Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Br:12]Br>C(OCC)C>[Br:12][CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[O:4]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
4-Chloropropiophenone (33.6 g.) was dissolved in anhydrous diethyl ether (50 ml.), stirred and cooled in an ice bath while bromine (32 g.) was added dropwise over 30 minutes. The solid which formed was filtered off, washed with water and air-dried to give 2-bromo-4'-chloropropiophenone, m.p. 77°-79°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([O:7][C:8](Cl)=[O:9])=[CH:3][CH:2]=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][NH:18][CH2:19][CH2:20][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[CH2:17][N:18]([C:8]([O:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)=[O:9])[CH2:19][CH2:20][CH:21]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: CON=CC1=CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=CC1=CCCN(C(=O)Oc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
A solution of p-tolylchloroformate (1.5 mL, 10.3 mmoles) in dichloromethane (15 mL) was added under nitrogen at 0° C. to a stirred solution of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime (1.3 g, 9.3 mmoles) and triethylamine (1.3 mL, 2.3 mmoles) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 20 minutes, the solvent was evaporated and the residue was partitioned between water and ethylacetate. The organic layer was dried (Na2SO4) and evaporated. The solid was triturated with cyclohexane to afford 2.3 g (91%) of a white solid with mp 70°-71° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][OH:25])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:26])[CH2:21][S:22][CH2:23][CH2:24][O:25][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(=O)Cl
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: CCCC(=O)OCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 7, but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) and butyryl chloride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 88% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]([OH:12])[CH:10]=[CH2:11])[CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Oc1ccc(-c2cccc(Cl)c2)cc1)C(F)(F)F
Reactant: C=CC(O)CCc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(CCc1ccc(-c2cccc(Cl)c2)cc1)CCc1cccnc1
Yield: 28.7 %

Procedure:
Prepared according to the method described in Example 7b) from (±)-5-(3-pyridyl)-1-penten-3-ol (Example 7a, 0.66 g), 3'-chloro-4-trifluoromethanesulfonyloxybiphenyl (1.34 g), palladium(II) acetate (0.09 g), tri-o-tolylphosphine (5 ml) and triethylamine (1 ml) at 80° C. for 5 hours. Work up and purification by column chromatography over silica eluting with dichloromethane:methanol (19:1) gave (±)-1-(3'-chlorobiphenyl-4-yl)-5-(3-pyridyl)-3-pentanone (0.4 g). The latter was immediately dissolved in methanol (10 ml), cooled to 0° C. and sodium borohydride (0.043 g) added. The reaction mixture was stirred at 25° C. for 2 hours and was then concentrated under reduced pressure. Water was added to the residue and the mixture extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate. Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a solid (0.094 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[S:11]1[C:15]([NH2:16])=[N:14][CH:13]=[N:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:16][C:15]2[S:11][N:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1ncns1
Reactant: COc1ccc(C=O)cc1
Agent: Cl[Ti+3]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNc2ncns2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-methoxybenzaldehyde (10.0 g, 73.4 mmol) and 1,2,4-thiadiazol-5-amine (7.40 g, 73.4 mmol) in dichloromethane (200 mL) was added chlorotitanium triisopropoxide (28.6 g, 110 mmol) portionwise over 5 min. After stirring for 3 hours, sodium triacetoxyborohydride (38.9 g, 184 mmol) was added portionwise at 0° C. and allowed to stir for additional 1 hour. The reaction was cooled in an ice and water mixture, quenched with saturated NaHCO3 solution (300 mL) and extracted with dichloromethane (2×300 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to obtain the product, which was purified by column chromatography using silica gel (100 to 200 mesh) and 0 to 30% ethyl acetate in hexane to give 5.5 g of as an off-white solid. MS (ESI, positive) m/z: 222.1; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.92 (s, 1H), 7.27 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.5 Hz, 2H), 4.42 (d, J=5.4 Hz, 2H), 3.73 (s, 3H).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)(=[O:47])[NH2:46]>CN(C)C=O>[C:45]([C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(=[O:47])[NH2:46]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CCCN1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (3.0 g) in dimethylformamide (30 ml) was added (2S)-2-carbamoylpyrrolidine (10.76 g) and the mixture was stirred at 100°-110° C. for 5 hours. The reaction mixture was poured into ice-water (100 ml). The resulting precipitates were collected by filtration and washed with water (100 ml). The precipitates were dissolved in ethyl acetate (80 ml) and the solution was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S ,4S )-2-[(2S)-2-carbamoylpyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (0.78 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22].C(N(CC)CC)C>>[CH2:21]([O:23][CH2:24][C:25]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Yield: 99.8 %

