Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].O1CCCC1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][Si](C(C)(C)C)(C)C)[CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)OCc2ccccc2)c1
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc(O)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
A 1.0 M solution oftetrabutylammonium fluoride in tetrahydrofuran (26.6 mL, 26.6 mmol) was added to neat benzyl ester 24 (5.00 g, 13.3 mmol), the reaction stirred 10 minutes at ambient temperature, and evaporated in vacuo. The crude product was dissolved in methylcne chloride, the solution washed with dilute aqueous NaHCO3, dried over Na2SO4, and filtered. The evaporated filtrate was then washed repeatedly with hexanes and dried in vacuo giving product 25 as a gold oil (3.40 g, 98%), 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 7H), 7.1 (t, 1H, J=2.1 Hz), 5.28 (s, 2H).
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][O:9]C(=O)C)=[C:6]([I:13])[C:5]([CH2:14][O:15]C(=O)C)=[C:4]([I:19])[C:3]=1[CH2:20][O:21]C(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[I:1][C:2]1[C:3]([CH2:20][OH:21])=[C:4]([I:19])[C:5]([CH2:14][OH:15])=[C:6]([I:13])[C:7]=1[CH2:8][OH:9]
Reactant: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1c(I)c(CO)c(I)c(CO)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,3,5-Triiodo-2,4,6-triacetoxymethylbenzene (9.3 g, 13.8 mmol) was suspended in methanol (120 ml) and K2CO3 (0.32 g, 2.3 mmol) was added. The mixture was stirred at ambient temperature for 16 h, and , after neutralization of the solution with 2M aqueous HCl, the organic solvent was evaporated. The residue was suspended in water and the white solid was collected by filtration and washed with water, methanol and ether. Yield: 7.1 g (94%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.7 g, 3.06 mmol) in methanol (20 mL), was added 10 wt % palladium on carbon (0.5 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.2 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:20])[CH2:16][CH2:17][C:18]=3[O:19][CH3:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Temperature: 40 °C
Yield: 35.4 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-cyclopentane-1,3-dione (2.21 g, 7.25 mmol) in acetone (50 ml) was added potassium carbonate (1514 g, 10.87 mmol) followed by iodomethane (670 μl, 10.87 mmol) and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (818 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([O:15][CH:16]([CH3:18])[CH3:17])[CH:8]=1.CN(C)[CH:21]=[O:22].B(F)(F)F.CCOCC>O1CCCC1.O>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([CH:21]=[O:22])=[CH:8][C:9]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: CSc1ccc(Br)cc1OC(C)C
Reactant: CN(C)C=O
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(C=O)cc1OC(C)C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexanes (14.82 mL; 2.5M) is added to a solution of 4-bromo-2-prop-2-yloxythioanisole (8.8 g) in dry tetrahydrofuran (70 mL), whilst cooling the mixture to -70° C. under nitrogen. The mixture is stirred for 1 hour at -70° C. Dry dimethylformamide (5.22 mL) and boron trifluoride diethyl etherate (8.29 mL) are added sequentially and the mixture is allowed to warm to room temperature. The mixture is poured into water and the product is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated in vacuo, and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (9:1 v/v) to give 4-methylthio-3-prop-2-yloxybenzaldehyde, in the form of a soft yellow solid, m.p. 50°-54° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][C:10](=O)[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:11][C:10](=[S:28])[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CC(c2cccnc2)=NN1c1ccccc1
Solvent: Cc1ccccc1
Product: S=C1CC(c2cccnc2)=NN1c1ccccc1
Yield: 116.1 %

