Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:12]1[C:16](Br)=[CH:15][S:14][CH:13]=1.Cl>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.[Ni]>[CH2:1]([C:12]1[C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][S:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Brc1cscc1Br
Reactant: CCCCCCCC[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCc1cscc1CCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Synthesis: 2 M octylmagnesium bromide (100 milliliters, 0.2 mol) in anhydrous ethyl ether was added to a well-stirred mixture of dichloro[1,3-bis(diphenylphosphino)-propane]nickel (II) (0.2 gram) and 3,4-dibromothiophene (20.16 grams, 0.0833 mol) in 200 milliliters of anhydrous ethyl ether in a 500 milliliter round bottom flask cooled with an ice bath under an inert atmosphere. The nickel complex (II) reacted immediately with the Grignard reagent, and the resulting reaction mixture was then allowed to warm up to room temperature. An exothermic reaction started within 30 minutes and the ethyl ether began to reflux gently. After stirring for another 2 hours at room temperature, the reaction mixture was refluxed for 6 hours, then cooled in an ice bath, and hydrolyzed with an aqueous 2N hydrochloric acid. The resulting organic layer was separated and washed successively with water, brine, and again with water, dried over anhydrous sodium sulfate, and filtered. After evaporation of the solvent, the residue was distilled under reduced pressure using a Kugelrohr apparatus to provide 21.3 grams of 3,4-dioctylthiophene as a colorless liquid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Cl:7]Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].Cl.C(OC(=O)CN)C>C(Cl)Cl>[Cl:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([NH:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[O:5]
Reactant: CCOC(=O)CN
Reactant: ClCl
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(=O)CCl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
5.08 ml diketene are dissolved in 40 ml CH2Cl2. The solution is cooled to -30° C. and chlorine is passed through it for 1 h. The solution is then added rapidly dropwise to a solution of glycine ethyl ester prepared by suspending 9.30 g glycine ethyl ester hydrochloride in 160 ml methylene chloride containing 18.6 ml triethylamine, the mixture is stirred for 30 min and cooled to -30° C. Stirring is continued for 30 min, the solvent is evaporated in vacuo, and the residue taken up in ethyl acetate. The salts are filtered off, the solvent is evaporated and the residue chromatographed on silica, eluting with ethyl acetate. The compound is obtained as a white powder, m.p. 96°-7° C.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>C(O)C.[Ni]>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][N:2]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:23])=[O:22])=[CH:24][CH:25]=2)[CH3:1])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: CN(CCOc1ccc(C(N)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(C(N)=O)cc1)CCc1ccc(N)cc1
Yield: 93.9 %

Procedure:
A solution of 4-{2-[N-methyl-N-(4-nitrophenethyl)amino]ethoxy}benzamide (1.4 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney nickel ("Nicat 102", Trade Mark). The reaction mixture was filtered and evaporated to dryness to give a yellow solid (1.2 g) which crystallised from ethyl acetate to give the title compound, (1.1 g), m.p. 110°-112°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:28][OH:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C=O)=C1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(CO)=C1C(=O)OCC
Reaction time: 0.17 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.70 g) in ethanol (100 ml) was gradually added at 4° C. sodium borohydride (445.2 mg) and the resultant mixture was stirred at 4° C. for 1.5 hours under ice-cooling. The reaction mixture was acidified with 50% acetic acid and ethanol was removed. To the residue was added water and the aqueous mixture was stirred for 10 minutes. The powder was collected by filtration and washed with water to give crude crystals (4.49 g), which were recrystallized from methanol to give yellow crystals of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-hydroxymethyl-1,4-dihydropiridine-3,5-dicarboxylate, m.p. 124° to 126° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[O:18])=[CH:19][CH:20]=2)[N:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)O)cc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3nc(Cl)ccc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
A suspension of 4-(3-carbamoyl-6-chloropyridin-2-ylamino)benzoic acid (700 mg, 2.400 mmol), 1-methylpiperazine (288 mg, 2.88 mmol), HOBT (441 mg, 2.88 mmol), and EDC (552 mg, 2.88 mmol) in DMF (4 mL) was stirred at rt for 2 h. The reaction mixture was diluted with water and the resulting precipitate filtered and purified by MPLC chromatography (ISCO, solid loaded on CELITE®, 10% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to give 175 mg of 6-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)nicotinamide. LCMS: (M+H)+=374.05, 376.07 (Cl pattern); 1H NMR (400 MHz, CDCl3) δ ppm 10.74 (1H, s), 7.64 (3H, dd, J=8.13, 5.49 Hz), 7.21 (2H, d, J=8.79 Hz), 6.67 (1H, d, J=7.91 Hz), 3.38-3.97 (4 H, m), 2.34-2.59 (4H, m), 2.33 (3H, s), 1.70 (2H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].I[CH:10]([CH3:12])[CH3:11].[OH-].[Na+]>C(O)C.O.[OH-].[K+]>[CH:10]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)I
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(O)cc1
Yield: 46969.8 %