Procedure:
Ethyl 4-(3-amino[1,5]naphthyridin-4-ylamino)butanoate (2.5 g, 9.1 mmol, prepared in Parts A and B of Example 37) was treated with ethoxyacetyl chloride (1.02 mL, 10.0 mmol) and cyclized according to a modification of the method described in Part C of Example 37. The reaction with triethylamine (3.8 mL, 27 mmol) was heated at reflux overnight and was complete. Following the work-up procedure, 3.11 g of ethyl 4-(2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanoate were obtained as a brown oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17](O)=[O:18])=[CH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].C(O[C:26]([C:28]1[N:29]([NH:33][CH2:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=1)=[O:27])C=C.[O-]CC.[Na+].C(O)C>ClCCl.CN(C)C=O>[CH3:39][C:36]([CH3:37])([CH3:38])[CH2:35][CH2:34][N:33]1[C:17](=[O:18])[C:16]([C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:15])(=[O:14])[CH:12]=2)=[C:26]([OH:27])[C:28]2=[CH:32][CH:31]=[CH:30][N:29]12
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)C=C(CC(=O)O)N2
Reactant: C=CCOC(=O)c1cccn1NCCC(C)(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)CCn1c(=O)c(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
N,N-Dicyclohexylcarbodiimide (0.476 mL of a 1.0 M solution in dichloromethane, 0.476 mmol) was added to a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (Example 8h, 0.190 g, 0.572 mmol) and 1-(3,3-dimethyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 4c, 0.119 g, 0.475 mmol) in a 3:1 mixture of dichloromethane and N,N-dimethylformamide (6 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h then was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in ethanol (12 mL) at 25° C. A 21% solution of sodium ethoxide in ethanol (0.23 mL, 0.71 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. After cooling to 25° C., the mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Merck silica gel 60, 40-63 μm, 40→100% ethyl acetate in hexanes) afforded a solid which was triturated with diethyl ether to afford the desired product, N-{3-[1-(3,3-dimethyl-butyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (0.101 g, 0.20 mmol, 42% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.07 (9H, s), 1.65-1.72 (2H, m), 3.09 (3H, s), 4.25-4.29 (2H, m), 5.54 (2H, s), 6.43-6.45 (1H, m), 7.01-7.03 (1H, m), 7.08-7.09 (1H, m), 7.30 (1H, d, J=8.5 Hz), 7.39 (1H, bs), 7.61 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.73 (1H, d, J=2.4 Hz). LC-MS (ESI) calcd for C22H26N4O6S2 506.13. found 507.27 [M+H+].
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@@H:30]([C:32]3[CH:43]=[CH:42][C:35]4[O:36][C:37](C)([CH3:40])[O:38][CH2:39][C:34]=4[CH:33]=3)[OH:31])[CH:12]=2)=[O:9])=[CH:3][CH:2]=1>C(O)(=O)C.O>[C:37]([OH:38])(=[O:36])[CH3:40].[C:1]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:31])[C:32]3[CH:43]=[CH:42][C:35]([OH:36])=[C:34]([CH2:39][OH:38])[CH:33]=3)[CH:12]=2)=[O:9])=[CH:5][CH:6]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3cccc(NC(=O)Nc4ccc(-c5ccccc5)cc4)c3)ccc2O1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(-c2ccccc2)cc1)Nc1cccc(COCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 25 °C
Yield: 211.6 %

Procedure:
A solution of N-(1,1′-biphenyl-4-yl)-N′-[3-({2-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]ethoxy}methyl)phenyl]urea (0.089 g) in acetic acid (4 ml) and water (2 ml) were stirred under nitrogen at 70° C. for 30 min. The reaction mixture was cooled to room temperature before concentrating under vacuum and azeotroping with MeOH (2×10 ml) to give the title compound (0.097 g). LCMS RT=3.08 min, ES+ve 628 (MH)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([OH:24])=O)[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:27])=O>>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([C:22]([Cl:27])=[O:24])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)Cl)c1

Procedure:
40 ml of thionyl chloride was added to 5.0 g of 4-octyloxybiphenylcarboxylic acid and the mixture was refluxed under heat for 3 hours. Excess of thionyl chloride was distilled off to obtain 4-octyloxybiphenylcarboxylic acid chloride, which was then added to a solution of 5.0 g of hydroquinone in 50 ml of pyridine. After 2 hours of reaction, the mixture was refluxed under heat for 10 hours, charged into ice water, and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 4-hydroxyphenyl estcr of 4-octyloxybiphenylcarboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:32][CH3:33])[CH:3]=1.C(N(CC)CC)C.[C:41]1([C:46](Cl)=[O:47])[S:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:33][O:32][C:4]1[CH:3]=[C:2]([O:1][C:46]([C:41]2[S:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC(=O)c2cccs2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.6 mg, 0.0577 mmol) was dissolved in anhydrous methylene dichloride (1 mL), and then triethylamine (19 μL, 0.14 mmol) and 2-thenoyl chloride (11.2 mg, 0.0764 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.8 mg) as a pale yellow amorphous product. (Yield 93%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH3:19])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: COC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux heated The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:16][CH:14]([C:11]1[O:12][C:13]2[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)=[CH:6][CH:7]=[CH:8][C:9]=2[CH:10]=1)[CH3:15]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(O)c1cc2cccc(OCC3CO3)c2o1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)O)oc23)CC1

