Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.Cl.[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH2:29])=[CH:21][CH:20]=1)=[O:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:26][C:27](=[O:40])[C@@H:28]([CH2:30][CH2:31][CH2:32][NH:33][C:34]([NH2:39])=[N:35][N+:36]([O-:38])=[O:37])[NH:29][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:12])=[CH:23][CH:24]=1)=[O:16]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)c2cc3ccccc3[nH]2)cc1
Yield: 20 %

Procedure:
Prepared analogously to Example 69a) from 1H-indole-2-carboxylic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 20% of theory.
Reaction SMILES: C1(S([C:10]([F:21])([F:20])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)C=CC=CC=1.CC([O-])(C)C.[K+]>C1COCC1.CN(C=O)C>[F:20][C:10]([F:21])=[CH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)C(F)(F)CCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: FC(F)=CCCc1ccccc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Typical Procedures for the Preparation of 1,1-Difluoro-1-alkenes (10) from Alkyl-substitued Difluoromethyl Sulfones (4): Under an argon atmosphere, into a Schlenk flask containing 1,1-difluoro-4-phenylbutyl phenyl sulfone (4g) (100 mg, 0.32 mmol) in THF (4 mL) at −20° C., was added dropwise via a syringe t-BuOK (224 mg, 2 mmol) in DMF (4 mL). The reaction mixture was stirred at −20° C.˜rt for 1 h, and the completion of the reaction was monitored by 19F NMR [δ −89.6 (d, J=46.6 Hz, 1F); −91.6 (dd, J=46.6 Hz, 24.8 Hz, 1F)]. The reaction was then quenched by adding aqueous NaCl solution (10 mL), followed by extraction with Et2O (15 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the solvent was removed. The crude product was purified by a flash chromatography to give 1,1-difluoro-4-phenyl-1-butene (10a) (46 mg, 85% yield) as a colorless liquid. The characterization data is consistent with that early reported.8h
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]([NH:13][C:14]1[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=3)[N:15]=1)[CH2:10][CH2:9][CH2:8]2.[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:29]([NH:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH:13][CH:11]1[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH2:8][CH2:9][CH2:10]1)[CH:23]=[CH:22]2)=[O:30])([CH3:27])[CH3:26]
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: CC(C)N=C=O
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=405.5 (M+H+).
Reaction SMILES: C=O.[CH3:3][NH:4][C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].C(N(CC)CC)C.[O:18]1[CH2:23]COC[CH2:19]1>C1(C)C=CC=CC=1>[CH3:3][N:4]1[C:5](=[N:7][N+:8]([O-:10])=[O:9])[NH:6][CH2:23][O:18][CH2:19]1
Reactant: C1COCCO1
Reactant: CNC(=N)N[N+](=O)[O-]
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1COCNC1=N[N+](=O)[O-]

Procedure:
30.5 g of paraformaldehyde are added, at room temperature, to a mixture of 20 g of N-methyl-N′-nitroguanidine, 17 g of triethylamine, 100 ml of dioxane and 100 ml of toluene, and the mixture is refluxed for 16 hours and subsequently evaporated in vacuo. The residue is purified by column chromatography [silica gel; dichloromethane/methanol (95:5)], giving the title compound which melts at 137 to 139°.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]2[CH:20]=[C:21]([Cl:23])[CH:22]=[C:7]2[C:6]=1[OH:24])=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:23][C:21]1[CH:22]=[C:7]2[C:6]([OH:24])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:10](=[O:11])[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:8]2[CH:20]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cn2n(Cc2ccc(Cl)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 6-chloro-4-hydroxy-2-oxo-1-(4-chloro-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14](OS(C)(=O)=O)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CS(=O)(=O)OCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCn2cnc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-phenyl-1H-imidazole (1 g, 8.75 mmoles) in DMF (8 mL) is added NaH 60% dispersion in mineral oil (455 mg, 11 mmoles). The reaction mixture is stirred at room temperature for 1 hour, then methanesulfonic acid phenethyl ester (example 4D) (1.84 g, 9.12 mmoles) is added. The reaction mixture is then heated at 60° C. for 2 hours. Water is added, and the aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (100:0) then (98:2) to give 1-phenethyl-4-phenyl-imidazole.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].CN1CCOCC1>C(#N)C>[CH2:12]([O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[NH:22][C@@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH3:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(C)Br
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
Leucine benzyl ester para-toluene sulphonic acid salt (113 g) in dry acetonitrile (800 ml) was treated with methyl 2-bromopropionate (62.7 ml) and N-methyl morpholine (100 ml) under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue in ethyl acetate washed with brine, dried (Na2SO4) and evaporated. Chromatography of the resulting oil on silica in 1:4 ethyl acetate-hexane gave N-[1-(R)-methoxycarbonylethyl]-L-leucine benzyl ester (45 g) as the faster running fraction. This material was treated exactly as described above in Example 2 to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH:37]1[CH2:41][CH2:40][C@@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:48])[CH3:47])[CH2:38]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 61.7 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (950 mg) and tert-butyl (3R)-3-pyrrolidinylcarbamate (560 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (390 mg), and the mixture was stirred under reflux for 23 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 4% methanol/chloroform to give tert-butyl [(3R)-1-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-3-pyrrolidinyl]carbamate (700 mg) as a solid.
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:19]=2[C:20]([NH:14][C@@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@@H:8]2[N:3]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:21])[CH2:17][CH2:16]1
Reactant: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Product: O=C(N[C@@H]1CCCC[C@@H]1N1CCCC1)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, white solid, MS: m/e=449.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AN).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O)([O-])=O.[H][H]>C(O)C.[Pd]>[CH:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Cn2cccc2C=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2

