Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1.[C:16]([O:20][C:21]([N:23]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:24]1[CH:29]=[C:28]([C:30]2[O:31][CH:32]=[C:33]([C:35](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:36])[N:34]=2)[CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CO.[C].[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:35]([C:33]2[N:34]=[C:30]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:23]([CH2:49][C:50]([F:52])([F:51])[F:53])[C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:29]=3)[O:31][CH:32]=2)=[O:36])[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)co2)ccn1
Reactant: Cn1cc([N+](=O)[O-])c(N2CCOC2=O)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCOC2=O)n1
Yield: 18.6 %

Procedure:
A solution of 3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (58 mg), pentafluorophenyl 2-(2-((tert-butoxycarbonyl) (2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (197 mg), 10% palladium-carbon (29 mg) and triethylamine (76 μL) in methanol (1.4 mL) was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])SC.O.[NH2:12][NH2:13]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:12][NH2:13]
Reactant: COCCCNC(=S)SC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCCCNC(=S)NN
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 98.5 %

Procedure:
A solution of methyl N-(3-methoxypropyl)-dithiocarbamate (100.2 g) in ethanol (300 ml) was added dropwise at 3° C. over 30 minutes to a solution of hydrazine hydrate (28 g) in ethanol (200 ml). The mixture was stirred for 4.5 hours at 70° C. The reaction mixture was concentrated and to the residue were added water and diethyl ether. The diethyl ether extract was dried over magnesium sulfate and evaporated in vacuo to give pinkish oil of 4-(3-methoxypropyl)thiosemicarbazide (89.9 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[F:11][CH:12]([F:33])[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15](Cl)[C:14]=1[C:29]([O:31][CH3:32])=[O:30].[Li].N1C=CC=N1>O1CCCC1.O>[F:22][C:19]([F:20])([F:21])[C:17]1[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:14]([C:29]([O:31][CH3:32])=[O:30])=[C:13]([CH:12]([F:11])[F:33])[N:18]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: c1cn[nH]c1
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1-n1cccn1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
To a solution of 0.94 g (0.014 mol) of pyrazole in 25 ml of anhydrous tetrahydrofuran was added 0.9 g (0.014 mol) of n-butyllithium. This cloudy solution was then transferred to a solution of 5 g (0.014 mol) of product of Example 103 in 25 ml of anhydrous THF. The solution turned red upon addition of the pyrazole lithium salt. After 45 minutes at room temperature the reaction was complete. The mixture was poured into 100 ml of water and extracted with two 75 ml portions of ether. The combined ether layers were washed with two 100 ml portions of water, dried (CaSO4), filtered and concentrated to 4.1 g of oil which was about 80% product. Trituration with petroleum ether gave 2.4 g (45%) of pure product; mp 42°-52° C. Recrystallization from cyclohexane afforded an analytical sample; mp 48.5°-50° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C

Procedure:
4-carboxyphthalic anhydride (benzene tricarboxylic acid anhydride) (1.0 g, 0.0052 mol), glycine (0.3907 g, 0.0052 mol) and 50–60 mls of glacial acetic acid were added to a 100 ml round-bottom flask equipped with a reflux condenser, heating mantle and stir plate. The system was placed under a N2 atmosphere and heated to a gentle reflux. The progress of the reaction was monitored by TLC. After 7 hours the clear colourless solution was cooled to room temperature. The resulting white precipitate was filtered through a Buchner funnel and washed three times with 10 mls of distilled water. This crude material was recrystallized in EtOH/H2O to afford the desired product as a powdery white solid. The filtrate was evaporated under vacuum using a rotary evaporator. The crude material was recrystallized from EtOH/H2O to yield a second batch of white powdery product. Individual batches were dried in air for 24 hours and then in vacuo for 48–72 hours to afford 100 in a combined yield of 1.02 g (78%): mp=262–265° C.; Rf 0.70 (A): Rf 0.47 (B): Rf 0.20 (D): 1H NMR (DMSO-d6) δ 4.33 (s, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.24 (bs, 1H), 8.36 (d, J=7.8 Hz, 1H); MS m/z (rel intensity) 249 (13), 248 (100), 204 (36); IR (cm−1): 2750–3300 (OH), 3052 (C═CH), 2671 (C—H), 1776 (C═O), 1731 (C═O), 1705 (C═O), 1620 (C═C), 1420 (C═C), 1300 (C—O), 1122 (C—O), 746 (C═CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C)C=O>[CH2:33]([NH:40][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A suspension of 29.4 mg (0.10 mmol) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 18.4 mg (0.11 mmol) 1.1′-carbonyl-diimidazole in 3 ml dimethylformamide was stirred at room temperature for one hour. 12.1 μl (0.11 mmol) benzylamine were added, stirring was continued and after 20 hours 15 ml water were added. Extraction with ethyl acetate and chromatography on silicagel with dichloromethane/ethyl acetate 95/5 yielded 31.2 mg (41%) of yellow 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid benzylamide with mp.: 156-158° C., MS m/e (%): 384 (M+H+, 100).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([F:12])=[C:6]([F:13])[C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21].[OH:23][CH2:24][CH2:25][NH:26][NH2:27]>CCO>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:5]1[C:6]([F:13])=[C:7]([F:12])[CH:8]=[C:9]2[C:4]=1[C:3](=[O:22])[N:26]([CH2:25][CH2:24][OH:23])[N:27]=[CH:10]2
Reactant: COC(=O)c1c(C=O)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: NNCCO
Solvent: CCO
Product: O=c1c2c(Nc3ccccc3Cl)c(F)c(F)cc2cnn1CCO
Temperature: 25 °C
Yield: 29.6 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-6-formyl benzoic acid methyl ester (0.400 mg, 1.228 mmol) and 2-hydroxyethyl hydrazine (0.102 mL, 1.351 mmol) in EtOH (10 mL) was heated at reflux under N2 for 16 hours. After cooling to room temperature, a yellow precipitate formed which was collected by filtration. The yellow solid was washed with EtOH and dried to yield 0.128 g (30%) pure desired product.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([O-:20])[C:17]([C:21](OC)=[O:22])=[CH:16][N:15]=2)=[N:6]1.[Na+:29].CO.[NH3:32]>>[C:21]([C:17]1[C:18]([O-:20])=[N:19][C:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]([CH2:4][C:3]3[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=3[F:1])[N:6]=2)=[N:15][CH:16]=1)(=[O:22])[NH2:32].[Na+:29]
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]
Reactant: N
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1[O-]
Temperature: 60 °C
Reaction time: 24 h

