Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10]O)=[S:7])(C)(C)C.Cl.O.C(O)C>C(OCC)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(CO)NC(=S)NC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2CSC(N)=N2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
A mixture of 1.3 g of N-(tert-butyl)-N′-[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea in 12.3 cm3 of aqueous 6N hydrochloric acid is heated with stirring at a temperature in the region of 100° C. for 1 hour. The dense oil which precipitates is separated out after settling from the supernatant hydrochloric aqueous phase. After cooling to about 20° C., this aqueous phase is extracted with 5 cm3 of ethyl acetate and the resulting aqueous phase is then evaporated under reduced pressure (5 kPa) at a temperature in the region of 50° C. An oil is obtained, which is freed of its residual water by azeotropic entrainment first with 10 cm3 of ethanol and then with 10 cm3 of diethyl ether, each repetition being followed by concentrating under the above conditions. 6 cm3 of 1N sodium hydroxide are added to the oil obtained and the mixture is then extracted with 30 cm3 of diethyl ether containing 15 cm3 of ethyl acetate. The organic phase is separated out after settling has taken place and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.1 g of oxalic acid predissolved in 1 cm3 of acetone is added to the residue obtained. The white precipitate formed is separated out by filtration, washed once with acetone, twice with chloroform and then once with ethyl acetate, and dried under reduced pressure (10 Pa) at a temperature in the region of 40° C. 0.063 g of 4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine is obtained in the form of a white solid melting at 180° C. [1H NMR spectrum (300 MHz, d6-(CD3)SO, δ in ppm): 3.40 (dd, J=14 and 8.5 Hz 1H); 3.80 (s: 3H); 3.93 (dd, J=14 and 8.5 Hz: 1H); 4.22 (unres. mult.: 2H); 3.58 (t, J=8.5 Hz : 1H); 7.00 (d, J=8.5 Hz: 2H); 7.34 (d, J=8.5 Hz : 2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:18][CH:19]=1>>[ClH:1].[CH3:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[N:9][CH:10]=[CH:11][C:2]=2[NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:18][CH:19]=2)[N:7]=1
Reactant: Nc1ccc(Oc2cccnc2)nc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3ccc(Oc4cccnc4)nc3)ccnc2n1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 5-chloro-2-methyl-1,8-naphthyridine (1.8 g), 5-amino-2-(pyrid-3-yloxy)pyridine (1.87 g) and IMS (35 ml) was boiled under reflux for 5 hours. The mixture was cooled to ambient temperature and filtered to give a solid which was recrystallised from IMS to give 2-methyl-5-[2-(pyrid-3-yloxy)pyrid-5-ylamino]-1,8-naphthyridine hydrochloride 2.5 hydrate, m.p. 235°-237° C. Borderline active (1/1) at 30 mg/kg.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]3)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:3])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nc(N2CCN(CCO)CC2)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cn1c(N2CCN(CCO)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
5-Hydroxy-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.024 g, 0.074 mmol) was dissolved in DMF (1 mL) to which was added 4-fluoro-benzyl amine (0.047 mL, 0.37 mmol). The mixture was stirred at 70° C. for 2 hours. The resulting mixture was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (0.0149 g, 50% yield). 1H NMR (500 MHz, MeOD) δ: 8.81 (1H, bs), 7.40 (2H, dd, J=8.5, 5.5 Hz), 7.08 (2H, t, J=8.8 Hz), 4.59 (2H, d, J=6.1 Hz), 3.94 (2H, t, J=5.2 Hz), 3.70 (4H, d, J=11.3 Hz), 3.58 (3H, s), 3.47–3.35 (6H, m). HRMS (M+H) calcd for C19H25FN4O5: 406.18907. found: 406.1895.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH2:11]2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2].C([OH:25])C.[OH-].[Na+].OO>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH:14]([OH:25])[CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[C:6]([F:21])[C:5]=1[F:22])[CH3:2]
Reactant: CCCCCC1=CCC(c2ccc(OCC)c(F)c2F)CC1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2ccc(OCC)c(F)c2F)CC1O
Temperature: 2 °C