Procedure:
To a mixture of hydroquinone (20.0 g, 0.182 mmol), 2-iodopropane (30.9 g, 0.182 mmol) in ethanol (25 mL) at refluxing was added KOH (88%, 12.2 mg, 0.191 mmol) in water (30 mL) over a period of 60 min. The resulting mixture was refluxed for 3 hours. The mixture was poured into 1N NaOH and extracted with ether (1×). The aqueous layer was acidified with 10% HCl to pH ˜5 and extracted with ether (2×). The combined extracts were washed with brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate:hexane (1:8) to give the desired product as a brownish liquid (13.01 g, 47.0%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]#[CH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[CH:1]([N:4]([CH2:5][C:6]#[CH:7])[C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#CCNC(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C#CCN(C(=O)C(Cl)Cl)C(C)C
Temperature: 25 °C
Yield: 84.7 %

Procedure:
118 g of isopropylpropargylamine and 123 g of triethylamine are dissolved in 670 ml of toluene. While cooling and at room temperature, a solution of 180 g of dichloroacetyl chloride in 450 ml of toluene is dripped into this solution. The mixture is allowed to react for 1 hour before being filtered, and the filtrate is washed with water. The residue remaining after removal of the solvent is washed with petroleum ether. There is obtained 214 g (84% of theory) of N-isopropyl-N-propargyldichloroacetamide; b.p. (0.013 mbar): 80°-82° C.; m.p.: 58°-59° C.
Reaction SMILES: [C:1]([OH:10])(=O)[C@@H:2]([C@H:4]([C:6](O)=[O:7])[OH:5])[OH:3].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[CH2:11]([N:18]1[C:6](=[O:7])[C@H:4]([OH:5])[C@@H:2]([OH:3])[C:1]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: Cc1ccccc1C
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Temperature: 150 °C

Procedure:
L-Tartaric acid (30 g) and benzylamine (22 ml) were added to xylene (150 ml), and the mixture was heated under reflux at 150° C. for 3 hours using a Dean-Stark trap. After the reaction mixture was allowed to cool overnight, crystals were collected by filtration and washed with acetone. The resultant crude product was recrystallized from ethanol to obtain the title compound (23.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 817.5 %

Procedure:
4-Acetylbenzoic acid (4.00 g, 24.4 mmol), 5-aminotetrazole monohydrate (3.00 g, 2.91 mmol) and ethyl dimethylaminopropyl carbodiimide hydrochloride (7.00 g, 3.55 mmol) were dissolved in DMF (25 mL) and stirred at ambient temperature for 48 hours. The reaction mixture was poured into ice-water, and the precipitate collected by filtration to afford 5.50 g (98%) of pure 4-acetyl-N-(2H-tetrazol-5-yl)benzamide after drying overnight in a vacuum oven.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=C.[CH3:11]OC1C=CC(O)=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:11])(=[O:5])[CH:2]=[CH2:4]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C=CC(=O)OCCCC
Temperature: 25 °C

