Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[C:7](/[CH:9]=[CH:19]/[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(CC=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C/C=C/C#N)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
To a solution of 1 M of potassium tert-butoxide in THF (45.5 mL, 0.0455 mol) at 0° C. was added drop wise a solution of diethyl cyanomethylphosphonate (7.72 mL, 0.0477 mol) in THF (70 mL). The reaction mixture was warmed up to at RT, cooled to 0° C. again, and a solution of tert-butyl 4-(2-oxoethyl)piperazine-1-carboxylate (9.90 g, 0.0434 mol) in THF (10 mL) was added. The reaction mixture was allowed to warm up to RT and stirred for 2 more hours. After being quenched with water, the mixture was extracted with EtOAc. The organic layers were dried and concentrated. The residue was purified by silica gel column eluting with DCM to give the desired product (7.5 g, 69%).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([F:15])[CH:6]=1>CO>[F:15][C:7]1[CH:6]=[C:5]([CH2:4][NH:2][CH3:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1
Reactant: CN
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Solvent: CO
Product: CNCc1cc(F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
Methylamine 33% in MeOH (1.5 mL, 46.5 mmol) was dissolved in MeOH (15 mL). The mixture was heated at 50° C. under stirring and 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (1 g, 3.88 mmol) was added. The reaction mixture was stirred at this temperature for 3 h. The solvent was removed under vacuo, then NaOH 1M (50 mL) was added and the aqueous layer was extracted with DCM (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated under vacuo to give the title compound as a yellow oil (0.5 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (s, 1H), 7.30 (m, 2H), 7.25 (m, 1H), 3.88 (s, 2H), 2.54, (s, 3H). UPLC-MS: Rt=0.51; m/z (ES+): 208.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: S=C=Nc1ccccc1-c1ccc(Cl)cc1

Procedure:
Reaction of 2-amino-4'-chlorobiphenyl (8.7 g) and thiophosgene (7.4 g) in a mixture of dioxane (10 ml) and water (10 ml) at 0°-5° C. for 20 minutes and then at ambient temperature for 3 hours yielded 4'-chloro-2-biphenylylisothiocyanate (m.p. 63° C.) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:30])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[CH2:8][NH:30][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: BrCC1OCCO1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(NCC2OCCO2)ccc1OCCN1CCCC1

Procedure:
A suspension of K2CO3 (235 mg, 1.70 mmol), 2-(bromomethyl)-1,3-dioxolane (400 mg, 1.70 mmol), and 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (3.0 g, 14.5 mmol), preparation described in Patent: WO2002/101146, in DMSO (17 mL) was heated at 80° C. for 24 hr. After removal of any precipitate by filtration, the filtrate was partitioned between EtOAc/H2O (100/20 mL). The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 0%-20% gradient EtOAc/Hexanes to elute the title compound as a yellow brownish oil (150 mg, 27%) MS (ESI) 323 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:24])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (5.0 g, 25 mmol), phenyl isothiocyanate (3.72 g, 25 mmol) and toluene (20 ml) was heated at reflux for 1.5 hours, then left at room temperature overnight. The solution was diluted with ether, and the product filtered off; yield 5.6 g (67%), m.p. 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[C@H:21]([C:22]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH:7]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([N:12]2[C@H:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)=[O:23])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)/C=C/c2cc(Cl)ccc2-n2cnnn2)cc1

Procedure:
(S,E)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)benzoate: To 1B (0.1 g, 0.284 mmol) and Intermediate 1 (0.099 g, 0.284 mmol) in DMF (2 ml) was added DIEA (0.149 ml, 0.851 mmol). The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (MgSO4). Purified by normal phase chromatography to afford 0.15 g of desired product as yellow solid. MS (ESI) m/z: 585.2 (M+H)+. (M+H)+.
Reaction SMILES: Cl[Si:2]([CH3:13])([CH3:12])[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11].[C:14]1([C-:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+]>CCOCC>[CH3:12][Si:2]([CH3:13])([CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21]1)[CH:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]1[CH3:11]
Reactant: c1ccc(-[c-]2ccc3ccccc32)cc1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccccc3)c3ccccc32)C(C)=C1C
Reaction time: 23 h

