Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][OH:5].O1CCC[CH2:23]1.[H-].[Na+].CN(C)C=O>O>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[C:8](/[F:21])=[C:9](\[CH3:20])/[CH:10]=[CH:11]/[C:12]1[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=1[CH3:19])=[CH:3]\[CH2:4][O:5][CH3:23]
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\CO
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Temperature: 23 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
A solution of 0.400 g. (1.31 mmole) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraen-1-ol in 5 ml. of tetrahydrofuran was added to a suspension of 0.11 g. (2.6 mmol) of a 56% sodium hydride dispersion in a mixture of 10 ml. of dry tetrahydrofuran and 20 ml. of dry dimethylformamide. This reaction mixture was stirred at 23° C. for 14 hours, poured into water and extracted with ether-hexane (1:1 parts by volume). The extracts were washed with water, dried with magnesium sulfate, filtered and evaporated to give an orange product which was crystallized from ether-hexane (1:4 parts by volume) to give 220 mg. (52% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-1-methoxy-2,4,6,8-nonatetraene as a light orange solid, m.p. 117°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C1C(=O)N([O:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=O)C(=O)C1.C1COCC1>C([O-])(O)=O.[Na+]>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[O:21])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 4-(4-aminophenyl)butyric acid (3.0 g, 16.7 mmol) in 30 mL of saturated NaHCO3 was added Fmoc-Osu and 20 mL of THF. The mixture was stirred at room temperature overnight. After dilution with 1 N HCl, the product was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with dilute HCl, brine, dried (Na2SO4) and concentrated to give a white solid 6.6 g (26) (98%). 1H NMR (500 MHz, CD3OD) δ 7.80 (m, 2H), 7.70 (m, 2H), 7.39 (m, 3H), 7.32 (m, 4H), 7.90 (m, 2H), 4.46 (m, 2H), 4.27 (t, J=7.0 Hz, 1H), 2.60 (t, J=8.0 Hz, 2H), 2.28 (t, J=7.0 Hz, 2H), 1.87 (m, 2H); MS (ESI+) m/z 424.19 (M+Na+).
Reaction SMILES: Cl[CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17].[C:18]([O-:21])(=[S:20])[CH3:19].[K+].[I-].[Na+]>CC(C)=O>[C:18]([S:20][CH2:2][N:3]1[C:15](=[O:16])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:17])(=[O:21])[CH3:19]
Reactant: CC([O-])=S
Reactant: COC(=O)C1C=CCn2c(=O)n(CCl)c(=O)n21
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCn2c(=O)n(CSC(C)=O)c(=O)n21
Yield: 58.5 %

Procedure:
3.24 g (0.0125 mol) of methyl 2-chloromethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate and 2.29 g (0.02 mol) of potassium thioacetate were refluxed together in 400 ml of acetone with a catalytic amount of sodium iodide for 19 hours. The acetone was removed by evaporation and the residue was partitioned between 250 ml of ethyl acetate and 200 ml of saturated sodium chloride solution. The organic layer was separated, dried over magnesium sulphate and evaporated to give a yellow oil. This oil was chromatographed on silica gel using chloroform/ethyl acetate (1:1) for the elution to give 2.19 g (59%) of methyl 2-acetylthiomethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate in the form of a colourless solid of melting point 110°-111° C. (from chloroform/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]=[N+]=[N-])=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31]CC2C=CC=CC=2)[N:3]=1>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3O)nc(N)c2CN)C1

Procedure:
A solution of tert-butyl 3-{2-amino-3-(azidomethyl)-6-[2-(benzyloxy)phenyl]-4-pyridinyl}-1-piperidinecarboxylate (0.030 g, 0.058 mmol) in ethyl acetate (1.0 mL) was hydrogenated at 1 atm in the presence of palladium on charcoal (10%, 0.015 g) overnight. The resulting mixture was filtered and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to give tert-butyl 3-[2-amino-3-(aminomethyl)-6-(2-hydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate, which was used for the next step without further purification.