Procedure:
After the completion of the reaction, the solution was cooled to room temperature. To the solution, 3 g of glycidyl methacrylate, 0.1 g of p-methoxyphenol and 0.3 g of tetrabutylammonium bromide were added. The mixture was stirred until these added compounds dissolved completely. The solution thus obtained was heated to 80° C., and an addition reaction was allowed to take place for 16 hours between the carboxyl group in the copolymer and the epoxy group in the glycidyl methacrylate. Thereafter, the solution was cooled to room temperature to obtain an alkali soluble resin (A-3) in the form of resin solution.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH3:10][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([CH3:12])=[C:2]2[C:7]=1[CH:8]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]([C:20]([F:19])([F:29])[F:28])[O:1]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Cc1cc(C)c(C=O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(C)cc(C)c(C)c2OC1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-hydroxy-2,4,5-trimethylbenzaldehyde (2.77 g, 17.1 mmoles) in 50 mL of dry DMF was added anhydrous K2CO3 (5.19 g, 37.6 mmoles), and ethyl 4,4,4-trifluorocrotonate (3.16 g, 18.8 mmoles). The mixture was stirred rapidly under a drying tube at 100° C. for 3 h. After cooling, the mixture was diluted with DMF, filtered, and evaporated. Chromatography of the residue over silica gel using DCM as eluent gave ethyl 5,7,8-trimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 3.75 g, as an oil.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:23]([CH2:25][CH3:26])[CH3:24])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](O)=[O:12])[C:6]1=[O:22])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][O:61][C:62]1[CH:91]=[CH:90][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH2:88])[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:64][CH:63]=1>ClCCl>[CH3:60][O:61][C:62]1[CH:63]=[CH:64][C:65]([CH2:66][N:67]2[C@@H:76]([C@@H:77]([OH:89])[C@@H:78]([NH:88][C:11](=[O:12])[C@@H:10]([N:7]3[CH2:8][CH2:9][C@:5]([NH:4][C:1](=[O:3])[CH3:2])([C@@H:23]([CH2:25][CH3:26])[CH3:24])[C:6]3=[O:22])[CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:79][C:80]3[CH:85]=[C:84]([F:86])[CH:83]=[C:82]([F:87])[CH:81]=3)[CH2:75][C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[CH2:68]2)=[CH:90][CH:91]=1
Reactant: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2Cc3ccccc3CN2Cc2ccc(OC)cc2)C1=O
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-4-phenylbutanoic acid (Preparation B, 25 mg, 0.069 mmol) in dichloromethane (1 mL) was added Hunig's base (27 mg, 0.21 mmol) to make a clear solution and HATU (34 mg, 0.090 mmol) was then added. After stirring for 1 h, to the reaction mixture was added (1S,2S)-1-((R)-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation A, 33.5 mg, 0.076 mmol) and the reaction mixture was stirred at rt overnight. Solvent was removed and the crude mixture was purified by silica gel Flash Chromatography to give 50 mg of the title compound: 1H NMR (CD3OD, 500 MHz) δ 0.68 (3H, d, J=5 Hz), 0.94-1.08 (4H, m), 1.61-1.66 (2H, m), 1.94 (3H, s), 2.01-2.20 (4H, m), 2.46 (1H, m), 2.60-2.69 (2H, m), 2.76-2.94 (2H, m), 3.00 (1H, m), 3.07 (1H, dd, J=5, 15 Hz), 3.22 (1H, m), 3.46 (1H, dt, J=5, 10 Hz), 3.62-3.69 (3H, m), 3.74 (3H, s), 3.82 (1H, m), 4.02 (1H, d, J=15 Hz), 4.14 (1H, dd, J=5, 10 Hz), 4.72 (1H, m), 6.70 (1H, m), 6.81 (2H, d, J=10 Hz), 6.87 (2H, d, J=10 Hz), 6.96 (1H, d, J=5 Hz), 7.08-7.13 (6H, m), 7.17-7.20 (2H, m), 7.24 (2H, d, J=5 Hz). MS (ESI)(M+H)+ 781.39.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+].CN(C)C=O.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1OCCOCCOCCOCCOCCOC1.O>[CH2:8]([C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCOC(=O)CS
Reactant: CCCCCC(=O)Cc1sccc1Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1c(C(=O)OCC)sc2ccsc12
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Compound 59 (35.4 g, 0.13 mol) and K2CO3 (27.6 g, 0.2 mol) are mixed with N,N-dimethylformamide (100 mL). A catalytic amount (˜25 mg) 18-crown-6 is added, and to this mixture, ethyl 2-mercaptoacetate (14.0 mL, 0.13 mol) is added dropwise at 60° C. The mixture is stirred overnight and poured into water (500 mL). The organic component is extracted with ethyl acetate (3×80 mL). The combined organic layers are washed with brine (2×100 mL) and water (100 mL). The organic layer is then dried over MgSO4. After evaporation of the solvent, the crude compound 61 is obtained and purified by column chromatography (SiO2/5% ethyl acetate in hexanes) to yield pure compound 61 (32.1 g, 84.5%). GC/MS: 296 g/mol (M). 1H NMR (CD2Cl2): δ 7.56 (d, 1H), 7.24 (d, 1H), 4.34 (q, 2H), 3.15 (t, 2H), 1.71 (m, 2H), 1.32 (m, 6H), 0.88 (m, 6H). 13C NMR: 163.24, 143.31, 141.85, 141.09, 131.13, 128.44, 120.35, 61.25, 31.99, 29.72 (overlap), 22.98, 14.52, 14.23.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13].[C:20](#N)C>>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][C:4]([CH3:20])=[N:3][CH:2]=1)#[N:13]
Reactant: CC#N
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NC#N)SC
Product: CNC(=NCCSCc1cnc(C)[nH]1)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((methyl-5-imidazolyl)methylthio)ethyl]guanidine m.p. 141°-2°.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[N:49]([CH:50]2[CH2:52][CH2:51]2)[N:48]=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH:50]4[CH2:52][CH2:51]4)[N:48]=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: ClCc1nnnn1C1CC1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3nnnn3C3CC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as red gum. MS (m/e): 405.3 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:10][C:11](C)=S)[CH:7]([CH3:9])[CH3:8])=[O:4].[OH:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C(OO)(=[O:25])C>ClCCl>[CH3:1][CH:2]([CH3:14])[C:3]([O:5][CH:6]([O:10][C:11]([O:15][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:25])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Reactant: CC(=O)OO
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Yield: 70 %

