Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]([Cl:10])(Cl)=[O:8].[ClH:11]>[Cl-].C[N+](C)(C)CC1C=CC=CC=1>[Cl:11][CH2:3][CH2:2][CH2:1][C:7]([Cl:10])=[O:8].[C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: O=C1CCCO1
Product: O=C(Cl)CCCCl
Temperature: 130 °C

Procedure:
430 parts of 4-butyrolactone and 47 parts of trimethylbenzylammonium chloride are initially taken in a 1 l stirred reactor which is equipped with a thermometer, inlet tubes for phosgene and hydrogen chloride and 2 low-temperature coolers set at -20° C. and -70° C. respectively. The mixture is heated to 130° C. 560 parts of phosgene and 120 parts of hydrogen chloride are passed in over 5.5 hours. Thereafter, nitrogen is passed in until the reaction mixture no longer contains any phosgene. Working up by distillation gives 620 g of 4-chlorobutyryl chloride and 30.5 g of butyrolactone. The distillation residue of 75 g, which consists of the catalyst and chlorobutyroyloxybutyryl chloride, can be reused for further batches. The yield of 4-chlorobutyryl chloride is 88 mol %, based on butyrolactone used.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:11]\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])/[CH2:9]O)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:26].O>C(OC)(C)(C)C>[Br:26][CH2:9]/[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: BrP(Br)Br
Reactant: OC/C(=C/c1ccccc1Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: O
Product: Fc1ccc(/C(=C\c2ccccc2Cl)CBr)cc1
Yield: 236 %

Procedure:
103.1 g of E-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-enol are dissolved in 700 ml of methyl tert-butyl ether, and 2 ml of pyridine are added. The reaction solution is stirred under a nitrogen atmosphere at 0° C., while 27.2 g of phosphorus tribromide are added in the course of 90 minutes. After the end of the addition, the mixture is refluxed for two hours and then poured onto 500 ml of water and extracted several times with methyl tert-butyl ether. The organic phase is washed with sodium bicarbonate solution and water and dried over sodium sulfate, and the solvent is evaporated down under reduced pressure. 77.2 g (61%) of E-1-bromo-2-(4-fluorophenyl)-3-(2-chlorophenyl)-prop-2-ene of melting point 68° C. are obtained from ethanol.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20]OS([O-])=O.[K+].[OH2:26]>C(O)C>[CH2:1]([S:8]([C:9]1[S:19][C:12]2=[N:13][CH:14]=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)(=[O:20])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: Cc1cnc2sc(SCc3ccccc3)nn2c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCO
Product: Cc1cnc2sc(S(=O)(=O)Cc3ccccc3)nn2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
In 75 ml of ethanol, 2.8 g of 2-benzylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one prepared in Preparation Example 1 was added and dissolved by warming the mixture to 60° C. To this solution, an aqueous suspension of 35.7 g OXONE ® of in 150 ml of water was added, and the mixture was stirred at 60° C. for 2 hours. After cooling, water was added to dissolve inorganic materials, and the deposited crystals were collected by filtration. The crystals were recrystallized from ethanol, and thus 1.6 g of 2-benzylsulfonyl-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 171°-173° C. Yield 52%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
4-(Trifluoromethylsulfonyl)aniline (0.452 g, 2.005 mmol), triethylamine (0.203 g, 2.005 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.339 g, 2.005 mmol) were added to a methylene chloride solution (70 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.241 mmol, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:16]1[CH2:17][CH2:18][CH2:19][CH:14]([OH:13])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(O)C1
Reaction time: 3 h

Procedure:
Benzylchloroformate (15 ml) was added dropwise to a stirred suspension of 3-hydroxypiperidine hydrochloride (13.7 g) and triethylamine (30 ml) in dichloromethane (150 ml), maintaining the temperature below 15° C. throughout. Stirring was continued for three hours, then the solution was washed with water (4×100 ml) and saturated aqueous sodium chloride (100 ml), dried (PS paper) and concentrated. The residual oil was dissolved in ether (300 ml), washed with dilute hydrochloric acid (2×100 ml) and water (100 ml), dried (PS paper) and concentrated. The residue was purified by flash column chromatography, eluting first with hexane/ether (1:1) then ether to give 1-benzyloxycarbonylpiperidine-3-ol (7.1 g) as a colourless oil. NMR(d6DMSO): δ 1.2-1.4(2H,m); 1.6-1.9(1H,m+1H,m); 2.8(1H,br s); 2.95(1H,m); 3.45(1H,m); 3.65(1H,br.d); 3.8(1H,dd); 4.85(1H,d); 5.1(2H,s); 7.3(5H,m); m/e 236(M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>CN(C)C=O.C(O)C>[C:12]([C:11]1[C:2]([NH:20][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:21])=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: N#Cc1c2cccccc-2nc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1nc2cccccc-2c1C#N
Yield: 73.5 %