Procedure:
A mixture of 1.2 g (4.5 mmol) of 3-(3-pyridyl)-1-phenyl-4, 5-dihydropyrazol-5-one, 1.4 g (3.4 mmol) of Lawesson's reagent and 10 ml of toluene was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2 (v/v)) and recrystallized from ethanol to give 1.0 g of 3-(3-pyridyl)-1-phenyl-4, 5-dihydropyrazole-5-thione.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20](B1OC(C)(C)C(C)(C)O1)=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]([C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:21]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, vinylboronic acid pinacol ester (0.221 mL), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 ml,) was stirred at 85° C. for 1.5 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (239 mg, 68%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25](O)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:17][NH:18][C:19]2[C:24]([C:25]([NH:55][CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[O:26])=[CH:23][N:22]=[C:21]3[N:28]([CH2:31][CH3:32])[N:29]=[CH:30][C:20]=23)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: NCc1ccncc1
Reactant: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)O)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1ncc2c(NCc3ccc(OC)c(Cl)c3)c(C(=O)NCc3ccncc3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Using the procedure of method 1A, triethylamine (4.0 ml, 28.0 mmol) was added to a mixture of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2.0 g, 5.6 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC.HCl, 1.6 g, 8.4 mmol), and 1-hydroxybenzotriazole (1.1 g, 8.4 mmol) in anhydrous THF (50 ml). The resulting solution was stirred at rt for 10 min. To the resulting reaction solution was then added 4-aminomethylpyridine (0.72 g, 6.7 mmol) and this solution was stirred at rt for 24 h. The resulting reaction solution was concentrated via evaporation under reduced pressure, and the residual solid was resuspended in EtOAc (250 mL). This EtOAc suspension was washed with H2O (200 ml), NaOH (0.1 N, 2×200 ml), potassium phosphate buffer (50 mM, pH 7, 2×200 ml) and H2O (200 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated via evaporation under reduced pressure until a solid began to precipitate. This mixture was allowed to stand at rt, and the precipitated solid was collected and washed thoroughly with Et2O and once with 50% Et2O-EtOAc to afford a white solid (2.2 g, 90%): mp: 209-210.5 C; LRMS (m/z) 450; 13C NMR (CDCl3): δ 171.8, 156.4, 153.7, 153.1, 151.7, 150.8, 150.5, 135.7, 132.0, 130.5, 128.3, 124.5, 124.3, 114.2, 105.6, 104.4, 57.4, 49.8, 43.7, 43.6, 15.9. Anal. Calc'd for C23H23C1N6O2: C, 61.26; H, 5.14; N, 18.64; Cl, 7.86. Found: C, 61.03; H, 5.22; N, 18.66; Cl, 8.02.
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([O-:8])=[O:7].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH:22]([OH:23])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:24][CH:25]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCC[N+](=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCC(C(O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitrohexane (1.4 mL, 10 mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes 4-nitrobenzaldehyde (0.75 mL, 5 mmol) in CH2Cl2 (3 mL) was added and the mixture allowed to warm up to room temperature (18 30 min.). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5 mmol) and extracted with Et2O (3×75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatography [SiO2, hexane:Et2O, 4:1 v/v] gave 1-(4-nitrophenyl)2 -nitro-heptan-1-ol (1.13 g, 81% Erythro:threo ratio 3.9:1
Reaction SMILES: COCC(O)C.[OH-].[Na+].[C:9]([O:17]C)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>>[C:19]([CH2:20][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCC(C)O
Product: O=C(CC(=O)c1ccccc1)c1ccccc1

Procedure:
1-Methoxy-2-propanol (923 g; 10.24 mol), sodium hydroxide (256 g; 6.4 mol), and xylenes (1820 g; 2.12 L) were placed into a four-necked, round bottom, five liter flask equipped with a stirrer, a thermometer, and an Oldershaw column with a Dean-Stark trap and a condenser. The mixture was heated to boiling with stirring under a blanket of nitrogen and the water was azeotroped out (temperature of reflux 106-116° C.). When no more water was collected (280 mL of lower phase), some solvent was distilled off (1,200 mL), while xylenes (432.2 g, dry) were replaced, until no more alcohol was detected in the distillate. The mixture in the flask was cooled down to and kept at 95° C., and the fractionation column and trap were replaced with a reflux condenser, while maintaining the nitrogen stream. Methyl benzoate (1089 g; 8.0 mol) was added and slow addition (over a period of 38 minutes) of acetophenone (481 g; 4.0 mol) by means of a peristaltic pump was begun. After 75 minutes from the beginning of the addition of the ketone, the mixture was cooled down (an ice bath was used), and then acidified by the slow addition of 98% sulfuric acid (392 g) with stirring. Sodium bicarbonate (185 g) was added for neutralizing the mixture. The slurry was distilled under vacuum (18 cm Hg, Tpot=84° C.), and at the same time 1,400 g of xylenes was added. The distillate (2,094 g) contains methoxypropanol, which can be recovered (see below).
Reaction SMILES: [CH:1](O)=O.[C:4]([N:12]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:13]1[CH2:14][NH:15]2)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O>>[C:4]([N:12]1[CH2:17][CH:16]2[CH2:18][CH2:19][CH:13]1[CH2:14][N:15]2[CH3:1])(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(c1ccccc1)N1CC2CCC1CN2
Reactant: O=CO
Agent: C=O
Product: CN1CC2CCC1CN2C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 91 h
Yield: 100.3 %

Procedure:
To 7.4 ml of 88% formic acid (0.17 mole) was added 14.6 g (0.0675 mole) of 2-benzoyl-2,5-diazabicyclo[2.2.2]octane with stirring at 0° C. A 36% aqueous solution of formaldehyde (6.0 ml, 0.078 mole) was added, and, after visible gas evolution had ceased, the mixture was heated at 80° C until renewed gas evolution has stopped 91 hour). After 3 hours at 90°-100° C, volatiles were removed in vacuo. The residue was dissolved in water, made alkaline with 20% aqueous sodium hydroxide, and extracted with chloroform. After drying with sodium sulfate, the extracts yielded 15.6 g (100%) of colorless oily 2-benzoyl-5-methyl-2,5-diazabicyclo[2.2.2]octane that was homogeneous by thin layer chromatography. It was characterized as the oxalate salt, melting point 167°-169° (dec.).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:21][C:2](=[O:1])[NH:3][C:4]4=[CH:13][C:12]=3[CH:11]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)NC1CCCCC1