Procedure:
53 g of 1-ethoxy-2,3-difluoro-4-(4-pentylcyclohex-3-enyl)benzene were dissolved in 500 ml of THF, and the mixture was cooled to 2° C. 195 ml of borane/THF complex were subsequently added dropwise over the course of 30 minutes with stirring. After the mixture had been stirred for a further 2 hours, 48 ml of ethanol were added dropwise to the solution at RT. Subsequently, firstly a solution of 10.6 g of sodium hydroxide and then 63 ml of 30% hydrogen peroxide were added dropwise. The mixture was subsequently refluxed for 2 hours and subjected to conventional work-up, giving 5-(4-ethoxy-2,3-difluorophenyl)-2-pentylcyclohexanol.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][N:19]3[N:23]=[C:24](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)=[C:30]([O:40][CH3:41])[CH:29]=4)[N:25]=[C:18]23)=[CH:13][CH:12]=1.C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:7][C:17]1([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][N:19]2[N:23]=[C:24](/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([N:34]4[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]4)=[C:30]([O:40][CH3:41])[CH:29]=3)[N:25]=[C:18]12.[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[N:19]([N:23]=[C:24](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]5)=[C:30]([O:40][CH3:41])[CH:29]=4)[N:25]=3)[CH2:20][CH2:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCC=C3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(F)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DAST (0.04 mL) was added to a solution of (+)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine synthesized by the method in Example 51 (51 mg) in methylene chloride (2 mL) at 0° C., and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase:hexane:ethanol=1:1) to obtain (+)-8-fluoro-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine with a retention time of 11 minutes (6 mg, >99% ee), (−)-8-fluoro-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine with a retention time of 12 minutes (5 mg, >99% ee) and 8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-dihydro[1,2,4]triazolo[1,5-a]pyridine with a retention time of 14 minutes (2 mg).
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:15])[CH2:4][C:5](=O)[CH2:6][C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:16][NH:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH2:4]([C:5]1[N:17]([CH3:16])[N:18]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1)[CH:3]([CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)CC(C)C
Reactant: CNN
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC(C)C)n(C)n1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
A 1 L round bottom flask was charged with ethyl 6-methyl-2,4-dioxoheptanoate sodium salt (30.0 g, 135 mmol) and acetic acid (200 mL). Methylhydrazine (7.20 mL, 135 mmol) was added dropwise via syringe, and the resultant solution was allowed to stir under a nitrogen atmosphere for 2 hours. The pH was then adjusted to 9 by addition of saturated aqueous sodium carbonate, and the reaction mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 27.5 g of ethyl 5-isobutyl-1-methyl-1H-pyrazole-3-carboxylate as a yellow oil. This material was utilized without any further purification.
Reaction SMILES: C([Li])(CC)C.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:30]=[CH:29][C:28]2[C@@H:27]3[C@:18]([CH:38]=[CH2:39])([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C@@H:22]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH2:21][CH2:20]4)[CH2:17][CH2:16][C:15]=2[CH:14]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1>C1COCC1>[F:50][C:30]1[C:13]([O:12][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][O:6]2)=[CH:14][C:15]2[CH2:16][CH2:17][C@:18]3([CH:38]=[CH2:39])[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: C=C[C@@]12CCc3cc(OC4CCCCO4)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: C=C[C@@]12CCc3cc(OC4CCCCO4)c(F)cc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3 ml of a 1.3 M s-butyllithium solution was added in drops under argon to a solution of 120 mg of 3,17β-bis-(tetrahydropyran-2-yloxy)-8β-vinyl-estra-1,3,5(10)-triene in 4 ml of THF that was cooled to −78° C., it was stirred for 30 minutes and then a solution that consists of 650 mg of N-fluorodibenzenesulfonimide in 4 ml of THF was added in drops while being exposed to continuous cooling. The reaction mixture was stirred first for 1 hour at −78° C. then for another 16 hours while being heated to room temperature. The reaction solution was poured onto ice water, extracted several times with ethyl acetate, the collected organic phases were washed with saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The dark, oily crude product (330 mg) was used in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1(P(=[CH:29][CH:30]=[O:31])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:29][CH:30]=[O:31])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=CC=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
Part A. 4-bromobenzaldehyde (9.11 gm, 49.28 mmol) and (triphenylphosphoranylidene) acetaldehyde (15.00 gm, 49.28 mmol) were combined in 250 mL of methylene chloride and stirred overnight at room temperature. The volatiles were removed under vacuum and the residue dissolved in 200 mL of EtOAc, filtered through a pad of silica gel and concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel eluting hexane:ethyl acetate (3:1, v:v) to give 3-(4-bromophenyl) acrolein as a pale yellow solid 3.67 gm, (35%). MS m/e 211 (M+H)+ 1 H NMR (CDCl3) 6.70 (dd, 1H), 7.43 (m, 3H), 7.54 (d, 2H), 9.69 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[OH:20])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(=Cc1ccccc1O)c1ccccc1-2
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (250 mg, 1.18 mmol) and salicylaldehyde (159 mg, 1.30 mmol) in 10 mL of methanol was added KF—Al2O3 (170 mg, 1.06 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 11% EtOAc in hexane afforded 125 mg of CYD-1-87 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 10.05 (br s, 1H), 8.39 (s, 1H), 8.27 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.16 (d, 1H, J=8.4 Hz), 8.09 (m, 2H), 8.04 (s, 1H), 7.52 (m, 3H), 7.37 (m, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13](=[O:15])[CH3:14]>O1CCCC1.C(O)(=O)C.[Zn]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([CH3:11])[CH:5]=1
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cc(N)cc1C
Temperature: 0 °C
Yield: 27.5 %