Procedure:
To a suspended solution of 3 g (0.016 mol) of 2-chloro-3-cyano-1-azaazulene in 10 ml of dimethylformamide and 50 ml of ethanol were added 6.7 g (0.048 mol) of glycine ethylester hydrochloride and 6.5 g (0.064 mol) of triethylamine. The reaction mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, and the chloroform layer was washed with water and dried. Then, the chloroform was evaporated under reduced pressure to give 3.0 g of 3-cyano-2-ethoxycarbonylmethylamino-1-azaazulene having mp of 186° to 188° C. To a solution of obtained 3-cyano-2-ethoxycarbonylmethylamino-1-azaazulene in 100 ml of ethanol were added 5 to 6 ml of 2N aqueous solution of sodium hydroxide, and the reaction mixture was heated at 60° to 70° C. for 30 minutes. The precipitate of sodium salt of title compound was filtered, washed with ether and dried to give 2.6 g of sodium salt of title compound (yield: 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[Cl:18][C:19]1[C:27]2[N:26]=[CH:25][N:24](C3CCCCO3)[C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:34][NH:35][CH3:36].CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CCCCO>[Cl:18][C:19]1[C:27]2[N:26]=[CH:25][NH:24][C:23]=2[CH:22]=[CH:21][C:20]=1[CH2:34][N:35]([CH3:36])[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Reactant: FC(F)c1cc(Nc2ccnc(Cl)n2)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCCCO
Product: CN(Cc1ccc2[nH]cnc2c1Cl)c1nccc(Nc2cc(C(F)F)[nH]n2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A vial was charged with 2-chloro-N-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (80 mg, 0.33 mmol), the bis HCl salt of 1-(4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)-N-methylmethanamine (138 mg, 0.39 mmol), DIPEA (0.29 mL, 1.63 mmol) and n-BuOH (1.5 mL), sealed and heated at 90° C. for 8 h. The reaction mixture was then cooled to RT, and 4N HCl/dioxane (0.81 mL, 3.26 mmol) was added. The mixture was stirred at 40° C. for 3 h and then concentrated in vacuo. The crude mixture was purified by preparative HPLC to afford 15.1 Mg9 12%) of N2-((4-chloro-1H-benzo[d]imidazol-5-yl)methyl)-N4-(5-(difluoromethyl)-1H-pyrazol-3-yl)-N2-methylpyrimidine-2,4-diamine (II-81).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][CH2:30][CH2:31]Br)C.C(N(CC)C(C)C)(C)C.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH3:4].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][N:24]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:27])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc(C3(CN)CCOCC3)cc2)CC1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCCC4=O)CCOCC3)cc2)CC1
Product: N
Temperature: 80 °C
Yield: 11.6 %

Procedure:
To a solution of (4-{4-[(1-isopropylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methylamine (100 mg, 0.301 mmol) in toluene (2 ml) was added ethyl-4-bromobutyrate (43 μl, 0.301 mmol), N,N-diisopropylethylamine (157 μl, 0.904 mmol) and potassium iodide (5 mg, 0.030 mmol). Reaction mixture heated at 80° C. for 48 hours, then increased to reflux. Potassium carbonate (83 mg, 0.602 mmol) was added and reaction left at reflux for a further 24 hours until reaction complete. Reaction mixture was partitioned between ethyl acetate (20 ml) and saturated NaHCO3 (10 ml). Organic washings were dried over Na2SO4 and concentrated in vacuo to give a brown oil (101 mg crude, 84%). The compound was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:ammonia, 100:0:0 to 98:2:0.2, to give the title compound as an oil (7 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 7.90 (d, 2H), 4.22-4.36 (m, 1H), 4.80-4.90 (m, 2H), 3.52-3.67 (m, 2H), 3.40 (s, 2H), 2.72-3.88 (several multiplets, 3H), 2.50 (t, 2H), 2.34-2.44 (m, 2H), 2.21-2.30 (t, 2H), 1.60-2.10 (several multiplets, 10H), 1.08 (d, 6H).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=1)=[O:13]>O.C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1)=[O:13]
Reactant: COC(=O)c1ccccc1COc1ccc(CCNC(=O)Nc2ccc(F)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(OCc2ccccc2C(=O)O)cc1)Nc1ccc(F)cc1F
Yield: 54.8 %

Procedure:
Lithium hydroxide (3.7 mg, 0.154 mmol) in water (1 ml) was added into methyl 2-({4-[2-({[(2,4-difluorophenyl)amino]carbonyl}amino)ethyl]phenoxy}methyl)benzoate (34 mg, 0.077 mmol) dissolved in THF (2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 1 g/6 ml) using MeOH/DCM (1:99, 2:98, 4:96 and then 10:90) as eluant gave 18 mg the desired product, yield 55%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][C:13]([CH3:23])=[C:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[H][H].Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C.C1(C)C=CC=CC=1>[F:30][C:4]([F:29])([F:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:23])[N:14]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:15]([CH3:22])=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)N(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reaction time: 4 h

Procedure:
To a slurry of sodium hydride (2.6 g g., 55 mmole, 50:50 oil dispersion) in dry, distilled DMF (50 mL) under nitrogen atmosphere was added a solution of diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine-dicarboxylate (19.9 g., 50 mmole) in DMF (125 mL). After hydrogen bubbling ceased, the reaction mixture was warmed in a water bath for 1/2 hour, and a toluene (200 mL) solution of N-(2-chloroethyl)-morpholine (8.1 g., 60 mmole) was added dropwise. The reaction mixture was stirred at 110°-115° for 4 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:32]12[CH2:38][CH:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]2[CH:39]=O>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:39][CH:33]1[CH2:34][CH:35]2[CH2:38][CH:32]1[CH2:37][CH2:36]2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: O=CC1CC2CCC1C2
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=CC1CC2CCC1C2)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
In a round bottom flask was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (2.05 g, 6.18 mmol) in dichloromethane (5 mL) and cooled to 0° C. in an ice bath. To this mixture was then added slowly 1,8-diazabicyclo[5.4.0]undec-7-ene (801 μL, 5.36 mmol) and it was stirred at 0° C. for 20 min. The mixture was then treated with a solution of bicyclo[2.2.1]heptane-2-carbaldehyde (512 mg, 4.12 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was allowed to warm to 25° C. and stirred overnight. The mixture was concentrated in vacuo and then dissolved in ethyl acetate (50 mL) and washed with a saturated aqueous ammonium chloride solution (2×25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix IntelliFlash chromatography (25 g column, 15% ethyl acetate/hexanes to 34% ethyl acetate/hexanes) afforded 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-2-yl-acrylic acid methyl ester (491 mg, 36%) as a clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13]1([S:19]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([S:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClSc1ccccc1
Reactant: Clc1cccc(-c2cccs2)c1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccc(Sc3ccccc3)s2)c1
Reaction time: 96 h
Yield: 21.5 %

Procedure:
A mixture of 89 g (0.46 mole) of 2-(m-chlorophenyl)thiophene, 400 ml of reagent carbon tetrachloride, 54 ml (67 g, 0.46 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was allowed to stand for four days at room temperature. A further 12 ml (15 g, 0.10 mole) of benzenesulfenyl chloride and 0.05 g of iron powder were added. After four days the carbon tetrachloride was removed by distillation. The residue was distilled at reduced pressure to give 30 g (22%) of 2-(m-chlorophenyl)-5-(phenylthio)thiophene, b.p. 200°-205° C. (0.15 mm).
Reaction SMILES: FC(F)(F)C1C=CC(N2C=NC(C3C=CC(C[CH2:21][C:22](N=[N+]=[N-])=[O:23])=CC=3)=N2)=CC=1.[N:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[C:30]=[O:31].[Cl:55][C:56]1[CH:57]=[CH:58][C:59]([CH:66]([CH3:68])[CH3:67])=[C:60]([NH:62][C:63]([NH2:65])=[S:64])[CH:61]=1>>[Cl:55][C:56]1[CH:57]=[CH:58][C:59]([CH:66]([CH3:68])[CH3:67])=[C:60]([N:62]2[C:22](=[O:23])[CH2:21][S:64]/[C:63]/2=[N:65]\[C:30]([NH:29][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[N:44]=[CH:43][N:42]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=4)[N:41]=3)=[CH:36][CH:35]=2)=[O:31])[CH:61]=1
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NC(=O)CCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccc(Cl)cc1NC(N)=S
Product: CC(C)c1ccc(Cl)cc1N1C(=O)CS/C1=N\C(=O)NCCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 35 using 3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoyl azide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C35b) and 1-(5-chloro-2-isopropylphenyl)thiourea (CB32) at a temperature of 60° C.; isolated as a clear oil (0.019 g, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH:13]=1.C(N(CC)CC)C>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:19]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: Nc1cccc(-c2cccnc2)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Yield: 47.4 %