Procedure:
Following the above general procedure, 2-methyl-1-(methylthiocarbonyloxy)-propyl 2-methylpropanoate (2.34 g, 10.0 mmol) and N-hydroxysuccinimide (5.76 g, 50 mmol) were reacted in dichloromethane (30 mL) with peracetic acid (32 wt. %, 8.17 mL). After aqueous workup, isolation and removal of residual solvents in vacuo, the crude product 3 (2.12 g, 70%) was obtained as a pale yellow oil. The material was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.04 (d, J=7.2 Hz, 6H), 1.21 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.8 Hz, 3H), 2.15-2.21 (m, 1H), 2.63 (hept., J=7.2 Hz, 1H), 2.84 (s, 4H), 6.59 (d, J=5.2 Hz, 1H). MS (ESI) m/z 324.10 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].OO.C(=O)([O-])[O-:34].[K+].[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:27])[C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])(=[O:34])[NH2:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C(N)=O)c2)cc1
Reaction time: 24 h
Yield: 166.6 %

Procedure:
To a solution of N1-(3-cyanobenzoyl)-N2-(4-tert-butylbenzoyl)-1,2-benzenediamine (200 mg, 0.5 mmol) in methyl sulfoxide (10 mL) was added 30% hydrogen peroxide solution (0.5 mL, 5.8 mmol) and potassium carbonate (17 mg, 0.13 mmol). After stirring for 24 h, the reaction mixture was diluted with water (20 mL), filtered, washed with water, and dried to give 90 mg (43%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][CH:8]=2)[N:3]=1.CC(O)=O.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Zn]>[F:15][C:12]([F:13])([F:14])[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:16][C:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][CH:8]=2)[N:3]=[CH:2][CH:11]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3ccc4c(C(F)(F)F)cc(Cl)nc4c3)ncn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4c(C(F)(F)F)ccnc4c3)ncn2)cc1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To a 100-mL, round-bottomed flask containing a solution of 2-chloro-4-trifluoromethyl-7-[6-(4-trifluromethyl-phenyl)-pyrimidin-4-yloxy]-quinoline, (Example 22(b)), (0.25 g, 0.53 mmol) in EtOAc (20 mL) was added Zn (0.87 g, 13 mmol, Aldrich), AcOH (61 mg, 1.1 mmol), and water (40 mg, 1.1 mmol). The mixture was heated at 70° C. with stirring for 2.5 h. After cooling to room temperature, 5% aq. Na2CO3 was added and the reaction mixture was extracted with EtOAc (30 mL). The organic phase was washed with water (2×10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Purification of the residue by silica gel chromatography (gradient: 3:1 hexanes:EtOAc) gave the title compound. Mp: 129–131° C. MS (ESI, pos. ion) m/z: 436 (M+1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH2:9][CH:8]=[C:7]2[CH2:15][C:16]([O:18]C)=O.C[OH:21]>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:21])[CH:8]=[C:7]2[CH2:15][CH2:16][OH:18]
Reactant: CO
Reactant: COC(=O)CC1=CCN(C)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)cc(CCO)c2cc(Cl)ccc21

Procedure:
3.0 g (79 mmol) of sodium borohydride are added to a suspension of 5.9 g (23.4 mmol) of methyl 6-chloro-1-methyl-1,2-dihydro-4-quinolineacetate in 10 ml of methanol and 100 ml of dry tetrahydrofuran, and the mixture is then heated to reflux for 9 hours. After cooling, the solvents are evaporated off under vacuum and the residue is taken up in 400 ml of dichloromethane and 100 ml of 3 N hydrochloric acid. The organic phase is washed with water, dried over sodium sulphate and filtered and the filtrate is condensed. The crude product is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture.