Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][NH:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:32]([CH2:4][C:5]3[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]4[N:12]=[C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[S:14][CH:15]=4)=[CH:7][CH:6]=3)[N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (760 mg) and ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (580 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1110 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[C:14]#[N:15]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[Cl:10]
Reactant: Nc1ccc(Cl)cc1O
Reactant: N#Cc1ccc(F)c(Cl)c1
Product: N#Cc1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 3 step viii) using 2-amino-5-chlorophenol and 3-chloro-4-fluorobenzonitrile. Yield 2.70 g
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][NH:60][CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[ClH:3].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][N:60]([CH3:4])[CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: Cc1cnc(NCCN2CCNC[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: Cc1cnc(NCCN2CCN(C)C[C@H]2C)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (R)-2-{5-methyl-2-[2-(2-methylpiperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 465 [M(free base)+H].
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2ccccc2c1=O
Yield: 80.9 %

Procedure:
Ethyl 2-butyryl-3-(phenylamino)acrylate (70 g, 0.27 mol) was added in portions to boiling diphenyl ether (500 ml), then heated at reflux for 1.5 hours. After partial cooling, the mixture was poured into high boiling petroleum ether. Filtration and washing with petroleum ether gave 3-butyryl-4(1H)-quinolone (47 g) as a pale solid, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:14]2[CH2:19][CH2:18][N:17]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)(C)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:14]2[CH2:15][CH2:16][N:17]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:18][CH2:19]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Solvent: CC(C)O
Product: Nc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
The title compound, MS (ISP): m/e=490.3 (M+H+), was prepared by hydrogenation of (+/−)-4-nitro-N-phenyl-N-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide according to the following procedure. (+/−)-4-Nitro-N-phenyl-N-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide (0.05 g, 0.096 mmol) was suspended in isopropanol (3 ml) and the mixture was purged with argon. Palladium hydroxide on charcoal was added to the suspension, which was then put under a hydrogen atmosphere and stirred at room temperature for 20 h. The catalyst was then filtered off and the solvent was evaporated, leaving the title compound as a white foamy solid (0.039 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20]OS(C)(=O)=O)[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:26][NH:27][CH3:28]>O>[CH3:26][N:27]([CH2:20][C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=1)[CH3:28]
Reactant: CNC
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Solvent: O
Product: Cc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) was added a 40% aqueous dimethylamine (1 mL), and the mixture was stirred at 80° C. for 2 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. The mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel [chloroform/methanol (40/1)] to yield the title compound as a yellow oil (69.7 mg, 80.9%).
Reaction SMILES: C(N(/[CH:6]=[C:7]1/[C:8](=O)[C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]/1=2)CC)C.[Cl-].[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH2:28][NH:29][C:30]([NH2:32])=[NH2+:31].[O-]CC.[Na+]>C(O)C.ClCCl>[Cl:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[CH2:28][NH:29][C:30]1[N:32]=[CH:6][C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[C:8]=2[N:31]=1
Reactant: NC(=[NH2+])NCc1cccc(Cl)c1
Reactant: CCN(/C=C1/C(=O)c2cccnc2Nc2ccccc21)CC
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Clc1cccc(CNc2ncc3c(n2)-c2cccnc2Nc2ccccc2-3)c1
Temperature: 80 °C

Procedure:
A mixture of (E)-6-((diethylamino)methylene)-6,11-dihydro-5H-benzo[f]pyrido[2,3-b]azepin-5-one (0.1 g, 0.38 mmol), 1-(3-chlorobenzyl)guanidinium chloride (2 equivalents), and sodium ethoxide (21% solution in ethanol) (1.9 equivalents) in absolute ethanol (3 mL) was heated at 80° C. overnight. The reaction mixture was cooled and diluted with dichloromethane (10 mL), washed with water (2×5 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 50% ethyl acetate in hexane) to give the pure desired product as solid. 400 MHz 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 8.23 (s, 1H), 8.15 (s, 2H), 8.00 (t, J=6.0 Hz, 1H), 7.42 (s, 1H), 7.37-7.27 (m, 4H), 7.21-7.14 (m, 2H), 7.08-7.04 (m, 2H), 4.57 (d, J=5.2 Hz, 2H); LCMS (M+H)=386.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([O:13]C)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:25][CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28].Cl>CS(C)=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:11]([NH:25][CH2:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: NCC(=O)NCC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
330 mg (1 mmole) of Z-L-Tyr-OMe, 400 mg (2.2 mmole) of H-Gly-Gly-Ome, HCl were suspended in 5 mL DMSO and 5 mL 0.1 M tris-HCl, pH 8.9. 25 mg of α-chymotrypsin were added and the reaction stirred for 30 minutes. Five volumes of ice water were added, and the precipitate collected by filtration. Yield 312 mg (70%, based on acyl-donor). Amino acid analysis: tyr1.0,gly2.1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(I)cc1)C(=O)OCC
Yield: 56 %

Procedure:
Diethyl N-(4-iodobenzoyl)-L-glutamate is prepared from 4-iodobenzoyl chloride and diethyl L-glutamate in 56% yield by the same method. m.p. 105°-106° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz), 2.11-2.60 (m, 4H), 4.14 (q, 2H, J=7.2 Hz), 4.78 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.83 (d, 2H, J=8.4 Hz)
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:15][C:16]1[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>COCCOC>[F:15][C:16]1[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:22]=[CH:21][C:17]=1[C:18]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OCC)c(F)c1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 2-fluoro-4-(hexadecylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 2-fluoro-4-(hexadecylamino)benzoylmalonate.
Reaction SMILES: [CH:1](=[PH3])[CH2:2][CH:3]=[CH2:4].[F:6][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=O>C1C=CC=CC=1>[F:6][C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[CH:4][CH2:3][CH:2]=[CH2:1]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C=CCC=[PH3]
Solvent: c1ccccc1
Product: C=CCC=C(OCC)C(F)(F)F

Procedure:
A mixture of 20 ml of 1-bromo-3-butyne and 25 mmole of tirphenylphosphine in 50 ml of benzene is heated at reflux for 3 days. The solid which separates upon cooling is filtered, washed with benzene and dried under reduced pressure is afford triphenyl-3-butenylphosphonium bromide. To a solution of 100 ml of liquid ammonia is added 0.26 g of finely divided sodium and a catalytic amount of ferric nitrate. When the blue solution turns gray finely powdered triphenyl-3-butenylphosphonium bromide (2.10-2 mole) is added. The reaction mixture is stirred for 15 minutes after which the ammonia is evaporated under a stream of nitrogen. To the resulting residue is added 100 ml of benzene, and the heterogeneous mixture is heated at reflux temperature for 10 minutes. The solid residue is filtered off and the filtrate is evaporated to dryness to give 3-butenylidenephosphorane. To a solution of salt free 3-butenylidenephosphorane (2.10-2 mole) in 100 ml of benzene is added 6.6 g (5.10-2 mole) of ethyl trifluoroacetate. The reaction mixture is heated at reflux temperature for 12 hours under nitrogen. Concentration of the solvent leaves an oily residue which is purified by distillation to give 1-trifluoromethyl-1-ethoxy-1,4-pentadiene. A suspension of 10 g of 1-trifluoromethyl-1-ethoxy-1,4-pentadiene in 20 ml of 1 N aqueous sulfuric acid is stirred for 20 minutes. Continuous extraction of the mixture with ether affords 1-trifluoromethylpent-4-ene-1-one.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][C:5]2=[O:10].[Br:11]Br>CCOCC.CC(O)=O>[Br:11][CH:6]1[CH2:7][CH2:8][C:9]2[C:4](=[CH:3][NH:2][N:1]=2)[C:5]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCc2n[nH]cc21
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1c2c[nH]nc2CCC1Br
Yield: 80 %

Procedure:
To a solution of 2,5,6,7-tetrahydro-indazol-4-one (5.28 mmol), optionally protected as the trityl derivative, in Et2O (20 mL) and AcOH (15 mL), at 0° C., a solution of Br2 (10.56 mmol) in AcOH (20 mL) was slowly added dropwise. The solution was then heated at 60° C. for 1h then the organic solvents were evaporated to dryness and the white precipitate was suspended in Et2O, filtered and dried. The title compound was obtained in 80% yield. ESI (+) MS: m/z 216 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:31]=[CH:30][C:29]([N:32]5[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]5)=[CH:28][CH:27]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:42]1([OH:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[CH:42]1([O:48][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([CH2:12][C:13]4[N:14]([C:26]5[CH:27]=[CH:28][C:29]([N:32]6[S:36](=[O:38])(=[O:37])[NH:35][C:34](=[O:39])[CH2:33]6)=[CH:30][CH:31]=5)[CH:15]=[C:16]([C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=5[Cl:25])[N:17]=4)=[CH:40][CH:41]=3)=[CH:4][CH:3]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: OC1CCCCC1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(OC5CCCCC5)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-[4-(6-Chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (63 mg, 0.1 mmol) was treated as described in general procedure L using cyclohexanol (20 mg, 0.2 mmol) to give 5-{4-[2[4-(6-cyclohexyloxy-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[O:4]=[C:3]([CH3:5])[CH2:2][C:1]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([O:12][C:11]([F:20])([F:21])[F:10])=[CH:14][CH:15]=1)=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: CC(=O)CC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Trifluoromethoxy)aniline (10 mL) was added dropwise to ethyl acetoacetate (44 mL) at 160° C., and the mixture was stirred at the same temperature for 1 h. The mixture was left stand for cooling to room temperature and crystallized with hexane to obtain 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g). (2) To concentrated sulfuric acid (32.5 mL) was added 3-oxo-N-(4-(trifluoromethoxy)phenyl)butane amide (6.5 g), and the mixture was stirred at 95° C. for 3 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration. The resulting crystals were suspended in water, the suspension was made basic with aqueous ammonia, and the precipitated crystals were collected by filtration to obtain 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g). (3) A mixture of 4-methyl-6-(trifluoromethoxy)quinoline-2(1H)-one (1.87 g) and phosphorus oxychloride (19 mL) was stirred at 105° C. for 2.5 h. The reaction solution was added dropwise to water with ice cooling, and the precipitated crystals were collected by filtration to obtain 2-chloro-4-methyl-6-trifluoromethoxyquinoline (1.98 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)[NH2:29]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1cccc(C(N)=NO)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(OC)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.2 eq.) of N′-hydroxy-3-methoxybenzenecarboximidamide were reacted according to the General Method 1. Yield:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:21]2[CH2:22][CH2:23][NH:24][C@H:19]([CH3:18])[CH2:20]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1c(Cl)nnc(C(=O)c2cccnc2)c1C
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 89.6 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-3-yl-methanone (1.2 g, 4.84 mmol) and (R)-2-methy 1-piperazine (485 mg, 4.84 mmol) are added to a microwave vial followed by NMP (17 mL) and triethylamine (2.01 mL, 14.49 mmol). The vial is sealed and irradiated in the microwave at 170° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2). The resulting oil is co-evaporated with CH2Cl2 and heptane to afford the title compound as a powder (1350 mg, 90%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][N:10]([CH3:22])[CH:11]=[N:12][C:13]1[N:14]=[CH:15][C:16]2[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>CN(C=O)C>[I:1][C:19]1[C:17]2[N:18]=[C:13]([N:12]=[CH:11][N:10]([CH3:22])[CH3:9])[N:14]=[CH:15][C:16]=2[NH:21][CH:20]=1
Reactant: CN(C)C=Nc1ncc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ncc2[nH]cc(I)c2n1
Temperature: 0 °C
Yield: 84.9 %

Procedure:
N-Iodosuccinimide (3.2 g, 14.2 mmol) was added portionwise to an ice-cold stirred suspension of N,N-dimethyl-N′-(5H-pyrrolo[3,2-d]pyrimidin-2-yl)-formamidine (Journal of Medicinal Chemistry, 2003, 46(14), 3060-3071, 2.68 g, 14.2 mmol) in DMF (50 mL). After stirring at ambient temperature overnight, the reaction was concentrated, dissolved in DCM (40 mL) and the product was precipitated using EtOAc (250 mL). After filtration, the pale yellow powder was collected, washed with EtOAc (2×20 mL) and dried under a vacuum overnight to afford N′-(7-iodo-5H-pyrrolo[3,2-d]pyrimidin-2-yl)-N,N-dimethyl-formamidine (3.8 g, 85%) as a yellow powder; 1H NMR (DMSO-d6, 400 MHz) δ 12.38 (s, 1H), 8.74 (s, 1H), 8.04 (s, 1 H), 7.93 (s, 1H), 3.29 (s, 3H), 3.19 (s, 3H); ESI−MS [M+H]+=316.1.
Reaction SMILES: N[CH2:2][CH2:3]N.[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6]>C(O)C>[CH:3]1[CH:2]=[C:10]2[C:8]([CH:9]=[C:10]3[C:8](=[CH:9]2)[CH:5]=[CH:6][CH:3]=[CH:2]3)=[CH:5][CH:6]=1
Reactant: CC(=O)CC(C)=O
Reactant: NCCN
Solvent: CCO
Product: c1ccc2cc3ccccc3cc2c1
Yield: 129.9 %

Procedure:
Prepared by the method of McCarthy, P. J., et al., J. Am. Chem. Soc., 1955, 77, 5820. 1,2-Diaminoethane (1) (3.0 g, 3.3 mL, 49.9 mmol) was dissolved in ethanol (70 mL) and acetylacetone (2) (10.3 mL, 99.8 mmol) was added in a steady stream over a period of about 10 minutes whilst stirring the reaction mixture. The reaction was refluxed for 3 hours. After cooling, evaporation of the solvent in vacuo left a yellow solid which was purified by the addition of diethyl ether (ca. 100 mL). The desired ligand (3) (7.3 g, 32.4 mmol, 65%) was obtained as an off-white crystalline solid by suction filtration.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1.[CH3:28][NH:29][CH3:30]>CN(C)C(=O)C>[CH3:28][N:29]([CH3:30])[CH2:2]/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:7][CH2:6]1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: CN(C)C/C=C/[C@H]1CC[C@H](CCN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with dimethyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{2-[4-(3-dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 433 (MH+).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:20]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: COc1cccc(C=O)c1F
Product: COc1cccc(C=C2c3ccccc3CCc3ccccc32)c1F
Yield: 29.5 %

Procedure:
Following procedures essentially as described in Example 28 and using 2-fluoro-3-methoxybenzaldehyde (2.4 g, 15.4 mmol) and dibenzosuberane (3.0 g, 15.4 mmol), provides 1.5 g of title compound as white crystals. mp 148.9° C. HPLC shows 96% purity.