Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and benzoyl chloride. Yield: 62% of theory, C33H31N7O4 (589.7) Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1) ##EQU80##
Reaction SMILES: C(N[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)#N.[CH:17]([NH2:20])([CH3:19])[CH3:18]>O>[CH:17]([NH:20][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)([CH3:19])[CH3:18]
Reactant: N#CNC=Nc1ccc(-c2nc[nH]n2)cc1
Reactant: CC(C)N
Solvent: O
Product: CC(C)NC=Nc1ccc(-c2nc[nH]n2)cc1

Procedure:
A solution of N-Cyano-N'-[4-(1,2,4-triazol-3-yl)-phenyl]-formamidine (3 g) and isopropylamine (8.5 g) in water (1.5 ml) was stirred for twenty minutes. The crystallized solid was filtered off and purified via its maleate salt in ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10]O)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:10][Cl:14])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cnc(CO)c(Cl)n1
Solvent: ClCCl
Product: COc1cnc(CCl)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-5-methoxy-pyrazin-2-yl)-methanol (100 mg, 0.57 mmol) in DCM (5 mL) was added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 110 mg of 3-chloro-2-chloromethyl-5-methoxy-pyrazine as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26]Cl)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[I-].[Na+].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(CCCCl)C(C(=O)OC)C(C)C)cc1
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(CCCN(CC)CC)C(C(=O)OC)C(C)C)cc1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
To a solution of 0.45 g (1.08 mmol) of methyl 2-[{[4-(2-butynyloxy)-phenyl]-sulfonyl}(3-chloropropyl)amino]-3-methylbutanoate in 5.0 mL of DMF was added 0.163 g (1.08 mmol) of sodium iodide and 0.34 mL (3.24 mmol) of diethylamine. The reaction was heated to 80° C. for 3 h and then cooled to room temperature. The mixture was then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.441 g of methyl 2-{{[4-(2-butynyloxy)-phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-3-methylbutanoate as a brown oil. Electrospray Mass Spec 453.5 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH3:4].S(C1C=CC(C)=CC=1)(O[CH2:14][C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O>CN(C)C=O>[CH2:3]([C:5]1[N:6]([CH2:14][C@@H:15]2[CH2:29][C@H:28]3[C@@H:18]([CH2:19][C:20]4[C:30]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]3=5)[NH:22][CH:21]=4)[N:17]([CH3:31])[CH2:16]2)[CH:7]=[CH:8][N:9]=1)[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: CCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
0.9 g of 50% sodium hydride in an oil was added in small portions to a mixture of 3.0 g of 2-ethylimidazole and 60 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with acetone). The product was recrystallized from methanolisopropyl alcohol to obtain 1.5 g of the titled compound having a melting point of 232°-237° C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)C=C.[CH3:15][C:16]1C=CC(C)=C[CH:21]=1>>[CH2:21]([C:6]1[C:5]([OH:4])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)[CH:16]=[CH2:15]
Reactant: Cc1ccc(C)cc1
Reactant: C=CCOc1ccc2ncccc2c1
Product: C=CCc1c(O)ccc2ncccc12
Yield: 72 %

Procedure:
A solution of 6-allyloxyquinoline (intermediate 4) (1.14 g, 6.2 mmol) in p-xylene (30 ml) was allowed to reflux for 3 days. The organic solvent was removed under vacuum. Chromatography (30% hexanes-ethyl acetate) afforded 0.82 g (72%) of 5-allyl-quinolin-6-ol as a white solid: mp 162–164° C. Elemental Analysis for C12H11NO: Calculated: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.82; H, 5.99; N, 7.45.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][NH:11][CH3:12]>>[CH3:10][N:11]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:12]
Reactant: Cc1cccc(CBr)n1
Reactant: CNC
Product: Cc1cccc(CN(C)C)n1