Reaction SMILES: [F:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]C(C)(C)C)=O.[NH2:13][C:14]1[N:18]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:16][N:15]=1>C(O)(=O)C>[CH2:20]([S:19][C:17]1[N:18]=[C:14]2[N:13]=[C:3]([CH2:2][F:1])[CH:4]=[C:5]([OH:7])[N:15]2[N:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CF
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: Oc1cc(CF)nc2nc(SCc3ccccc3)nn12
Reaction time: 5.5 h

Procedure:
A solution containing 20.0 g (114 mmol) of t-butyl 4-fluoroacetoacetate, 23.4 g (114 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 250 ml of glacial acetic acid was heated at reflux with stirring for 5.5 hr and then allowed to cool and stand overnight. The crystals that formed were ground to reduce their size and then recovered by filtration and dried in a vacuum oven to obtain 18.3 g (55 percent of theory) of the title product as a white powder melting with decomposition at 214°-218° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[C:19]1([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:32]1([S+:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(O)c1ccc(Cc2ccccc2)cc1
Agent: [Cl-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
The 4-phenylmethylbenzenesulfonic acid crude product obtained in Synthesis Example 1 was added to the aqueous triphenylsulfonium chloride solution obtained in Synthesis Example 2 and 90 g of dichloromethane, which was stirred for one hour at room temperature. The organic layer was separated, washed with 100 g of water, and evaporated in vacuum. The residue, 27 g, was purified by silica gel column chromatography (eluent, dichloromethane/methanol), obtaining the end product, triphenylsulfonium 4-phenylmethylbenzenesulfonate. It was 21 g (yield 52%) of an oily matter containing a minor amount of solvents (methanol, etc.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].ClC(Cl)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]2[CH2:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23][C:22]=2[CH:32]=1)#[N:17]>>[C:5]([C:29]1[CH:30]=[CH:31][C:24]2[S:23][C:22]3[CH:32]=[C:18]([C:16]#[N:17])[CH:19]=[CH:20][C:21]=3[CH2:27][CH2:26][C:25]=2[CH:28]=1)(=[O:7])[CH3:6]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C#N)cc1S2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add 125.5 g. (0.94 mole) of aluminum chloride and 47.9 g. (0.47 mole) of acetic anhydride to 1.01 of dichloroethane. Stir at room temperature for 10 minutes. Add 14 g. (0.058 mole) of 3-cyano-10,11-dihydrodibenzo[b,f]thiepin in portions. Stir at room temperature for 4 hours. Pour the reaction mixture over ice and extract into ethyl acetate. Wash with water, dry over sodium sulfate, filter and evaporate to dryness to obtain the title product. (m.p. 138°-141° C.)
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[C:9]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C.[Na+].[Cl-]>[Si:13]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
To a solution of (S)-(−)-ethyl lactate (20 mL, 191.06 mmol) in DMF (191 mL) was added tert-butyldimethyl silyl chloride (39.6 g, 262.59 mmol) and imidazole (41.6 g, 612.72 mmol). After stirring at room temperature for 20 hr, the reaction mixture was diluted with a saturated aqueous NaCl solution (600 mL) and extracted with petroleum ether (3×400 mL). The organic layer was washed with a cold 3% HCl solution (200 mL) and a saturated aqueous NaCl solution (200 mL), dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel (700 g) with petroleum ether (2 L), followed by 3% ethyl acetate in petroleum ether (4 L). The 3% ethyl acetate in the petroleum ether fractions was collected and the solvent was removed to give 36.57 g of (S)-(−)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate as colorless oil (82% yield). 1H NMR (CDCl3): δ 4.23 (q, 1H, J=6.8 Hz, H2, —CH—), 4.11 (q, 2H, J=7.2 Hz, —CH2—), 1.32 (d, 3H, J=6.8 Hz, H3, —CH3), 1.21 (t, 3H, J=7.2 Hz, —CH3), 0.83 (s, 9H, Si—(CH3)3), 0.03 (s, 3H, Si—CH3), 0.00 (s, 3H, Si—CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[C:11]([OH:14])(=[O:13])[CH3:12].C(ON1C(=O)N(OC(=O)C)C(=O)N(OC(=O)C)C1=O)(=O)C.O=O>[Ti].C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[C:8]([OH:10])(=[O:9])[C:5]1[CH:6]=[CH:7][C:12]([C:11]([OH:14])=[O:13])=[CH:3][CH:4]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a 500-ml titanium autoclave equipped with a stirrer and a pressure gauge, 15.36 g of p-toluic acid, 104.0 g of acetic acid, 0.114 g of 1,3,5-triacetoxy-hexahydro-1,3,5-triazine-2,4,6-trione (1,3,5-triacetoxyisocyanuric acid) (0.33% by mole relative to p-toluic acid), 0.112 g of cobalt(II) acetate.4H2O and 0.277 g of manganese(II) acetate.4H2O were placed. The autoclave was charged with 2 MPa of oxygen gas and 2 MPa of nitrogen gas and placed in a heated oil bath. The mixture was stirred at 150° C. for 1 hour. After the completion of the reaction, the autoclave was placed on cold water to cool down the reaction mixture quickly. The resulting mixture was analyzed by high performance liquid chromatography and was found to yield terephthalic acid in 90% yield at 93% conversion of p-toluic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7](O)[C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4]