Procedure:
To a solution of chlorodimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silane (5.00 g, 23.3 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium(1-phenylindenide) (4.85 g, 24.5 mmol, 1.05 eq.). The reaction was stirred for 23 hours, and the volatiles were then removed under vacuum. The residue was extracted with pentane (40 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a thick oil. Yield 7.07 g (82%). 1H NMR(C6D6): δ 7.74 (d, 1H), 7.65 (d, 2H), 7.48 (d, 1H), 7.25 (m, 5H), 6.60 (s, 1H), 3.69, (s, 1H), 2.92 (br s, 1H), 1.93 (s, 3H), 1.90 (s, 3H), 1.82 (s, 3H), 1.821 (s, 3H), −0.09 (s, 3H), −0.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:27]([O:29][CH:30]([O:34][CH2:35][CH3:36])[CH2:31][CH2:32]Cl)[CH3:28]>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH2:32][CH2:31][CH:30]([O:34][CH2:35][CH3:36])[O:29][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: CCOC(CCCl)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC)OCC
Yield: 82.1 %

Procedure:
To a solution of 27.6 g, (0.1 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (D. E. Schwartz, W. Vetter, and G. Englert, Arzneim.-Forsch. (Drug Res.) 1970, 20, 1867; G. Rey-Bellet and R. Reiner, Helv. Chim. Acta 1970, 53, 945) in 400 mL of dry dimethyl sulfoxide was added 11.22 g (0.10 mole) of potassium t-butoxide. To the resulting suspension was added dropwise 17.92 g (0.107 mole) of β-chloropropionaldehyde diethylacetal. The mixture was heated at 65° overnight. The solvent was removed under vacuum and the residue was partitioned between 750 mL methylene chloride and 750 mL of 0.1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with an additional 750 mL of methylene chloride. The organic layers were combined, washed with 750 mL of water, dried (MgSO4), and purified by flash column chromatography to yield 33.38 g (83%) of the title compound (mp 105°-106.5°). Anal. Calcd for C 20 H30N4O5 : C, 59.10; H, 7.44; N, 13.78. Found: C, 58.71; H, 7.40; N, 13.58.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:13]2[C:12](=[O:24])[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4].[CH3:26][C:27]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:28]=1[O:29][CH2:30][CH:31]1[O:33][CH2:32]1>CO.Cl>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:13]2[C:12](=[O:24])[CH2:11][N:10]([CH2:32][CH:31]([OH:33])[CH2:30][O:29][C:28]3[CH:34]=[CH:35][CH:36]=[C:37]([CH3:38])[C:27]=3[CH3:26])[CH2:9][C:8]=2[NH:7][C:6]=1[CH3:25])=[O:4]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1c(F)ccc(Cl)c1Cl
Reactant: Cc1cccc(OCC2CO2)c1C
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(CC(O)COc3cccc(C)c3C)C2)C1c1c(F)ccc(Cl)c1Cl
Yield: 16.7 %

Procedure:
4-(2,3-Dichloro-6-fluorophenyl)-1,4,5,6,7,8-hexahydro-2-methyl-5-oxo-1,7-naphthyridine-3-carboxylic acid methyl ester (12.1 g), 5.3 g of 3-(2,3-dimethylphenoxy)-1,2-epoxypropane and 150 ml of methanol were combined and refluxed for 18 hours. The alcohol was evaporated in vacuo. The residue was chromatographed on silica-gel using a 5% methanol-ethyl acetate system. The residue obtained on evaporation was dissolved in methanol and saturated with hydrogen chloride. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. A precipitate formed on standing at room temperature. The solid was separated and treated with boiling acetonitrile. The solid was dried in vacuo to obtain 2.8 g of the title compound as the hydrochloride salt, m.p. 190°-3° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:3][CH2:2][CH2:1][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCCOCc1ccccc1
Yield: 53 %

