Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[N:13]=[C:12]([C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])[CH2:11]1
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(C3=CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
5-(2,4-Difluoro-phenyl)-1-[3-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 213, triethylamine (28.0 uL, 0.20 mmol) and methanesulfonyl chloride (5.0 uL, 0.06 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and 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=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:33]3[CH2:38][CH2:37][C@@H:36]([C:39](=[O:44])[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:35][CH2:34]3)[C:11]3[CH:16]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:20][CH2:19]4)[N:14]=[CH:13][C:12]=3[NH:32]/2)=[O:7])=[CH:4][CH:3]=1.[ClH:47]>O1CCOCC1.Cl>[ClH:47].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2/[N:10]([C@H:33]3[CH2:38][CH2:37][C@@H:36]([C:39](=[O:44])[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:35][CH2:34]3)[C:11]3[CH:16]=[C:15]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:19]4)[N:14]=[CH:13][C:12]=3[NH:32]/2)=[O:7])=[CH:45][CH:46]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OC4CCN(CC(=O)OC(C)(C)C)CC4)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OC4CCN(CC(=O)O)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 2-(4-((E)-2-(4-fluorobenzoylimino)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-6-yloxy)piperidin-1-yl)acetate (81 mg, 0.127 mmol) in dioxane (1.2 mL) was added HCl (4N dioxane) (0.127 mL, 0.509 mmol) and 2 drops of concentrated HCl (0.010 mL, 0.127 mmol). The resulting mixture was stirred at RT for 4 hours. The reaction mixture was concentrated and triturated with about 2 mL of dioxane to produce a precipitate. The off-white solid was collected to afford the title compound (70 mg, 89% yield). M/Z calc'd for C30H37FN6O5: 580.28. found 581 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[K].[S:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:16][S:15]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:7]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCCC3)n2)cc1
Yield: 58.9 %

Procedure:
0.58 g (0.00266 mol) of 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine and 1.36 g (0.00539 mol) of N-(4-sulfamoyl-phenyl) -acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with ethyl acetate. Both organic phases were combined and concentrated. The residue was recrystallized from a small amount of ethanol and the mother liquor was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained a total of 0.62 g (66%) of N-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as whitish crystals; m.p. 229-233° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[C:13]3[C:9]([CH2:10][C:11](=[O:15])[NH:12]3)=[CH:8][CH:7]=2)=[CH:2]1.[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C(O)C>[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: O=C1Cc2ccc(-c3ccsc3)cc2N1
Reactant: O=Cc1ccccc1O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3ccsc3)ccc2C1=Cc1ccccc1O
Yield: 68.9 %

Procedure:
A mixture of 6-thiophen-3-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hyroxy-benzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110 mg (69%) of 3-(2-hydroxybenzylidene)-6-thiophen-3-yl-1,3-dihydroindol-2-one as yellow-red crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].C(N(CC)CC)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>ClCCl>[Cl:32][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][S:40]([CH3:43])(=[O:42])=[O:41])[CH3:6])=[CH:30][CH:29]=[C:28]([Cl:31])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNS(C)(=O)=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg) and triethylamine (22.4 mg) in dichloromethane (1 ml) was dropwise added mesyl chloride (21.4 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[2,6-dichloro-3-[N-(mesylglycyl)-N-methylamino]benzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (70 mg) as colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1)(=[O:12])[CH3:11]
Reactant: NC(=O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(C(N)=O)cs1
Yield: 90.6 %

Procedure:
g (28 mmol) 2-Aminothiazol-4-carboxamide was dissolved in 40 ml glacial acetic acid, to which added 2.8 ml (29.6 mmol) acetic anhydride, followed by reacting under reflux for 2 hr, and naturally cooling down to precipitate a large quantity of solids, which were filtered, washed and dried to obtain 4.7 g 2-acetylaminothiazol-4-carboxamide (yield 92%) with mp>250° C.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([N:11]3C(=O)C4=CC=CC=C4C3=O)[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1>CCO>[N:1]1([C@H:6]2[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](n2cccn2)C1
Solvent: CCO
Product: N[C@H]1CC[C@H](n2cccn2)C1
Yield: 51.9 %

Procedure:
A mixture of trans-N-[3-(1H-pyrazol-1-yl)cyclopentyl]phthalimide (F) (1.53 g, 5.44 mmol), and hydrazinemonohydorate (0.53 mL, 10.9 mmol) in EtOH (30 mL) was stirred at reflux for 4 h. After cooling, the reaction mixture was filtered followed by the removal of solvent. The crude product was purified by column chromatography (Chromatrex, CH2Cl2/EtOH=30/1) to yield trans-3-(1H-pyrazol-1-yl)cyclopentylamine (427 mg, 52%) as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[OH:11][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[C:4]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN1CCNCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Temperature: 100 °C