Procedure:
This compound, m.p. >320° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and cyclohexylamine.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][S:16][CH2:17][CH:18]=3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][S:16][CH2:17][CH:18]=3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1sc(C2=CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1sc(C2=CCSCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a mixture of 4-({cyclohexyl[5-(3,6-dihydro-2H-thiopyran-4-yl)-2-ethylthiophen-3-yl]methyl}amino)benzoic acid (240 mg) synthesized in Example 266 (2), ethyl 3-(methylamino)propanoate (82.1 mg), 1-hydroxybenzotriazole monohydrate (95.9 mg) and triethylamine (87 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a brown oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (153 mg, 53%) as a brown solid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1>CN(C=O)C.O>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
An ice water bath-cooled mixture of 2.0 g (0.01 mol) of 2,6-dinitrobenzonitrile (Lancaster Synthesis, Inc., Windham, N.H. 03087), 1.06 ml (0.01 mol) of thiophenol, and 1.44 g (0.01 mol) of anhydrous K2CO3 in 50 mL of DMF was stirred for 0.5 h. Pyridine was added to the reaction mixture until it became basic, and was followed by the addition of approximately 100 mL of H2O. The yellow precipitate was collected by filtration, washed with 1N NaOH, water and dried to give 1.94 g (89%) of 2-nitro-6-(phenylthio)benzonitrile as a yellow solid: mp 106°-107° C.
Reaction SMILES: [CH:1]1([C:7](=[CH2:12])[C:8](OC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[CH:1]1([C:7](=[CH2:12])[CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C(=O)OC)C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: C=C(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 2-cyclohexyl-2-propenoate (2.0 g., 11.0 mmol) in 200 mi ethyl ether at -60° under argon was added diisobutylaluminum hydride (22 ml 1M solution in toluene). The solution was stirred for 0.5 hour, quenched with 3 ml isopropanol and warmed to room temperature. To this solution was added 25 ml water, and a white suspension formed. The mixture was filtered through celite, and the ether layer was washed twice with water, once with sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow liquid. This material was purified by flash chromatography (20% ethyl acetate/hexane) to give the alcohol as a clear liquid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].C[O-].[Na+]>CO>[CH2:4]([C:5]1[CH:6]=[N:15][C:14]([C:13]2[CH:17]=[CH:18][C:10]([C:5]3[CH:6]=[CH:7][C:8]([F:9])=[C:3]([F:2])[CH:4]=3)=[CH:11][CH:12]=2)=[N:16][CH:10]=1)[CH2:3][CH3:8]
Reactant: N=C(N)c1ccc(-c2ccc(F)c(F)c2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1cnc(-c2ccc(-c3ccc(F)c(F)c3)cc2)nc1

Procedure:
0.01 mol of 4-(3,4-difluorophenyl)benzamidine hydrochloride and 0.01 mol of α-propyl-β-dimethylaminoacrolein are introduced into a solution of sodium methylate and methanol, and the mixture is refluxed for 5 hours. The methanol is evaporated off, the residue is taken up in toluene, and the solution is subjected to customary aqueous work-up, to give 5-n-propyl-2-[4-(3,4-difluorophenyl)phenyl]pyrimidine.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O.[BH4-].[Li+].Cl>O1CCCC1>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[CH2:9][CH:5]1[CH2:3][OH:2])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
4-(Methanesulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.972 g) was dissolved in tetrahydrofuran (40 ml), and lithium borohydride (300 mg) was added thereto. The reaction mixture was stirred at room temperature overnight, additional lithium borohydride (1000 mg) was added, and the mixture was stirred at room temperature for 2 hours. 1 N Hydrochloric acid was added to the reaction solution, and then was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.715 g of the title compound.
Reaction SMILES: CC[O-].[Na+].[CH3:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH2:8][CH:7]1[SH:13].[CH:14](I)([CH3:16])[CH3:15]>C(O)C>[CH:14]([S:13][CH:7]1[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][CH:6]1[CH3:5])([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: CC1CCC(C)C(S)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CCC(C)C(SC(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N NaOEt in ethanol (50 ml.), was added dropwise to a stirred solution of 2,5-dimethylcyclohexyl mercaptan (4.5 g.) and isopropyl iodide (6 g.) in ethanol (15 ml.). The mixture was stirred at room temperature for 3 hours and refluxed for 1 hour. The ethanol was removed in a rotary evaporator and 2N HCl added to the residue. This was extracted twice with ether and the combined extracts dried (MgSO4). Removal of the ether left a yellow oil (6 g.) which g.l.c. indicated to be almost pure 2,5-dimethylcyclohexyl isopropyl sulphide.