Procedure:
A solution of 5-bromo-2-chloro-3-nitropyridine (7.0 g, 29 mmol) and 3-(pyridin-3-yl)phenylamine (5.0 g, 29 mmol) in 1-methyl-2-pyrrolidinone (10 ml) and triethylamine (4 ml, 29 mmol) was heated at 100° C. for 90 minutes. The reaction was cooled, suspended in ethyl acetate (400 ml) and insoluble material removed by filtration. The filtrate was then washed with water, brine and dried over anhydrous sodium sulphate. This solution was filtered and pre-adsorbed on to silica gel. Purification by silica gel chromatography eluting with hexane containing triethyline (1%) on a gradient of ethyl acetate from 20% to 35% gave N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(pyridin-3-yl)phenyl]amine as a red solid (5.1 g, 47%); δH (400 MHz, CDCl3) 7.35-7.45 (2H, m, ArH), 7.51 (1H, t, J 8, ArH), 7.62 (1H, d, J 8, ArH), 7.88-7.91 (2H, m, pyridyl-H and NH), 8.53 (1H, s, pyridyl-H), 8.62 (1H, d, J 5, pyridyl-H), 8.68 (1H, s, pyridyl-H), 9.88 (1H, s, pyridyl-H), 10.14 (1H, s, pyridyl-H); m/z (ES+) 371 and 373 (M++H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1.O.Cl>CCO>[CH3:3][O:4][C:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:6]=1
Reactant: CCOC(=O)c1cn(-c2ncccn2)nc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1nn(-c2ncccn2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1 N aqueous sodium hydroxide solution (10 mL) is added to a slurry of ethyl 3-methoxy-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylate (1.1 mg, 4.43 mmol) in 30 mL of EtOH. The reaction mixture becomes homogeneous and is stirred for 2 h at RT. Water (2-3 mL) is added, and the solution is cooled to 0° C. and acidified to pH=2-3 with cone. HCl. Most of the EtOH is removed in vacuo, and the resultant mixture is filtered. The collected solid is dried in vacuo to give the title compound as a white solid.
Reaction SMILES: COC1[CH:4]=[C:5]([CH:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20]C(F)=CC=2)[CH3:12])[CH:6]=[C:7]([O:9]C)C=1.O=[C:24]1[CH2:29][CH2:28][S:27][CH2:26][CH:25]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[CH2:36](O)C>>[OH:9][C:7]1[C:34]2[C:24]3[CH2:29][CH2:28][S:27][CH2:26][C:25]=3[C:30](=[O:31])[O:32][C:33]=2[CH:4]=[C:5]([CH:11]([CH:13]([CH3:36])[CH2:14][CH2:15][CH2:16][CH2:21][CH3:20])[CH3:12])[CH:6]=1
Reactant: CCOC(=O)C1CSCCC1=O
Reactant: CCO
Reactant: COc1cc(OC)cc(C(C)CCCc2ccc(F)cc2)c1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h
Yield: 68 %

Procedure:
A solution of 6.4 g. (0.027 mole) of 5-(3-methyl-2-octyl-resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-2,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate[prepared according to the method of Bennett and Scorah, J. Chem. Soc., 194 (1972)] in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day, yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured into a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the desired compound, m.p. 153°-155°.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[CH2:13][CH:14]([CH3:16])[CH3:15].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.C(Cl)Cl>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCO
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCOC(=O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-pyridylacetic acid hydrochloride 10.00 g (57.60 mmol), iso-amyl alcohol 6.09 g (69.12 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 14.35 g (74.88 mmol) in 20 ml of pyridine and 80 ml of methylene chloride was stirred at room temperature for 2 hr.