Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:31])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:26][CH2:27][N:28]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:29][CH:30]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(C3=CCNCC3)ccc2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCS(=O)(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-(2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)pyrimidine (90 mg, 0.216 mmol) and triethylamine (0.061 mL, 0.432 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (65 mg, 0.324 mmol). Upon completion of addition, the reaction mixture was warmed to room temperature, where it stirred for 3 h. After this time, the reaction mixture was diluted with CH2Cl2 (4 mL), and the resulting mixture was washed with aqueous NaHCO3 (saturated, 3×3 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified via preparative HPLC (solvent A: 10% MeOH/H2O with 0.1% TFA; solvent B: 90% MeOH/H2O with 0.1% TFA; Column: PHENOMENEX® Axia 5μ C18 30×100 mm, flow rate=40 mL/min) to afford Compound 11H as a white solid (46 mg, 0.079 mmol, 36.7% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (s, 2 H), 7.06 (s, 1 H), 7.01-7.05 (m, 1 H), 6.60 (d, J=8.3 Hz, 1 H), 5.82 (ddd, J=3.2, 1.9, 1.7 Hz, 1 H), 4.65-4.78 (m, 2 H), 3.85-3.92 (m, 2 H), 3.60 (s, 3 H), 3.46 (t, J=5.8 Hz, 2 H), 3.08 (d, J=15.7 Hz, 1 H), 2.98 (dd, J=8.4, 6.7 Hz, 2 H), 2.65-2.78 (m, 3 H), 2.50 (d, J=1.7 Hz, 2 H), 2.44 (t, J=7.0 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.76-1.87 (m, 2 H), 1.67-1.75 (m, 1 H), 1.56-1.65 (m, 1 H), 1.30 (s, 3 H), 1.15-1.28 (m, 2 H), 0.76-0.83 (m, 2 H), 0.45-0.51 (m, 2 H). LC/MS (m/z)=581 (M+H)+.
Reaction SMILES: O.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>[Zn].C1(C)C=CC=CC=1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2)cc1
Yield: 79.1 %

Procedure:
15 ml of water, 35 ml of concentrated hydrochloric acid, 50 ml of toluene and 10 gm of 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid were added to 20 gm of amalgamated zinc (Org. Synthesis, Coll. Vol. III, 786), and the mixture was refluxed for 6 hours while stirring, another 10 ml of concentrated hydrochloric acid being added after 3 hours. Subsequently, the mixture was vacuum-filtered to remove the unreacted zinc, and the filtrate was extracted with ether. The residue remaining after evaporation of the ether was recrystallized from cyclohexane, yielding 7.5 gm (79% of theory) of colorless 4-(4'-fluoro-4-biphenylyl)-butyric acid, m.p. 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1(Cl)[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.O.O.O.C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1Nc2ccc3ccccc3c2CCC1(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccc3ccccc3c2CCC1Cl
Reaction time: 0.08 h
Yield: 31.4 %