Procedure:
A solution of 10.0 g of 1-[2-nitro-5-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde in 150 ml of absolute ethanol containing 1.0 g of 10% Pd/c is hydrogenated in a Parr apparatus for 16 hours under 40 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to a residue of 5.5 g of the desired product as a solid; mass spectrum (M+H)255.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([O:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCCC(O)CCCCl
Product: CC(=O)OC(CCCCl)CCCC(C)C

Procedure:
A mixture of 1-chloro-8-methyl-4-nonanol (22.73 g.; 0.118 mole) and acetic anhydride (24.07 g.; 0.236 mole) is heated on a steam bath for 11/2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)=[O:6].[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][CH2:8][C:9]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:11])=[O:6]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1cccc(Cl)c1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1cccc(Cl)c1

Procedure:
The preceding compound is converted to 3-[3-chlorobenzoyl]propionic acid, hydroxysuccinimide ester as described in Example 15 and coupled with L-proline as described in Example 16 to give 1-[3-(3-chlorobenzoyl)propionyl]-L-proline. The preceding compound is reacted with bromine in acetic acid as described in Example 20 to give 1-[3-bromo-3-(3-chlorobenzoyl)propionyl]-L-proline. The preceding compound in a mixture of ethanol-water (1:1) is reacted with potassium thioacetate as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Reactant: Cc1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-7-nitro-1,3-benzothiazole (200 mg, 0.772 mmol), 2,4-dimethylphenol (0.093 ml, 0.772 mmol) and potassium carbonate (128 mg, 0.772 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h. The mixture was diluted with water and extracted with ethyl acetate (AcOEt). The extract was washed with saturated NaHCO3 solution and brine, dried over Magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][C:31]([F:34])([F:33])[F:32].C(OCC)(=O)C>CS(C)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([O:22][CH2:30][C:31]([F:34])([F:33])[F:32])[N:12]=2)=[CH:15][N:16]=1
Reactant: COc1ccc(-n2nc(O)nc2-c2ccc(OC)nc2)cc1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(OCC(F)(F)F)nc2-c2ccc(OC)nc2)cc1
Temperature: 100 °C
Yield: 23.5 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-5-(6-methoxypridin-3-yl)-1H-1,2,4-triazol-3-ol (200 mg, 0.67 mmol), potassium carbonate (278 mg, 2.01 mmol), and 2-iodo-1,1,1-trifluoroethane (0.198 mL, 2.01 mmol) in dimethylsulfoxide (1 mL) were heated at 100° C. for 1 hour. After cooling, ice water and ethyl acetate were poured into the mixture and the organic layer was separated, washed with brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (toluene-ethyl acetate 10:1). The desired product was washed with hexane to give 2-methoxy-5-(1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole-5-yl)pyridine. (60 mg, 23.5% yield)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1C(C(O)=O)=C(C)N(C2C=CC(C(F)(F)F)=CN=2)[N:21]=1>>[NH2:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)c(C)c1C(=O)O
Product: Nc1ccc(C2(O)CCC3(CC2)OCCO3)nc1

Procedure:
8-(5-Bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.0 g) described in Reference Example 76 (1) was used in place of 1-(5-bromopyridin-2-yl)-c-4-(tert-butyldimethylsilanyloxy)-r-1-cyclohexanecarbonitrile in Reference Example 144 (2) and (3), and reacted and treated in a similar manner to give the titled compound (1.28 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][OH:8])[CH:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Temperature: 110 °C
Reaction time: 18 h
Yield: 0.2 %