Procedure:
A mixture of 156.75 g of dry ethylene glycol and 64.37 g of 87.2% potassium hydroxide is warmed and stirred until a complete solution. The mixture is then stirred in a 90° C. oil bath and 130.51 g of benzyl chloride is added dropwise over 2 hours. This mixture is then stirred at 130° C. for 2 hours, cooled and 500 ml of water added. The oil is extracted twice with ether. The extracts are combined and evaporated. The residue is distilled, giving 83.2 g of ethylene glycol monobenzyl ether.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]3[C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1S[C:44]2C(C(OCC)=O)=CC=C[C:45]=2N=1>>[CH2:1]([NH:5][C@H:6]1[C@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:24][C:25]3[C:31]([C:32]([O:34][CH2:44][CH3:45])=[O:33])=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)O)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (77d) (16.3 mg, 0.038 mmol), sodium carbonate (40 mg, 0.38 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (1f) (13.2 mg, 0.046 mmol), to obtain 15.5 mg of the title compound (76%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>C(OCC)C>[C:20]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([Cl:12])([Cl:10])[Cl:11])[N:3]=1)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]
Reactant: C/C=C/C(=O)Cl
Reactant: Cc1cc(O)nc(C(Cl)(Cl)Cl)n1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C/C=C/C(=O)Oc1cc(C)nc(C(Cl)(Cl)Cl)n1
Yield: 30.5 %

Procedure:
To a solution of 3.0 g (0.02 mole) 4-hydroxy-6-methyl-2-trichloromethylpyrimidine and 1.3 g (0.02 mole) triethylamine in 75 ml diethyl ether was added 1.4 g (0.02 mole) crotonyl chloride. The reaction mixture was refluxed for 15 hours and filtered, and the filtrate was concentrated in-vacuo to give a viscous oil as residue. Trituration with petroleum ether caused the oil to solidify. Recrystallization from isopropyl alcohol gave 1.8 g (45% yield) of pure product; m.p. 55° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:15])([CH3:16])[C:12]([O:14][CH3:18])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2]
Reactant: CC(C)(Nc1ccc(C(N)=O)c(F)c1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Temperature: 57.5 °C

Procedure:
A solution of 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoic acid and K2CO3 (1.5 equivalents) in DMF (10 fold) was stirred at RT for 10 min. MeI (1.5 equivalents) was added and the reaction mixture was heated at 55-60° C. for 2 h. The solvent was removed under reduced pressure and the reaction mixture was poured in water, extracted with ethyl acetate (100 mL×2), dried over Na2SO4, concentrated and purified by column chromatography. 1H NMR (CDCl3, Freebase): δ (ppm) 7.9 (t, 1H), 6.5 (bs, 1H), 6.4 (d, 1H), 6.2 (d, 1H), 5.6 (bs, 1H), 4.6 (bs, 1H), 3.75 (s, 3H), 1.6 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:20]([C:29]1[CH:30]=[CH:31][C:32]([C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])=[O:10])=[CH:33][CH:34]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)CCCCC(=O)O
Reactant: CCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCc1ccc(C(=O)CCCCC(=O)OC)cc1

