Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][CH2:13][C:14](Cl)=[O:15]>ClC(Cl)C>[CH:6]([C:2]1[NH:1][CH:5]=[C:4]([C:14](=[O:15])[CH2:13][Cl:12])[CH:3]=1)=[O:7]
Reactant: O=Cc1ccc[nH]1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=Cc1cc(C(=O)CCl)c[nH]1
Temperature: 0 °C
Yield: 93.6 %

Procedure:
A mixture of 35 g (0.37 mole) pyrrole-2-carboxaldehyde in 325 ml dichloroethane was stirred under nitrogen in a three-necked, one-liter, round-bottomed flask fitted with an overhead stirrer and addition funnel. To this was added, in portions over a one-hour period, 294 g (2.21 mole) aluminum chloride. After the addition was completed, the mixture was stirred at room temperature for 10 minutes, then 124.7 g (88 ml, 1.10 mole) of chloroacetyl chloride was added dropwise over a one-hour period. The mixture was stirred at room temperature for 16 hours, then carefully poured into one liter of ice-water. The resulting precipitate (purple) was collected, washed well with water, and dried in vacuo. The dry solid was placed in a Soxhlet extractor and extracted with ethyl acetate for 20 hours. Concentration of the ethyl acetate solution afforded 59.4 g (94%) of the title compound as a yellow-green solid; m.p. 178°-179° C. This intermediate was used immediately in the next step. An analytical sample could be prepared by recrystallization from acetone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(C)=O)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
50 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in 2 ml of pyridine. 17 mg of acetic anhydride was added to the obtained solution, and they were stirred at room temperature for 16 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduce pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=4/1) to obtain 55 mg of ethyl 8-(4-acetylaminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: S(Cl)(Cl)=O.CC(CCCC)C(O)=O.CC(CCCC)C(Cl)=O.[CH3:23][CH:24]([CH2:30][CH2:31][CH2:32][CH3:33])[C:25]([N:27]=[C:28]=[S:29])=[O:26].[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:50]=[CH:51][C:52]([NH:53][C:28]([NH:27][C:25](=[O:26])[CH:24]([CH3:23])[CH2:30][CH2:31][CH2:32][CH3:33])=[S:29])=[CH:54][CH:55]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCC(C)C(=O)N=C=S
Agent: CCCCC(C)C(=O)Cl
Agent: CCCCC(C)C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCC(C)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-methylhexanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-methylhexanoyl isothiocyanate was prepared using the resultant 2-methylhexanoyl chloride as a starting compound according to the description of the literature. 2-Methylhexanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 68%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:7]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH:9]=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1ccn(-c2ccccc2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccccc1-n1ccc(C(=O)O)n1
Reaction time: 2 h
Yield: 78.6 %

Procedure:
1-o-Tolyl-1H-pyrazole-3-carboxylic acid ethyl ester (238 mg, 1.03 mmol) was dissolved in a mixture of THF (2.0 mL) and MeOH (2.0 mL). To this was added NaOH (20% aqueous, 1.0 mL). The reaction mixture was stirred for 2 h, and was then diluted with EtOAc and washed with 1M HCl. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated to give the product as a white solid (164 mg, 0.81 mmol, 79%).
Reaction SMILES: ClC1C=CC(C[N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:31])[CH2:16][NH:17][C:18](=[O:30])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=3[NH2:29])[CH2:9][CH2:8]2)=CC=1>C(O)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:29][C:20]1[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:24][C:19]=1[C:18]([NH:17][CH2:16][C:15]([NH:14][CH2:13][CH:10]1[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]1)=[O:31])=[O:30]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 85.2 %