Procedure:
A mixture of 5-chloro-2-nitrobenzyl alcohol (1.9 g, 10.0 mmol), morpholine (0.9 mL, 10 mmol), and K2CO3 (1.4 g, 10 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was concentrated in vacuo, poured into aqueous sodium bicarbonate (NaHCO3) (5% w/v, 25 mL), and extracted with dichloromethane (25 mL). The organic extract was washed with brine (25 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 EtOAc/MeOH) to yield a solid impure product. The residue was repurified in the same manner and the resulting solid was triturated with hexanes (10 mL) to afford the product as a yellow solid (5 mg, 2%).
Reaction SMILES: [CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][OH:23])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]N(C=O)C.[H-].[Na+].CI>O>[CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][O:23][CH3:26])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: Cc1nc(CN2CCOC[C@@H]2CO)c2cc(C3CCCCC3)sc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC[C@H]1COCCN1Cc1nc(C)nc2sc(C3CCCCC3)cc12
Reaction time: 0.08 h

Procedure:
To a mixture of {(3S)-4-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]morpholin-3-yl}methanol (132 mg) and DMF was added NaH (60% oil, 15 mg) under ice-cooling, followed by stirring at the same temperature for 5 minutes, and then CH3I (17 μL) was added thereto, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-{[(3S)-3-(methoxymethyl)morpholin-4-yl]methyl}-2-methylthieno[2,3-d]pyrimidine (102 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13](=O)[CH3:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:17][O:18][NH2:19]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:18][N:19]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: CC(=O)c1ccccc1N1CCOCC1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CON=C(C)c1ccccc1N1CCOCC1
Yield: 93.4 %

Procedure:
A mixture of Example 49A (1.22 g, 5.94 mmol) and methoxyamine hydrochloride (550 mg, 6.59 mmol) in pyridine (20 mL) was stirred at room temperature for 12 h. The reaction was diluted with ethyl acetate and washed sequentially with 3 N HCl, 1 N HCl and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure to give 1.3 g of the title compound. MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH2:24][CH3:25])[C:16]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])=[O:17].O>CN(C=O)C>[CH2:22]([O:21][CH2:20][CH2:19][O:18][C:16]([CH:15]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7])[CH2:24][CH3:25])=[O:17])[CH3:23]
Reactant: CCOCCOC(=O)C(Br)CC
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOC(=O)C(CC)n1cccc1C=O
Yield: 62 %

Procedure:
A mixture consisting of pyrrole-2-carboxaldehyde (9.5 g, 0.1 mole), anhydrous potassium carbonate (27.6 g, 0.2 mole) and 2-ethoxyethyl α-bromobutyrate (23.6 g, 0.105), as previously described, were kept under stirring in 20 ml DMF at room temperature for 12 hours. The reaction mixture was carefully poured into water, extracted with ethylacetate and the extracts were dried on sodium sulfate. After evaporation of the solvent, 15.5 g of 1-[1-(2-ethoxyethoxycarbonyl)-propyl]-2-formyl pyrrole were obtained as a brown oil, which was used in the subsequent step without any further purification.
Reaction SMILES: [CH3:1][CH:2]1[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.[OH-].[Na+].Cl.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O>[CH3:1][CH:2]1[O:3][C:4]2=[CH:13][C:8]3[NH:9][C:10]([S:12][CH2:25][C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=4)=[N:11][C:7]=3[CH:6]=[C:5]2[O:14]1
Reactant: Cc1ccc(CCl)nc1
Reactant: CC1Oc2cc3nc(S)[nH]c3cc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)OC(C)O4)nc1
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 3.9 g of 2-methyl-5H-1,3-dioxolo-(4,5-f)benzimidazole-6-thiol, suspended in 60 ml of alcohol, were added dropwise while stirring 1.57 g of sodium hydroxide in 30 ml of water and, after 30 minutes, there were added 3.44 g of 5-methyl-2-chloromethylpyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in 500 ml of ethyl acetate. This was washed with 100 ml of sodium hydroxide, three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/petroleum ether (low boiling) and there were obtained 4.8 g (81.7% of theory) of 2-methyl-6-[[(5-methyl-2-pyridyl)methyl]-thio]-5H-1,3-dioxolo(4,5-f)benzimidazole of melting point 147°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[CH3:23])=[CH:4][CH:3]=1.ClS([N:28]=[C:29]=O)(=O)=O>CN(C=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:29]#[N:28])=[C:9]2[CH3:23])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1c(C#N)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Temperature: 20 °C
Yield: 76.7 %

Procedure:
To a cold solution of 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (Example 1) (750 mg, 2.28 mmol) in DMF (8 ml) and acetonitrile (8 ml) at -78° C., chlorosulfonyl isocyanate (200 μl, 2.28 mmol) was added. The reaction mixture was warmed to 20° C. over 4 hours, quenched by adding excess of water, and extracted with ethyl acetate. The organic fractions were washed with brine, dried (MgSO4), filtered and concentrated. The crude colorless liquid (0.77 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole-3-carbonitrile (620 mg, 77%) as a white solid: mp (DSC) 205° C. Anal Calc'd. for C19H15N2SFO2 : C, 64.39; H, 4.27; N, 7.90. Found: C, 64.11; H, 4.45; N, 7.60.