Procedure:
Adipic acid monomethyl ester (50 g; 0.31 mole) is converted to the acid chloride with thionyl chloride (50 g) in the manner described in Example 1. This product is reacted with nonylbenzene (400 ml) and aluminum chloride (80 g; 0.6 mole) and the product purified in a manner analogous to that described in Example 1 to provide methyl 5-(4-n-nonylbenzoyl)pentanoate (35.2 g). This ester (35 g) is hydrolysed with sodium hydroxide in aqueous ethanol as in Example 1 to give, on recrystallization from aqueous ethanol, 5-(4-n-nonylbenzoyl)pentanoic acid (24 g) as colorless crystals, m.p. 29°-31° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](=O)[CH2:9][S:8][C:7]=2[CH:12]=1.[BH4-].[Na+]>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2c(c1)SCC2=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
6-Methoxybenzo[b]thiophen-3(2H)-one (1.4 g, 7.76 mmol) was dissolved in a mixture of methanol (18 mL) and 2.5 M sodium hydroxide (3 mL). The mixture was treated with sodium borohydride (0.589 g, 15 mmol) in 10 mL of methanol and 3 mL of 2.5 M sodium hydroxide. The reflux was heated to reflux for 1 h and then at 60° C. overnight. The reaction was cooled down to room temperature and the methanol removed in vacuo. The remaining aqueous layer was acidified to pH 4 with 1 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate and washed with 1 N HCl. The organic layer was further washed with water, saturated sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate, concentrated and purified by flash chromatography usng a gradient of 20 to 50% ethyl acetate in hexanes to afford a clear oil (0.843 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]2[CH2:28][S:27]C(=S)[S:25]2)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]([SH:25])[CH2:28][SH:27])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(S)CS)cc(OC)c1OC
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.20 g, 5.27 mmole) is added to 15 ml dry diethylether. To this slurry is added 4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (32) (1.0 g, 3.31 mmole) predissolved in 20 ml dry THF. The reaction is refluxed under an N2 atmosphere for 12 hours. The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (9.836 g, 97%). NMR: (DCDl3) 2.34,d,1H;2.95,m,1H;3.09,m,1H; 3.84,s,3H;3.87,s,6H;4.03,m,1H;6.53,s,2H. M.S. (IBu) 261 (100%). Melting Point: 72.5°-73.5° C. C,H,S Analysis: (theoretical, actual) C (50.74,50.85); H (6.19,6.20); S (24.63,24.53).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CNC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Product: CNC(=O)c1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using N-methyl-1H-indole-5-carboxamide (intermediate-14) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17](SC#N)[C:16]([N+:22]([O-:24])=[O:23])=[CH:15][N:14]=2)=[CH:8][CH:7]=1.O>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[N:14]=[C:15]([NH:4][CH:1]3[CH2:3][CH2:2]3)[C:16]([N+:22]([O-:24])=[O:23])=[CH:17][N:18]=2)=[CH:10][CH:11]=1
Reactant: N#CSc1nc(Nc2ccc(Cl)cc2)ncc1[N+](=O)[O-]
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(Nc2ccc(Cl)cc2)nc1NC1CC1
Temperature: 25 °C

Procedure:
0.93 g of cyclopropylamine are added to 1 g of 2-(4-chlorophenylamino)-4-thiocyanato-5-nitro-pyrimidine in 10 ml dimethylformamide and stirred for 1½ hours at ambient temperature. 30 ml of water are added, the solid is suction filtered, washed with water and dried.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)=[O:17])[CH3:14].[NH4+].[Cl-]>CCOCC>[CH2:13]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20]([OH:23])([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Yield: 61 %

Procedure:
364 mg magnesium was suspended in 2 ml ether, under nitrogen. 150 ul 4-bromobenzo-trifluoride was added and then a solution of 12.6 mmol 4-bromobenzotrifluoride in 1.5 ml ether was added dropwise over a period of 10 minutes at room temperature. The mixture came mildly exothermic and turned red-brown while the grignard reagent formed during 1.5 h of stirring. The mixture was cooled down to 0° C. A solution of 12.5 mmol 1-N-ethoxycarbonyl-3-pyrrolidone in 14 ml ether was added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 2 h30. 20% NH4Cl was added dropwise, at 0° C., to quench the reaction. The mixture was allowed to warm to room temperature. The aqueous layer was extracted 3 times with ether. The combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (eluent: heptane-ethyl acetate 1/1) to yield the title compound (61%) as a yellow solid. MS (m/e): 362.2 ([M+59], 100%).
Reaction SMILES: C(Cl)Cl.[OH:4][C:5]1[C:6]([CH3:19])=[C:7]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9].[F:20][C:21]([F:27])([F:26])[S:22](O)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:18][S:15]([C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:19])[C:5]=1[O:4][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23])(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(O)c1C
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)c1C
Temperature: 0 °C
Yield: 99 %

Procedure:
To 100 ml methylene chloride, was dissolved methyl 3-hydroxy-4-methanesulfonyl-2-methylbenzoate in an amount of 8.8 g (0.036 mole), and the resulting solution was then added with pyridine in an amount of 8.3 g (0.11 mole), cooled at 0° C. and then added with anhydrous trifluoromethanesulfonic acid in an amount of 12.2 g (0.043 mole). After stirring the mixture for an hour at an ambient temperature, the reacted-mixture was washed with 1N-hydrochloric acid and then with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent remained in the mixture was distillated out under reduced pressure to obtain methyl 4-methanesulfonyl-2-methyl-3-(trifluoromethanesulfonyl)oxybenzoate in an amount of 13.5 g. The yield was 99%.