Procedure:
The procedures of Example 1 were repeated except that 1.2 g (0.005 mole) of 7-(2,3-epoxypropoxy)-(1-hydroxyethyl)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed. The obtained concentrated residue was crystallized from ether acetate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:31][O:30][C:25]1[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: COc1ncccc1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: COc1ncccc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 3-bromo-2-methoxypyridine. Light yellow solid. MS (ESI): 422.1 (MH+)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1.[Na+].OP(O)(O)=O.[Na+].[Cl-]>O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C:7]([OH:9])=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](C(=O)[O-])O1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](C(=O)O)O1
Temperature: 0 °C

Procedure:
Sodium (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.03 g, 6.1 mmol) was dissolved in a mixture of water (1.2 ml) and ethyl acetate (1.2 ml) and cooled to 0° C. 2 M aqueous H3PO4 solution (7 ml) was added until the reaction mixture reached pH 2. After that the reaction mixture was saturated with NaCl and the reaction mixture was extracted with ethyl acetate (3×20 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The product (0.73 g, 4.9 mmol, 81%) was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl>[N+](CC)([O-])=O.ClC(Cl)C>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(Cl)Cl
Reactant: CCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC[N+](=O)[O-]
Product: CCCCCCCc1ccccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 87.7 g of n-heptylbenzene in a mixture of 160 ml of nitroethane and 480 ml of dichloroethane was added little by little 79.5 g of anhydrous aluminum chloride with ice cooling, followed by adding dropwise a solution of 54.5 ml. of dichloromethyl methyl ether in 60 ml of dichloroethane. After completion of the addition, the reaction was carried out at 0° C. for a further one hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on silica gel column with a solvent of n-hexane - isopropyl ether (10:1) to give 17.3 g of 2-heptylbenzaldehyde as a colorless oil from the first eluted fractions and 64.8 g of 4-heptylbenzaldehyde as a colorless oil from the later eluted fractions.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(Cl)cc1
Yield: 61.4 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and p-chlorobenzoyl chloride (0.72 mL, 5.5 mmol) in pyridine (10 mL) provided 4-chloro-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 214.0-214.5° C.; Anal. Calcd. for C19H16CINO2: C, 70.05; H, 4.95; N, 4.30; Found: C, 70.10; H, 4.72; N, 4.17.
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([NH:8][C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([O:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]([F:32])=[C:23]([NH:25]C(=O)C(F)(F)F)[CH:24]=1)[N:12]=2)(=[O:7])[CH3:6].O>C(O)C>[NH2:25][C:23]1[C:22]([F:32])=[CH:21][C:20]([Cl:33])=[C:19]([CH:24]=1)[O:18][C:13]1[N:12]=[C:11]2[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:17][C:16]2=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1nc2ccc(Oc3cc(N)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.1 %

Procedure:
To a solution of sodium borohydride (3.38 g, 100 mmol) in ethanol (60 mL) was added dropwise methanol (40 mL) under ice-cooling, and N-(5-{[2-(acetylamino) [1,3]thiazolo[5,4-b]pyridin-5-yl]oxy}-4-chloro-2-fluorophenyl)-2,2,2-trifluoroacetamide (2.16 g, 4.81 mmol) was added in portions thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (400 mL), and the mixture was extracted with ethyl acetate (200 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, collected by filtration, and dried under reduced pressure to give the title compound (3.26 g, 68%) as white powder crystals.
Reaction SMILES: [OH:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C:14]([O-])(=[O:18])[C:15]([CH3:17])=[CH2:16].[Cl-]>C(Cl)Cl>[C:14]([O:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)(=[O:18])[C:15]([CH3:17])=[CH2:16].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: OC[c-]1cccc1
Reactant: C=C(C)C(=O)[O-]
Agent: [Fe+2]
Agent: [Cl-]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Product: C=C(C)C(=O)OC[c-]1cccc1
Yield: 73.4 %

Procedure:
To 1.00 g (4.63 mmol) of hydroxymethylferrocene of formula (30) below dissolved in 20 ml of methylene chloride was added dropwise 0.73 g (7.00 mmol) of chloride methacrylate in 5 ml of methylene chloride. The reaction solution was washed with an aqueous solution of NaCl, dilute hydrochloric acid and an aqueous solution of dilute sodium hydroxide and dried over sodium sulfate, followed by distillation of the solvent thereby obtaining 0.97 g (3.4 mmol) of ferrocenylmethyl methacrylate of formula (31):