Procedure:
100 mg of sodium 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(methoxycarbonyl)pyrimidin-4-olate (1-12-1, 0.25 mmol, 1 eq.) were dissolved in 26.8 ml of 7N ammonia in methanol (187 mmol, 750 eq.) and stirred under a nitrogen atmosphere at 60° C. bath temperature for 24 hours, then at 65° C. bath temperature for six hours and further 24 hours at 70° C. bath temperature. The reaction mixture was concentrated in vacuo to yield 96 mg (0.22 mmol, 89.8%) of the analytically pure target compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].[Cl-].P([O-])([O-])([O-])=[O:12].[K+].[K+].[K+]>>[C:1]([NH2:2])(=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: NC(=O)c1cccnc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
A reaction mixture comprising 3-cyanopyridine 20 (0.1-1.0 M; 1.0-1.8 ml), aqueous NaCl solution (0.85% (w/v); 0.7 to 0.1 ml), potassium phosphate buffer (0.1 M; pH 7.0; 0.3 ml) and cell suspension (0.01 ml) was incubated with shaking at 30° C. for 10 min. The total volume of the reaction mixture was between 2.0 to 2.2 ml, depending on the 3-cyanopyridine concentration. The reaction was stopped by adding HC1(2 M; 0.1 ml). After centrifugation of the reaction mixture (12 000 rpm; 5 min), the amount of nicotinamide produced was determined by means of HPLC according to Example 1. The KM value determined was 160 mM (FIG. 10).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][C:26]=1Br)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[CH:24]=[CH:25][C:26]=1[CH:32]=[CH:31][C:30]([O:34][CH3:35])=[O:33])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(Br)c(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(OC)cc1CN(Cc1ccc(C(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A solution of 3-[N-(tert-butoxycarbonyl)-N-(4-trifluoromethylbenzyl)aminomethyl]-4-bromoanisole (37.08 g, 78 mmol), methyl acrylate (35 mL, 390 mmol), palladium acetate (0.88 g, 3.9 mmol), tri-o-tolylphosphine (2.38 g, 7.8 mol), and diisopropylethylamine (31 mL, 178 mmol) in acetonitrile (200 mL) was deoxygenated (3 evacuation/argon purge cycles), then was heated to reflux under argon (oil bath set at 80° C.). After 6 hr additional palladium acetate (0.88 g, 3.9 mmol) and tri-o-tolylphosphine ((2.38 g, 7.8 mmol) were added and the reaction was stirred under reflux for an additional 18 h. The reaction was concentrated to dryness, and the residue was taken up in 1:1 Et2O/petroleum ether (300 mL) and allowed to stand for 4 h. A gray-colored precipitate was filtered off and washed with a small volume of 1:1 Et2O/petroleum ether (100 mL). The orangish-red filtrate was concentrated and purified by flash chromatography on silica gel (15% ethyl acetate/hexanes). The resulting residue was taken up in hexane, and the mixture was allowed to stand for several hr, then was filtered to remove a yellow precipitate. Concentration of the filtrate left the title compound (34.52 g, 92%) as a thick yellow oil: TLC (silica, 20% EtOAc/hexanes) Rf 0.45; 1H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 7.29 (br s, 2H), 6.83 (dd, 1H), 6.72 (br s, 1H), 6.23 (d, J=15.7 Hz, 1H), 4.58 and 4.53 (2 br s, 2H), 4.46 and 4.37 (2 br s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:1]([CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(CCCCCCCC)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 107.8 %