Procedure:
Zinc dust (30 g) was added in portions over 10 minutes to N-(2,6-dimethyl-4-nitro-phenyl)-acetamide (5.09 g) in tetrahydrofuran (200 mL) and acetic acid (60 mL) cooled to 0° C. The reaction mixture was filtered after 30 minutes through silica-(50 g), which was washed with methanol/ethyl acetate (20:80, 100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (100 mL) and treated with heptane until the title compound precipitated, which was collected, washed with heptane and dried in vacuo to furnish 1.20 g (28% yield) of the title compound as a pale red solid. 1H NMR (500 MHz, DMSO-d6): 1.95 (s, 3H), 1.96 (s, 6H), 4.82 (s, 2H), 6.23 (s, 2H), 8.79 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH3-]C#N.[Na+].[OH-].[Na+].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1>C(O)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:36][CH2:35][N:34]([CH2:50][C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)[CH2:33][CH:32]=3)=[CH:27][CH:26]=2)(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCNCC2)cc1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCN(Cc3cccnc3)CC2)cc1

Procedure:
A mixture of Example 340A (65 mg, 0.1 mmol), NaBH3CN (48 mg, 0.75 mmol), 2N NaOH (0.15 mL), and 3-pyridinecarboxaldehyde (214 mg, 2 mmol) in acetic acid (0.5 mL) and methanol (1 mL) was stirred for 16 hours. The reaction mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC using 20-90% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(−)) m/e 628 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (br t, 1H), 8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d, 2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[OH-].[Na+].[CH:11](=[O:13])[CH3:12].Cl>O>[OH:13][CH:11]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[CH3:12]
Reactant: CC=O
Reactant: O=c1ccocc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1occc(=O)c1O
Reaction time: 8 h