Procedure:
2-bromomethyl-6-methylpyridine is treated with dimethylamine to give the corresponding tertiary amine, 2-dimethylaminomethyl-6-methylpyridine. The tertiary amine is treated with cyanomethyl benzenesulfonate, as in Preparation II, to give dimethylcyanomethyl-(6-methyl-2-picolyl) ammonium benzene sulfonate. The quaternary ammonium salt is rearranged using sodium hydride and alkylated with benzylbromide according to the procedure described in Example 2. The alkylated cyanoamine is decyanated with sodium borohydride in ethanol to give the desired product which can be purified through its picrate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[S:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8](=[S:10])[CH2:9][Br:15]
Reactant: BrBr
Reactant: CC(=S)c1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=S)CBr)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
m-Methylthioacetophenone (7.14 g, 43 mmol) was dissolved in chloroform (100 ml). Aluminium chloride (catalytic amount) and bromine (2.2 ml, 43 mmol) were added and stirred for 1 h. The reaction was quenched with aqueous sodium chloride-sodium bicarbonate and the organic layer separated, dried (MgSO4) and evaporated under reduced pressure. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, then brine, dried (MgSO4) and evaporated under reduced pressure to yield m-Methylthiophenacyl bromide (7.64 g, 73%); δH(CDCl3) 7.1-7.9(4H,m, aryl), 4.40(2H,S,CH2), 2.45(3H,S,SCH3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:8][N:9]=1)(=O)[CH3:2].[BH3-]C#[N:22].[Na+]>CO>[NH2:22][CH:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:8][N:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Agent: [Na+]
Solvent: CO
Product: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A sealed-cap vial was charged with tert-butyl 5-acetyl-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (225 mg, 0.86 mmol), NH4OAc ammonium acetate (666 mg, 8.6 mmol), NaBH3CN (71 mg, 1.1 mmol) and MeOH (7 mL). The reaction was stirred at RT for 24 h, after which additional NH4OAc (333 mg, 4.3 mmol) and NaBH3CN (27 mg, 0.43 mmol) were added. The reaction mixture was stirred for another 24 h then concentrated in vacuo. The residue was partitioned between 2N NaOH and EtOAc. The aqueous layer was thrice extracted with EtOAc. The organic extracts were combined and dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with a mixture of EtOAc containing 1% TEA and MeOH to afford 95 mg (42%) of tert-butyl 5-(1-aminoethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate: MS (ESI) m/z: 262.2 [M+1]+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10]>>[C:1]([O:4][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C=COCC
Solvent: CC(=O)Cl
Product: CCOC(C)OC(C)=O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Into a 500 ml reaction flask, equipped with stirrer, cooling bath, thermometer, addition funnel and nitrogen blanket apparatus, is added 60 ml of acetic acid (1.1 moles) and 0.1 ml of acetyl chloride. Dropwise over a period of one hour, while maintaining the reaction mass at 30° C., is added 100 ml (1.0 moles) of ethyl vinyl ether. At the end of the addition of said ethyl vinyl ether, the reaction mass is stirred for a period of twelve hours, while maintaining the temperature thereof at 30° C.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[S:10][C:9]([CH:11]=O)=[CH:8][CH:7]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: Cc1ccc(C=O)s1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1ccc(C)s1)CC(=O)O
Yield: 60.8 %

Procedure:
Sodium ethylate (6.5 g, 95 mmol) was added under vigorous stirring to a solution of 5-methylthiophene-2-carbaldehyde (10 g, 79 mmol) and diethyl succinate (27.6 g, 158 mmol) in ethanol (300 mL). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 200 mL of 10% HCl and 300 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 200 mL of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 400 mL of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions containing the target product were collected and evaporated in vacuum to give 12.3 g (48 mmol, 61%) of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid as a light-brown oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:14]2[NH:15][CH:16]=[CH:17][C:13]=2[C:7]2[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:12])=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)c1[nH]ccc1-c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 4.8 %

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared according to JOC, 62, 1997, 2650) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 160 mg of (2-chloro-pyridin-3-yl)-[3-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]2([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[CH3:21].[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]2([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[CH3:21]
Reactant: CCOC(=O)CC1(Nc2cc(C)c(OC)c(C)c2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cc(NC2(CC(=O)O)CCC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)cyclobutyl)acetate (1 g) in EtOH was added an aqueous solution of NaOH (2.5 g). The mixture was stirred at room temperature overnight, concentrated and water was added to the residue. After addition of HCl to adjust the pH 2-3, the solution was then washed with ethyl acetate (3×20 mL). The organic layer was dried over Na2SO4 and the solvent was removed by evaporation to give 2-(1-(4-methoxy-3,5-dimethylphenylamino)-cyclobutyl)acetic acid (650 mg) as a white solid. MS: m/z 264 (100, M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH2:24][OH:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:24]=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a solution of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)ethanol (300 mg, 0.86 mmol) in CH2Cl2 (5.7 mL) was added Dess-Martin periodinane (DMP, 437 mg, 1.03 mmol) at room temperature. The mixture was stirred at room temperature for 35 min, then the solids were filtered off and the filtrate was stirred with aqueous NaHCO3 and Na2S2O3 for one hour. The aqueous phase was re-extracted with CH2Cl2 and the combined organic layers were passed over a phase separator and concentrated under reduced pressure. The crude aldehyde 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetaldehyde (384 mg) was used directly in the following step.
Reaction SMILES: CON(C)[C:4](=[O:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[S:16]1[CH:20]=[CH:19][C:18]([Mg]I)=[CH:17]1.[NH4+].[Cl-]>C1COCC1>[O:14]=[C:4]([C:18]1[CH:19]=[CH:20][S:16][CH:17]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: I[Mg]c1ccsc1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
To a solution of the Weinreb amide 45 (1.53 g, 7 mmol) in anhydrous THF (10 mL) was added dropwise (over a 10-min period) a solution of thiophen-3-ylmagnesium iodide (0.3 M in THF, 50 mL) under nitrogen atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was poured into a saturated NH4Cl solution and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled compound (776 mg, 46%). MNa+264.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:39])([F:38])[S:36]Cl>ClCCl>[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH:12][S:36][C:35]([F:39])([F:38])[F:34])[N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: FC(F)(F)SCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NSC(F)(F)F)c1S(C)=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 3-acetyl-5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinylpyrazole (3 g) in dichloromethane containing diisopropylethylamine (1.44 ml) was added trifluoromethylsulfenyl chloride (0.97 ml) at −30° C. The mixture was stirred (2 hours) and when at 20° C. purged with nitrogen. Water was added and the organic phase dried (sodium sulfate) and evaporated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give 3-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinyl-5-trifluoromethylsulfenylaminopyrazole (Compound 10, 0.5 g), m.p. 67-102° C., mass spectral analysis M+/e=499.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([O:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ONC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)ONC(=O)c1cccc(N)c1
Reaction time: 6 h