Reactant: COC(=O)c1c(Cl)ccc2c1C(O)C(C)(C)C(c1cccc(Br)c1)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(Cl)ccc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (48 g, 113.2 mmol) and triethylsilane (60 mL) at 25° C. was added trifluoroacetic acid (30 mL) dropwise. The resulting mixture solution was stirred at 25° C. for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (4×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with methanol. The resulting precipitate was collected, dried in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (15 g, 32.6%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 (M+H)+: 409.73, observed: 407.9 & 409.9.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1)#[N:2].C(O)(C(F)(F)F)=[O:44]>C(Cl)Cl>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][S:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[C:1]([NH2:2])=[O:44])=[N:14][CH:15]=[CH:16]2)(=[O:25])=[O:24]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.085 g, 0.179 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (0.058 g, 0.268 mmol), Pd(PPh3)4 (0.021 g, 0.018 mmol), and potassium carbonate (0.123 g, 0.893 mmol). Dioxane (0.893 ml) and water (0.298 ml) were added, the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. A small amount of 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide was observed; however the predominant product was observed as the coupling product with hydrolysis of the nitrile. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and 2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide. The protected nitrile was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)-5-(trifluoromethyl)benzamide (0.049 g, 0.102 mmol, 57.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.61 (d, J=5.7 Hz, 1H), 8.54 (s, 1H), 8.10-8.03 (m, 3H), 7.98 (d, J=8.4 Hz, 1H), 7.87-7.81 (m, 1H), 7.79-7.68 (m, 2H), 7.34 (br. s., 1H), 7.27 (d, J=4.5 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=2)[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
5-Amino-1-(3,5-dichloropyridyl)-3-isopropyl-1H-pyrazole-4-carbonitrile (56 g, 189 mmole) was taken up in concentrated H2SO4 (160 mL) and stirred at room temp for 16 hours. The reaction was then poured onto 3M aqueous NaOH (2 L) at 0° C. The resulting solid was then filtered and washed with H2O (1 L). The product was then dried under vacuum to yield the desired amide (49 g, 82% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)=[O:19].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1)=[O:19]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CCOC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-bromopicolinamido)propanoate (800 mg, 2.7 mmol), 2-formylphenylboronic acid (518 mg, 3.5 mmol), Pd(dppf)Cl2 (217 mg, 0.27 mmol), and K2CO3 (734 mg, 5.3 mmol) were dissolved in 1,4-dioxane (16 mL) and water (4 mL) and heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH3:10][N:11]=[C:12]=[S:13]>C(O)C>[CH3:10][NH:11][C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)=[S:13]
Reactant: CN=C=S
Reactant: c1nc2c([nH]1)CCNC2
Solvent: CCO
Product: CNC(=S)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci., 1967, 22, 821) and 0.65 g of methyl isothiocyanate in 20 ml of ethanol are refluxed for 8 h. The solution is cooled and filtered: 1.15 g of 5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 228°, are collected.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43](=[O:50])[NH:44][C@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:50])[NH:44][C@H:45]1[CH2:49][CH2:48][N:47]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CC[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3081.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.ClC=C(Cl)Cl.Cl>O>[CH2:23]([NH:30][C:9]1[C:10]([F:15])=[C:11]([F:14])[CH:12]=[C:13]2[C:8]=1[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClC=C(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of 2.57 g of ethyl 1-cyclopropyl-5,6,7-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 1.8 ml of benzylamine and 180 ml of trichloroethylene was heated under reflux for 3 hours and 40 minutes. Water and 10 % hydrochloric acid were added to the reaction mixture to render the aqueous layer acidic. The trichloroethylene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to give 2.78 g of ethyl 5-benzylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxlate. m.p 144°-145° C.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:15])=[C:8]([CH3:14])[CH2:9][CH2:10][CH2:11][CH2:12][SH:13].[S:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]1=2.C(N(CC)CC)C>O>[S:16]1[C:20]([C:21](=[O:22])[S:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:14])=[C:7]([F:15])[F:6])=[CH:19][C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]1=2
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CC(CCCCS)=C(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(CCCCSC(=O)c1cc2ccccc2s1)=C(F)F
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To 10 ml of tetrahydrofuran were dissolved 0.25 g (1.5 mmol) of 6,6-difluoro-5-methyl-5-hexene-1-thiol and 0.39 g (2.0 mmol) of benzo[b]thiophene-2-carbonylchloride, followed by the drop-wise addition of 0.30 g (3.0 mmol) of triethylamine at room temperature, followed by stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:20) to obtain 0.39 g (yield: 80%) of S-(6,6-difluoro-5-methyl-5-hexenyl) benzo[b]thiophene-2-thiocarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH:16]([CH:17]([CH3:19])[CH3:18])[C:15](=[O:20])[O:14]C1=O.C1(O)C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:16]([C:15]([OH:20])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1F
Solvent: Oc1ccccc1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1F)C(=O)O

Procedure:
3-(2-Fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with phenol using the procedure of Example 75 to give the phenyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valine, which is reacted with NaHS using the method of Hirakayaski et al., Bull. Chem. Soc. Japan 38, 320 (1965) to give the sodium salt of the thioacid. ##STR27##