Procedure:
A mixture of 1-methylpiperazin-2-one (183 g, 1.6 mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to rt and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to −20° C., and the solid precipitated was filtered to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[O:28]1[C:32]2=[CH:33][CH:34]=[CH:35][C:36]([C:37](O)=[O:38])=[C:31]2[CH2:30][CH2:29]1>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[O:28][CH2:29][CH2:30][C:31]=23)=[O:38])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc2c1CCO2
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,3-dihydro-benzofuran-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:15])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(-c2ccc(Br)cc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2ccc(Br)cc2)n1

Procedure:
A solution of 4-(4-Bromo-phenyl)-2-methylsulfanyl-pyrimidine (1.1 g, 3.91 mmol) in DCM (33 ml) was cooled to 0° C. and treated within 1 hour with several portions of mCPBA (content 70%, 1.1 g, 4.46 mmol) under TLC-control. The reaction mixture was washed with 2N-solution of sodium carbonate, the organic phase dried over sodium sulfate, filtered and evaporated to dryness and purified by chromatography on silicagel (acetone/hexanes:50/50 to 75/25) to give the title compound as white crystals. Yield: 700 mg (60%).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C1CSCCN1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCSCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 90 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 78 μL of thiomorpholine in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thiomorpholinonicotinamide. MS (Q1) 425.3 (M)+.
Reaction SMILES: [K+].[NH:2]1[CH2:6][CH2:5][C@@H:4]([S:7][C:8]2[C@H:9]([CH3:22])[C@@H:10]3[C@@H:17]([C@H:18]([OH:20])[CH3:19])[C:16](=[O:21])[N:11]3[C:12]=2[C:13]([O-:15])=[O:14])[C:3]1=[S:23].[C:24]([O:29][CH2:30]I)(=[O:28])[CH:25]([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[C:24]([O:29][CH2:30][O:14][C:13]([C:12]1[N:11]2[C:16](=[O:21])[C@H:17]([C@H:18]([OH:20])[CH3:19])[C@H:10]2[C@@H:9]([CH3:22])[C:8]=1[S:7][C@@H:4]1[CH2:5][CH2:6][NH:2][C:3]1=[S:23])=[O:15])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S[C@@H]3CCNC3=S)[C@H](C)[C@H]12
Reactant: CC(C)C(=O)OCI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)OCOC(=O)C1=C(S[C@@H]2CCNC2=S)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
(1R, 5S, 6S)-2-[(3R)-Pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid potassium salt (0.5 g) is suspended in N,N-dimethylformamide (5 ml). To the suspension is added isobutyryloxymethyl iodide (338 mg) under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. To the reaction mixture is added ethyl acetate, and the mixture is washed with water, dried and concentrated to dryness under reduced pressure. The residue is purified by silica gel flash column chromatography (eluent, chloroform:methanol=20:1) to give (1R, 5S, 6S)-2-[(3R)-pyrrolidine-2-thion-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid isobutyryloxymethyl ester (0.14 g) as an amorphous powder.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:8][CH2:9][CH2:10][OH:11])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][OH:11])=[O:4]
Reactant: CCNCCO
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCO)C(=O)CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Chloroacetylchloride (97 g., 1 mole) in dry acetonitrile (100 ml) was added dropwise to a cold (0° C.) solution of N-ethylethanolamine (89 g., 1 mole) in acetonitrile (150 ml) and anhydrous sodium carbonate (119 g., 1.1 mole). The mixture was mechanically stirred for two hours at 0° C. and then for 14 hours at room temperature, filtered, evaporated to dryness at 40° C. and the residue was dissolved in chloroform. The resulting solution was mixed with 1N hydrochloric acid, followed by mixing with 10% aqueous sodium carbonate and aqueous saturated sodium chloride. It was then dried over anhydrous magnesium sulphate, filtered through activated charcoal and evaporated to dryness to yield N-chloroacetyl-N-ethyl-ethanolamine as a colorless oil (yield 85%) with the following indicia: MS m/e 165 (M+); 88 (M--COCH2Cl); since the IR spectrum of the liquid showed two C=O peaks, one minor at λmax 1750 cm-1 (C=O, ester) and one major at 1635 cm-1 (C=O, amide), the compound was purified on an alumina dry column using chloroform and chloroform:methanol (9:1) as eluents. The purified amide showed only one C=O group at 1635 cm-1. This pure compound (pure by TLC (thin layer chromatography), NMR (nuclear magnetic resonance), IR (infrared), MS (mass spectometry) was used for the next step. The NMR (250 MHz) of the pure amide showed peaks of the two structures which are at equilibrium in such amides: ##STR13## Therefore, δCDCl3ppm : 4.3 ##STR14## 3.9-3.2 (m, --CH2 --N--CH2CH2O--); 1.18 (--CH3, q, e.g., overlap of two triplets) s: singlet; m: multiplet; q: quartet.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6].S(Cl)([Cl:15])=O>N1C=CC=CC=1.ClC(Cl)Cl>[Cl:15][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:6]
Reactant: Cn1cccc1C(=O)NCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1cccc1C(=O)NCCCl
Reaction time: 8 h

