Reference Example 172, the title compound was obtained as colorless crystals (15.5 g) having a melting point of 130 to 131° C.