Procedure:
A suspension of 1-(4-chlorobenzyl)-4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine (447 mg, 0.93 mmol) and Pd(OH)2 (60 mg, 0.23 mmol) in 5% HCO2H/methanol (10 mL) was stirred at 50° C. for 14 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. To the residue was added 1N aqueous NaOH solution (15 mL) and the mixture was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=70/25/5) gave 4-[{(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine (284 mg, 86%): ESI/MS m/e 359.0 (M++H, C16H21F3N4O2).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2].CO[CH:34](OC)[N:35]([CH3:37])C.[C:40]1(C)C=CC=C[CH:41]=1>>[CH2:1]([O:3][C:4]([N:6]([CH2:8][CH:9]1[CH2:14][N:13]([C:15]2[C:28]([F:29])=[CH:27][C:18]([C:19]([C:21](=[CH:37][NH:35][CH:34]3[CH2:41][CH2:40]3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[C:17]([F:30])[C:16]=2[F:31])[CH2:12][CH2:11][O:10]1)[CH3:7])=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Reactant: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
4.14 (2H, q, J=7Hz), 7.08-7.52 (1H, m) (2) A solution of 4.46 g of ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate, 1.85 g of dimethylformamide dimethylacetal and 20 ml of toluene is refluxed for 6 hours. The reaction mixture is concentrated under reduced pressure and to the obtained residue is added 20 ml of ethanol. After the addition of 0.94 g of cyclopropylamine with ice-cooling, the mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure and the obtained residue is purified by chromatography on silica gel to give 4.06 g of ethyl 2-[4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoyl]-3-cyclopropylaminoacrylate in 89% yield, as an oily substance.
Reaction SMILES: [C:1]([N:8]([CH3:15])[C@H:9]([CH:13]=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:16]([CH2:21][CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl.O>[C:1]([N:8]([CH3:15])[C@@H:9]([CH:10]([CH3:12])[CH3:11])/[CH:13]=[C:21](\[CH3:22])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[C@@H](C=O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of aldehyde 13 (1.75 g, 8.7 mmol) in dry CH2Cl2 (9.0 mL) under an argon atmosphere at room temperature was added (carbethoxyethylidene)triphenylphosphorane (4.19 g, 11.3 mmol) and stirring was continued for a 4 h. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (100 mL), dried with magnesium sulfate and concentrated in vacuo. The crude oil was purified by flash chromatography (silica gel, 2:23 diethyl ether-pet. ether) to afford the required E-2-alkenoate 14 as a colourless oil (2.13 g, 82% yield). 1H-NMR (200 MHz, CDCl3) 0.74 (d, J=6 Hz, 3H, CH3), 0.79 (d, J=6 Hz, 3H, CH3), 1.17 (t, J=0.7 Hz, 3H, CH3), 1.34 (s, 9H, Boc-(CH3)3), 1.72 (m, 1H, CH), 1.78 (s, 3H, —CH3), 2.60 (bs, 3H, NCH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.15-4.20 (m, 0.5H, CH), 4.21-4.32 (m, 0.5H, CH), 6.54 (d, J=8 Hz, 1H, CH); Exact mass calc'd for C16H30N04 (M+H)+: 300.21750; Found (DCI): 300.21754. Optical rotation obtained was [α]D25 +61.1 (c 9.1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([CH2:17]O)=[C:11]3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.O=S(Cl)[Cl:23]>ClCCl>[Cl:23][CH2:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=12
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cn2cnc3c(CO)ccnc32)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(CCl)ccnc32)cc1
Reaction time: 1.5 h

Procedure:
[3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x183 (0.5 g, 1.86 mmol) is dissolved in dichloromethane (20 ml). SOCl2 (2 ml) is added dropwise. The reaction mixture is refluxed for 1 h. The volatiles are distilled off in the vacuum of a rotary evaporator. Then 50 ml of chloroform is distilled off additionally from the residue. The residual chloroform solution is added dropwise at 0° C. to a vigorously stirred saturated aqueous solution of NaHCO3. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is kept under 1 mmHg for 1.5 h at 40° C. to afford 7-(chloromethyl)-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine x185 sufficiently pure for the next step.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([O:16][C:15](=[O:17])[NH:14][CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7].CN(C)C=O.[H-].[Na+].Br[CH2:45][CH:46]([F:48])[F:47]>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([O:16][C:15](=[O:17])[N:14]([CH2:45][CH:46]([F:48])[F:47])[CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:26][CH2:27]1)=[O:7]
Reactant: O=C1NCC(c2ccc(F)c(F)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Reactant: FC(F)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C(c2ccc(F)c(F)c2)CN1CC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.7 %