Procedure:
To a stirred solution of 40 parts of N-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide in 450 parts of trichloromethane is added one drop of pyridine. Then there are added dropwise, during a 30 minutes-period, 28.3 parts of sulfinyl chloride (slightly exothermic reaction: temp. rises from 15° to 25° C). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 15 parts of N-(2-chloroethyl)-1-methyl-1H-pyrrole-2-carboxamide.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:17]([C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][O:31][C:32]2[CH:33]=[CH:34][C:35]([CH:36]=[CH:10][C:8]([O:7][CH3:6])=[O:9])=[CH:38][CH:39]=2)[CH2:26][CH2:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=O)cc2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1CC[C@H](COc2ccc(C=CC(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
27.6 ml of a 1.6 N butyllithium solution are added dropwise to a solution of 6.4 ml of trimethyl phosphonoacetate in 50 ml of dry tetrahydrofuran at 0° C. in the course of 10 minutes. Stirring is carried out for 1.5 hours at 0° C. and a solution of 10.3 g of crude 4-[(trans-4-heptylcyclohexyl)methoxy]benzaldehyde in 50 ml of dry tetrahydrofuran is then added dropwise in the course of 5 minutes at the same temperature. The mixture is then slowly warmed up to room temperature and is allowed to react for 15 hours. The reaction mixture is then partitioned between methylene chloride and 1 N hydrochloric acid and the organic phase is washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated down. Chromatography over silica gel using ethyl acetate/hexane (1:9) and subsequent repeated crystallization from hexane/ethyl acetate give methyl 4-[(trans-4-heptylcyclohexyl)methoxy]cinnamate.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13]Cl.O>CS(C)=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: ClCCBr
Reactant: N#CCc1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2cccs2)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (19.1 g) in DMSO (200 mL) was added dropwise a solution of thiophen-2-ylacetonitrile (25 g) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 0.5 hr. To the obtained reaction mixture was added dropwise a solution of 1-bromo-2-chloroethane (25 mL) in DMSO (20 mL) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound as a pale-brown oil (29.2 g).
Reaction SMILES: C[O:2][P:3]([CH2:7][N:8]([S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=1)(=[O:12])=[O:11])[CH3:9])(=[O:6])[O:4]C.Br[Si](C)(C)C>ClCCl>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH:17]=[C:13]1[S:10]([N:8]([CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH3:9])(=[O:11])=[O:12]
Reactant: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN(CP(=O)(O)O)S(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 550 mg (1.58 mmol) of the compound (xiv) in 10 mL of anhydrous dichloromethane at 0° C., 0.49 mL of bromotrimethylsilane was added. The mixture was warmed up to room temperature and left overnight. Dichloromethane was evaporated; the oily residue was dissolved in another 10 mL of dichloromethane, filtered, again evaporated and redissolved in 10 mL of MeOH. The methanolic solution stirred at room temperature 30 min., evaporated and the residue was triturated with a mixture ether/hexane to form a white crystalline product which was separated by filtration (390 mg, 70%): 1H NMR: (300 MHz, DMSO-D6) δH 2.88 (s, CH3), 3.21 (d, J=12.1 Hz, 2 H), 7.49–7.61 (m, 2 H, Ar—H), 8.01–8.17 (m, 3 H, Ar—H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br.C(O)(=O)C>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:19](=[CH:20][OH:21])[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=2)=[O:29])=[CH:27][CH:26]=1
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
1.60 g (3.66 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide, 925 mg (5.49 mmol) of 48% hydrobromic acid and 15 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 600 mg of 2-(4-chlorophenyl)-3-hydroxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]acrylamide.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].[C:5](OCC)(=[O:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C>C(#N)C>[OH:13][C:5]1[N:4]=[CH:2][N:3]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: N=CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(O)ncn1
Temperature: 25 °C

Procedure:
Formamidine hydrochloride (2.0 g, 45.4 mmol) and diethyl 2-butynedioate (7.23 mL, 45.4 mmol) were added together in acetonitrile (85 mL) and the resulting mixture was treated dropwise with triethylamine (6.33 mL, 45.4 mmol). The resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature, further cooled in an ice bath and the resulting solid was collected by filtration and discarded. The filtrate was evaporated under reduced pressure and the residue purified by column chromatography (Biotage SP4) eluting with a gradient of 0-100% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as an off white solid (0.995 g);