Procedure:
2-Octyl-1-dodecanol (20 ml, 56.14 mmol) and anhydrous triethylamine (16 ml, 112.28 mmol) were dissolved in dry dichloromethane (60 ml). The solution was cooled to 0° C. and methanesulfonyl chloride (5.2 ml, 67.36 mmol) in dry dichloromethane (40 ml) added dropwise. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then refrigerated (2-8° C.) overnight. The reaction mixture was poured on ice (500 grams), allowed to warm to room temperature, and extracted with ether (3×150 ml). The organic phase was washed consecutively with water (150 ml), 2% H2SO4 (150 ml), water (150 ml), saturated sodium bicarbonate (150 ml) and again with water (150 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure, yielding 22.8 grams of methanesulfonic acid 2-octyl-dodecyl ester as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26][CH:27]1[CH2:32][CH2:31][N:30]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: c1ccc2cc(SC3CCNCC3)ccc2c1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(Sc2ccc3ccccc3c2)CC1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 4-(2-naphthylthio)piperidine to give 4-(2-naphthylthio)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine in 62% yield;
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[OH-].[Na+].C(C(C)=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([CH2:19][CH2:20][CH2:21][Cl:22])[C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCC(C)=O
Product: ClCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A mixture of 14.9 g. (0.06 moles) of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine, 37.8 g. (0.24 moles) of 1-bromo-3-chloropropane, 19.6 g. (0.48 moles) of sodium hydroxide and 180 ml. of methyl ethyl ketone is stirred under reflux for 10 hours. Thereafter further 19.6 g. (0.48 moles) of sodium hydroxide are added and the stirring under reflux continued for 10 hours. The reaction mixture is cooled to 20° C. and poured to 300 g. of broken ice under stirring. 100 ml. of benzene are added, the organic phase is separated and the solvent is removed in vacuo. The residue is subjected to vacuum destillation. There are obtained 14.3 g. of a yellow viscous liquid, b.p./0.3 mmHg: 165° to 171° C. This liquid solidifies upon trituration with petrol ether. Recrystallization from isopropanol affords 12.5 g. (64.0%) of a white product, melting at 105° to 108° C.
Reaction SMILES: BrCCBr.Cl[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
96 g (4 moles) of Mg turnings in 60 ml of absolute tetrahydrofuran (THF) are initially taken under a nitrogen atmosphere. 1 ml of 1,2-dibromoethane is added at 65° C., after which a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 l of absolute THF is added dropwise in the course of 21/4 hours. Thereafter, the mixture is stirred for 4 hours under reflux and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF are added under nitrogen. When the reaction is complete, the Grignard reaction mixture is worked up in an aqueous medium in a conventional manner and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30°-107° C./0.27 mbar). The remaining crude product (676 g), which contains as much as 90% of 1-(3-chloro-2'-methylphenyl)-cyclohexanol, can be further purified by column chromatography using toluene as the mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)[CH3:25])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 1.0 g of 5-(4 chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of N,N-dimethylformamide at 0° C. was added 0.13 g of 60% sodiumhydride. After stirring at room temperature for 30 minutes, 0.42 g of methyl iodide added dropwise to the solution at 0° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours, poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.0 g of 5-(4-chloro-α-methylbenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1>>[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH:17][C:2]3[N:7]=[C:6]([NH:17][C:16]4[CH:18]=[CH:19][C:20]5[O:21][CH2:22][CH2:12][O:13][C:14]=5[CH:15]=4)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=3)=[CH:15][C:14]=2[O:13]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 3,4-ethylenedioxyaniline gave N2,N4-bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 30.78 min.; purity: 100%; MS (m/e): 424 (MH+); 1H NMR (CDCl3): δ 10.21 (1H, s), 9.10 (1H, s), 7.40 (1H, s), 7.11-6.71 (6H, m), 4.29 (4H, s), 4.25 (4H, s).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:15]([O:16][CH3:17])[CH3:14])=[O:9])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
4-Bromocinnamic acid (28.3 g, 124.6 mmol), N,O-dimethylhydroxylamine hydrochloride (14.6 g, 149.6 mmol), HOBT (33.7 g, 249.3 mmol), EDAC (47.8 g, 249.3 mmol) and triethylamine (34.7 mL, 249.3 mmol) were added to dichloromethane (800.0 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 26.8 g of the titled compound as a white solid.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[OH-].[K+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)=[O:15])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: Cc1ccc(S)cc1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(=O)C(Sc2ccc(C)cc2)C1

Procedure:
In a 2 l. three-necked flask provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 73.5 g. of p-toluenethiol and a solution of 33 g. of 85% potassium hydroxide in 500 ml. of ethanol. The solution was brought to reflux, and a solution of 146.4 g. of 3-bromo-4-ketocyclohexanecarboxylic acid ethyl ester in 500 ml. of ethanol was added over a period of one hour. After the addition, the solution was stirred at reflux for one hour. After removal of the ethanol in vacuo on the steam bath, 300 ml. of water was added, and the product was extracted three times with 200 ml. of ether. The ether solution was dried over anhydrous magnesium sulfate, and then the solvent was removed on the steam bath. The residue was crystallized from heptane; yield 66 g. of 3-(4-methylphenylthio)-4-ketocyclohexanecarboxylic acid ethyl ester, m.p. 87°-89°.