Procedure:
A solution of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (6.2 g, 22 mmol) in glacial acetic acid (200 ml) was placed under an atmosphere of nitrogen. Sodium acetate trihydrate (3.8 g, 28 mmol) was added. After 5 minutes palladium on carbon (10%, 0.6 g) was added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature using 450 ml of hydrogen gas. The reaction mixture was filtered through Celite and the solvent was evaporated in vacuo. After reevaporation with toluene (250 ml), the residue was suspended in water (100 ml), stirred for 5 minutes and the solid was isolated by filtration and dried in vacuo to afford 1.7 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CS(C)=O.C1C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)c1ccc(C(O)C(=O)O)cc1
Reactant: COc1ccc(CCl)cc1
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: COc1ccc(COC(=O)c2ccc(C(O)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4.9 g of the dipotassium salt of DL-α-hydroxy-4-carboxyphenylacetic acid (mp 201° ~ 203° C) in 40 ml of dimethylsulfoxide were added 6.2 g p-methoxybenzylchloride and stirred overnight at ambient temperature. 50 ml of ice-water were added to the reaction mixture, adjusted to pH 7.5 and extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue was dissolved in 60 ml of 50% acetone. To the solution was added a phenolphthalein reagent and then dropwise a 2N-sodium hydroxide solution at 40° ~ 45° C with stirring. The reaction was continued until the red color was maintained for 5 minutes. Then acetone was removed under weakly reduced pressure. The aqueous layer was washed several times with ethyl ether, and then adjusted to pH 2.5 with a 20% hydrochloric acid solution after the addition of ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed several times with a small amount of an aqueous sodium chloride saturated solution, dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give an oily residue. The residue was dissolved in benzene and left overnight in an ice-box, yielding crystals of DL-α-hydroxy-4-(p-methoxybenzyloxycarbonyl) phenylacetic acid of 7.4 g (78.5%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]=O.[CH3:15][C:16]1[C:20](=[O:21])[O:19][CH2:18][C:17]=1[N:22]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:23]1=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:12][CH2:13][N:29]2[CH2:30][CH2:31][C:24]3([C:23](=[O:32])[N:22]([C:17]4[CH2:18][O:19][C:20](=[O:21])[C:16]=4[CH3:15])[CH2:26][CH2:25]3)[CH2:27][CH2:28]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][O:8][C:7]2=[O:11]
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: CC1=C(N2CCC3(CCNCC3)C2=O)COC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(N2CCC3(CCN(CCc4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (I-3) (100 mg, crude) and 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-16) (145 mg, 0.58 mmol) in THF (5 mL) was stirred at rt for 2 hours and then NaBH(OAc)3 (167 mg, 0.79 mmol) was added to the mixture, which was further stirred at 50° C. for 3 hours. After quenching with saturated NH4Cl aq, the mixture was extracted with EtOAc and organic layer was dried over Na2SO4. Solvent was removed under reduced pressure and the residue was purified by prep-TLC (EtOAc/MeOH: 1/1) and prep-HPLC to give the title product. MS (ESI) m/z: 425 (M+H+); 1H NMR (400 MHz, MeOD): δ 7.69 (d, J=7.6 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 5.38 (s, 2H), 5.27-5.25 (m, 2H), 4.20-4.14 (m, 2H), 3.83-3.80 (m, 1H), 3.68-3.66 (m, 1H), 3.42-3.38 (m, 2H), 3.33-3.23 (m, 4H), 2.41 (s, 3H), 2.39-2.30 (m, 2H), 2.24-2.17 (m, 2H), 2.10-2.03 (m, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[OH:11][C:12]1[C:13]([SH:18])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:18][C:13]2[C:12]([OH:11])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Br)s1
Reactant: Oc1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Temperature: 90 °C
Yield: 110.3 %

Procedure:
A mixture of 2-acetylamino-5-bromothiazole (1.8 g), 3-hydroxy-2-mercaptopyridine (1.3 g) and potassium carbonate (2.0 g) in N,N-dimethylformamide (40 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2.4 g, yield: 89.9%). mp: 236°-238° C. (dec.) IR (Nujol): 3175, 1690, 1565, 1300 cm-1
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[CH3:23][S:20]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1)(=[O:22])=[O:21]
Reactant: N#CC(=NO)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(C#N)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-bromobenzyl cyanide was prepared in the following manner. Thus, 81.0 g (0.36 mole) of α-hydroxyimino-4-bromobenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 49.0 g (0.43 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 103.0 g of a solid residue which was purified by repeating recrystallization from acetonitrile to give 81.8 g of a white crystalline product having a melting point of 128° C. which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 75.0% of the theoretical value.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=CC(C(N3CCC3)=O)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38](Br)=[CH:37][C:36]=1[F:42])([CH3:32])([CH3:31])[CH3:30].COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:38]2[CH:39]=[CH:40][C:35]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:43])=[C:36]([F:42])[CH:37]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1F
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-bromo-2-fluoro-benzoic acid tert-butyl ester and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e). 1H NMR (400 MHz, CDCl3) δ 7.86 (t, J=8.59 Hz, 1 H) 7.25-7.31 (m, 1 H) 7.24 (s, 1 H) 6.74 (dd, J=8.84, 2.02 Hz, 1 H) 6.65 (dd, J=11.87, 2.27 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.59 (s, 9 H) 1.48 (s, 6 H); LCMS for C23H25FO6 m/z 439.00 (M+Na)+.
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.OC1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([OH:21])=[O:20]>C(O)(C)(C)C.O1CCCC1>[C:12]([O:11][C:9]([O:8][C:1]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:23]=[C:22]([CH3:30])[C:18]=1[C:19]([O:21][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: Cc1ccc(C(F)(F)F)c(O)c1C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
N,N-Dimethylaminopyridine (0.7 g, 5.7 mmol) and di-tert-butyl dicarbonate [(tBuOCO)2O] (16.7 g, 76.5 mmol) were added to a solution of 2-hydroxy-6-methyl-3-(trifluoromethyl)benzoic acid (4.21 g, 19.1 mmol) obtained in Example (28-3) in a mixture of tert-butyl alcohol-tetrahydrofuran (2:1, 60 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1) to give tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-methyl-3-(trifluoromethyl)benzoate (6.27 g, yield: 87%).
Reaction SMILES: CS(O[CH:6]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[C:10]([C:25]#[N:26])[CH:9]=1)[CH3:7])(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[N:27]([CH:6]([C:8]1[CH:9]=[C:10]([C:25]#[N:26])[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH3:7])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[5-cyano-8-(3-fluorophenyl)quinolin-7-yl]ethyl methanesulfonate (28 mg, 0.076 mmol) and sodium azide (24 mg, 0.38 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature overnight. The mixture was then quenched with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, and then dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step (20 mg, 83%). LCMS calculated for C18H13FN5 (M+H)+: m/z =318.1; Found: 318.1.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:18]1[CH:17]=[CH:16][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([O:13][CH3:12])[C:19]=1[O:20][CH3:21]
Reactant: BrCCCCCCBr
Agent: COc1cccc(-c2ccccc2)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(CCCCCCBr)ccc(-c2ccccc2)c1OC
Reaction time: 2.5 h

Procedure:
A solution of 2.5M butyl lithium in hexane (16 mL, 0.04 mol) was added dropwise over 15 min. to a stirred solution of 8.3 g (0.039 mol) of 2,3-dimethoxybiphenyl [J. M. Bruce and F. K. Sutcliffe, J. Chem. Soc. 4435 (1955)] in 160 mL of anhydrous tetrahydrofuran cooled at 0° under argon. The reaction mixture was stirred at 0° for 2.5 hours and then refluxed for 30 min. After cooling to 5°, 6.3 mL (0.039 mole) of 1,6-dibromohexane was added. Stirring was continued at 5° for 30 min., at 25° for 30 min. and at reflux for 20 hours. Workup as in Example 1 gave an oil. Purification by HPLC using 3% ethyl acetate-hexane gave 5.7 g of unreacted 2,3-dimethoxybiphenyl and 3.3 g of 4-(6-bromohexyl)-2,3-dimethoxy-1,1'-biphenyl as an oil. The structure was confirmed by the nmr and mass spectra (molecular ion at m/e 376).
Reaction SMILES: [Na].[CH2:2]([C:9]1[N:13]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:12](=[S:22])[NH:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23]I>CO>[CH2:2]([C:9]1[N:13]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:12]([S:22][CH3:23])=[N:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CI
Reactant: CCOC(Cn1c(Cc2ccccc2)n[nH]c1=S)OCC
Agent: [Na]
Solvent: CO
Product: CCOC(Cn1c(Cc2ccccc2)nnc1SC)OCC
Reaction time: 0.33 h

Procedure:
In 1 l of methanol was dissolved 11.0 g of sodium, followed by the addition of 134.4 g of 3-benzyl-4-(2,2-diethoxyethyl)-4H-1,2,4-triazole-5-thione. Then, 30.0 ml of methyl iodide was added dropwise and the mixture was stirred for 20 minutes. Thereafter, the reaction mixture was treated as in Reference Example 3 to obtain 140 g of 3-benzyl-4-(2,2-diethoxyethyl)-5-methylthio-1,2,4-triazole as an oil. This oil was gradually added to 430 ml of concentrated sulfuric acid previously cooled with ice-sodium chloride and, then at room temperature, the mixture was stirred for 30 minutes, after which it was poured into 5 l of ice-water. The mixture was neutralized with concentrated aqueous ammonia and the resultant crystals were collected by filtration. The crystalline 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine thus obtained was recrystallized from methanol. This procedure yielded colorless needles melting at 168°-169° C. Infrared absorption spectrum of this product was identical with that of the product obtained in Example 1.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH:19]O>C(Cl)Cl>[C:1]1([C:7]23[O:19][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: C1=C(c2ccccc2)CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(C23CCCCC2O3)cc1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
In a 50 mL flask equipped with a magnetic stirrer, 7.9 g (50 mmol) of 1-phenylcyclohexene and 63 mg (0.25 mmol, 0.5 mol %) of MTO are dissolved in 1.5 Molar CH2Cl2 and to this solution is added 0.48 mL (6 mmol, 12 mol %) of pyridine followed by 7.6 mL (75 mmol; 1.5 equivalents) of 30% aqueous H2O2 added dropwise from a syringe (circa 5-10 minutes). During the H2O2 -addition the temperature is kept at 20-25° C. by applying an external cooling bath. The reaction is complete after 6 h and the aqueous phase is seperated and discarded. The remaining H2O2 in the yellow organic phase is decomposed to O2 and H2O by stirring with a catalytic amount of MnO2 (circa 10 mg). After the yellow color has completely disappeared the mixture is dried over Na2SO4, concentrated, and purified by filtration through a short column of silica gel which has been deactivated with NEt3. The column is washed with hexane/CH2Cl2 and concentration of the eluate affords 7.9 g (91%) of 1-phenyl-1,2-epoxycyclohexane as a colorless oil.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([O:33]C1C=CC=CC=1)=O)(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:47][CH2:43][CH2:44][CH2:45][CH3:46])=[O:33])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Reactant: CCCCN
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sulfonyl]phenyl]benzamide produced in Example 45 and 0.09 ml (0.88 mmol) of butylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 130 mg (yield: 68.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11][C:10]1=O.O=P(Cl)(Cl)[Cl:25].C(N(C(C)C)CC)(C)C>>[Cl:25][C:10]1[N:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:18](=[O:19])[C:17]2[C:12]([N:11]=1)=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2
Reactant: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c(=O)[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(=O)n(-c3c(F)cccc3Cl)c(Cl)nc2n1

Procedure:
A mixture of Example 95A (0.960 g, 2.83 mmol) in POCl3 (3.5 ml, 37.5 mmol) and diisopropylethylamine (DIEA) (3.5 ml, 20.04 mmol) was heated at 90° C. for 1.5 hours. After concentrating the reaction mixture, the residue was treated with ice and aqueous NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, concentrated and purified on a 40 g silica column using the ISCO Companion flash system eluting with hexane/ethyl acetate (7:3 to 6:4) to provide the title compound.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].[ClH:6].[CH3:7][C:8]([CH2:10][C:11]([CH3:13])=O)=O>C(O)C>[ClH:6].[C:1]([N:4]1[C:11]([CH3:13])=[CH:10][C:8]([CH3:7])=[N:5]1)(=[NH:3])[NH2:2]
Reactant: N=C(N)NN
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(C(=N)N)n1
Reaction time: 3 h

Procedure:
To 850 ml of ethanol were added 188 g of aminoguanidine hydrochloride and 170 g of 2,4-pentadione and the mixture was heated with stirring for 3 hrs. under reflux. The precipitated crystals were filtered, sufficiently washed with ethanol and dried to obtain 1-amidino-3,5-dimethylpyrazole hydrochloride of 210 g. Next, 60 g of potassium hydroxide was dissolved in water of 120 g and 1-amidino-3,5-dimethylpyrazole hydrochloride of 61.1 g was added thereto withcooling with water and stirred further for 1 hr. Chloroform of 200 ml was added to the solution for extraction. A chloroform layer was separated, washed with water and dried with anhydrous sodium sulfate, thereafter, chloroform was removed to obtain 1-amidino-3,5-dimethylpyrazole of 46.0 g.