Procedure:
To an oven-dried 1-L r.b. flask containing 1-tert-butyloxycarbamoyl-3-nitrobenzene (20.0 g, 83.9 mmol) in 500 mL 1:1 ethyl acetate/ethanol at rt was added 10% Pd on C (approx 1 mol %), and the mixture was stirred under an atmosphere of H2 gas for 6 h. The reaction mixture was then filtered, and concentrated under diminished pressure to give 17.4 g (quant of 3-tert-butyloxycarbamoylaniline as a white oily solid. Data for 3-tert-butyloxycarbamoylaniline: 1H NMR (400 MHz, CDCl3) 7.04 (t, J=8.0, 8.0, 1H, 5-H), 6.98 (br s, 1H, NH), 6.53 (dd, J=7.9, 1.8, 1H, 4-H), 6.36 (m, 2H, 6,2-H), 3.66 (br s, 2H, NH2), 1.51 [s, 9H, (CH3)3(CO)].
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1>CCO.C(O)(=O)C.[Fe]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(N)c(C)nc1OC(F)F
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 89.8 %

Procedure:
Alternate route. To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (1.00 g, 4.58 mmol) in EtOH (40 mL) and acetic acid (4 mL) was added iron powder (1.26 g, 22.9 mmol). The reaction mixture was heated at a vigorous reflux with the aid of a heating mantle in a flask without a stir bar. After 1.75 h, the reaction mixture was cooled to room temperature and the iron powder was removed by filtration through a pad of Celite. The filtrate was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous NaHCO3 (50 ml). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by MPLC on silica gel (20%→50% ethyl acetate in hexanes) to afford 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (774 mg, 90% yield) as a pale yellow solid identical to that prepared by Method A: mp 38.4-39.4° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=74.5 Hz, 1H), 6.82 (s, 1H), 2.26 (s, 3H), 2.14 (s, 3H); 13C NMR 100 MHz, CDCl3) δ 149.6, 137.4, 137.1, 127.4, 119.0, 115.0 (J=251.3 Hz), 19.3, 14.8; LRMS (ESI) m/e 189.0 [(M+H)+, calcd for C8H11N2OF2 189.1.]
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].Br[CH2:11][C:12]1[C:13]([Cl:24])=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16].Cl>CO>[Cl:24][C:13]1[C:12]([CH:11]=[O:5])=[C:21]([O:22][CH3:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(OC)c(CBr)c1Cl
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(C=O)c1Cl
Yield: 54 %

Procedure:
To 40 ml methanol, was added 28% methanol solution of sodium methylate in an amount of 5.4 g and the resulting mixture was then fed dropwise with 2-nitropropane in an amount of 2.5 g at an ambient temperature. Then, the mixture was further added with methyl 3-bromomethyl-2-chloro-4-methoxybenzoate in an amount of 7.5 g and stirred for an hour under reflux and heating. After cooling the mixture, the reacted-mixture was added with 100 ml 1N-hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer obtained was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent remained in the layer was condensed under reduced pressure to obtain crystals. The crystals obtained were then washed with ethyl ether to obtain methyl 2-chloro-3-formyl-4-methoxybenzoate in an amount of 3.1 g in crystalline form. The yield was 54%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([S:26][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(Cl)n1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(SCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
12.8 g of 2-chloro-6-methylpyridine, 18 g of anhydrous potassium carbonate and 100 ml of dimethylsulfoxide were mixed to obtain a suspension. This suspension was preliminarily heated to a temperature of from 120° to 130° C., and 10 ml of a dimethylsulfoxide solution of 18.6 g of benzyl mercaptan was dropwise added thereto over a period of about 30 minutes. Then, the mixture was reacted at 150° C. for about one hour. Thereafter, the reaction solution was cooled, then put into water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 7.53 g of oily 2-benzylthio-6-methylpyridine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12]
Reactant: O=C1CCCc2c(O)cccc21
Reactant: Clc1ccc(Br)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2c(OCc3cc(Cl)ccc3Br)cccc21
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a stirred solution of 5-hydroxy-1-tetralone (2.0 g, 12.3 mmol) and 1-bromo-2-(bromomethyl)-4-chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromo-5-chlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one (4.25 g, 94% yield) was isolated by filtration.