Procedure:
3-Hydroxy-pyran-4(1H)-one (5.6 g, 50 mmol, 1 eq.) was added to 50 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxide. Acetaldehyde (2.64 g, 60 mmol, 1.25 eq.) dissolved in 20 ml water was slowly added dropwise over 1 hour and the solution allowed to stir overnight. The reaction mixture was acidified to pH 1 with 37% w/v hydrochloric acid and concentrated in vacuo to dryness. The residue was extracted with 2×70 ml of isopropanol at 90° C. The isopropanol extracts were combined and concentrated to yield after recrystallisation from toluene, the pure product (3.7 g, 47.4%) as a pale yellow crystalline solid. m.p. 131-132° C. [lit. 130—131° C. (Ichimoto, 1970)].
Reaction SMILES: C[C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].[Cl:22]C(C)C(N(C)C)=O>>[Cl:22][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:3]1[CH:2]=[CH:6][N:5]([CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:4]=1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: CCC(Br)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1ccc(-c2ccccc2Cl)n1

Procedure:
Following the procedure of Example 1, but substituting 3-(o-chlorophenyl)pyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide there was obtained 3-(o-chlorophenyl)-α-ethyl-N,N-dimethylpyrazole-1-acetamide having a melting point of 38.5°-40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14]([CH3:15])=[C:13]([C:16](O)=[O:17])[C:12](=[O:19])[N:11]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:13]2[C:12](=[O:19])[N:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]([CH3:9])[C:14]=2[CH3:15])=[O:17])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
To a mixture of 4-aminophenol (1.09 g, 10 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (2.37 g, 10.2 mmol) in DCM (30 mL) was added EDCI (2.3 g, 12 mmol) and HOAT (0.27 g, 2 mmol). The mixture was stirred at 46° C. for 4 hours, then cooled to rt and diluted with EtOAc (10 mL) and water (10 mL). The mixture was stirred at rt for 1 hour, then filtered to give the title compound as a white solid (1.7 g, 52.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[NH:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=[C:2]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[N:21]=[CH:20]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: c1cncc(-c2c[nH]cn2)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.1) (0.15 g, 0.5 mmol) and commercially available 3-(1H-imidazol-4-yl)-pyridine [CAS-No. 51746-85-1] (0.073 g, 0.5 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.09 g, 45%). MS (EI) 401.1 [(M)+]; mp 228° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:5])C.O1CCCC1.[OH-].[Li+]>O>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[N:13]=[CH:12][N:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[N:8]=3)[C:15]=2[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Yield: 100.1 %

Procedure:
A mixture of 3.5 g (7.14 mmole) of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.25a), 50 mL of tetrahydrofuran, 50 mL of water and 0.857 g (35.7 mmole) of lithium hydroxide was heated at 60 degrees for 3 hours. The mixture was concentrated under reduced pressure, and then 100 mL of water was added. The pH was adjusted to ca. 3-4 by the addition of hydrochloric acid. The resulting precipitate was collected by filtration to give 3.3 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid (I.25b) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl:21][CH2:22][CH:23]=O>CO>[ClH:21].[S:19]1[CH:23]=[CH:22][N:20]=[C:18]1[NH:17][N:16]=[C:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[N:2]([CH3:1])[C:3]2[C:8]1=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: O=CCCl
Reactant: Cn1c2ccccc2c(=NNC(N)=S)c2ccccc21
Solvent: CO
Product: Cl
Product: Cn1c2ccccc2c(=NNc2nccs2)c2ccccc21

Procedure:
1.9 g of 10-methyl-9acridanone thiosemicarbazone are suspended in 100 ml of methanol and stirred at 50° for 6 hours with 1.73 ml of chloroacetaldehyde (50percent aqueous solution). The mixture is concentrated, the crystalline product is filtered and washed successively with ethanol, water, ethanol and ether. There is obtained 10-methyl-9-acridanone (2-thiazolyl)hydrazone hydrochloride of melting point 224°-225° (decomposition).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CCN3CCCC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 1-(2-chloroethyl)pyrrolidine and cesium carbonate in N,N-dimethylacetamide for 3 days at r.t. to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-(2-pyrrolidin-1-yl-ethyl)-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 572.6 ([M+H]+)