Procedure:
To a solution of 261 mg (0.5 mmol) 9-(3,5-bis-trifluoromethyl-benzoyl)-5-(3,4-difluoro-phenyl)-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one in dimethylformamide 24 mg (0.5 mmol) of a 55% sodium hydride suspension in mineral oil was added at room temperature under argon. After 15 min, 80 mg (0.55 mmol) of 2-bromo-1,1-difluoroethane was added. The reaction mixture was stirred at room temperature under argon overnight. After evaporation of the solvent in vacuum water (1 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane/ethylacetate=1:1) to yield 96 mg (33%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[Br:10][CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>O.C1(C)C=CC=CC=1>[Br-:10].[CH3:1][N+:2]([CH3:3])=[C:14]1[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11][O:15]1
Reactant: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
In 100 mL of water were suspended 8 g (90 mmol) of a 50% aqueous solution of dimethylamine and 18 g (170 mmol) of sodium carbonate, followed by cooling to 0 to 5° C. A solution obtained by dissolving 23 g (68 mmol) of the 4-bromo-2,2-diphenylbutyric chloride mentioned above in 100 mL of toluene was then added dropwise. After stirring for 2 hours, the water layer taken out from the reaction mixture was washed with toluene. The resulting water layer was extracted with chloroform. The extract was washed with water and then dried. The residue obtained by concentrating the solvent under reduced pressure was crystallized from methyl isobutyl ketone, whereby 11 g (yield: 46.8%) of dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](N)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[OH2:22].C=O>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([OH:22])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: CCC1(CC(=O)OC)OCC(N)c2c1[nH]c1ccccc21
Reactant: O
Agent: C=O
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Yield: 66.4 %

Procedure:
To a solution of 4-amino-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (6 g, 0.020 mol) in 50 mL THF was added 50 mL of H2O and paraformaldehyde (5 g) and the solution was heated at reflux for 2 hours under nitrogen. It was then cooled, concentrated in vacuo, and diluted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane to give a white solid (4 g, 66.4% ) m.p. 86°-90° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[C:23]([C:35]([F:36])([F:37])[F:38])[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.9 %

Procedure:
To a cooled and stirred solution of 3′-[4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.36 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.25 g, 48%). MS (ISP) 524.2 [(M+H)+]; mp 202° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH:19]([N:32]1[CH2:35][C:34](=[O:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH:19]([N:32]1[CH2:35][C:34]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])([OH:36])[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1coc2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
A solution of 3-methylbenzofuran (550 mg, 4.16 mmol) in dry THF (17 mL) was cooled to −78° C. and LDA (1.8 M in THF/heptane/ethylbenzene) (2.8 mL, 5.04 mmol) was added dropwise under N2 over 5 min. After stirring for 30 min, 1-benzhydrylazetidin-3-one (1.61 g, 6.78 mmol) was added portionwise over 10 min. The reaction was stirred under N2 at −78° C. for 15 min, and was then allowed to warm to rt and stirred for 1.5 h. The reaction was quenched with 0.5N HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried on Na2SO4 and concentrated. The residue was purified by flash chromatography (heptane/EtOAc, 5%->35%), yielding the product (472 mg, 31%) as a yellow oil.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[C:8]1([C:14]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C(=O)([O-])[OH:32].[Na+]>O1CCCC1.CC(C)=O>[OH:32][C:1]([CH:19]([CH2:18][CH2:17][CH2:16]/[CH:15]=[C:14](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:20]([O:22][CH3:23])=[O:21])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCCC=C(c1ccccc1)c1cccnc1
Reactant: CC(C)NC(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CCC/C=C(\c1ccccc1)c1cccnc1)C(C)(C)O
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
Diisopropylamine (0.8 g, 8 mmole) was dissolved in tetrahydrofuran (10 ml) under argon, and the solution was cooled at -70° C., followed by adding dropwise 1.6M n-butyl lithium-hexane solution (5 ml) and stirring for 5 minutes. A tetrahydrofuran (2 ml) solution containing methyl 7-phenyl-7-(3-pyridyl)-6-heptenoate (1.19 g, 4 mmole) was added dropwise to the reaction solution. After stirring for 15 minutes under the same reaction conditions, acetone (0.5 ml) was added, and the reaction was carried out for another 10 minutes. Subsequently, 2N hydrochloric acid (5 ml) was added to terminate the reaction, and the temperature of the solution was allowed to rise to room temperature, followed by adding aqueous sodium hydrogencarbonate to adjust to pH 8. The product was extracted with ethyl acetate, and the organic layer was washed with water and dried. The residue was chromatographed on silica gel using isopropyl ether:ethyl acetate (1:1) to yield methyl (E)-2-(1-hydroxy-1-methylethyl)- 7-phenyl-7-(3-pyridyl)-6-heptenoate (5-a) (1.2 g).
Reaction SMILES: [N:1]1[C:6]([C:7](OC)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:11]([O:13][CH3:14])=[O:12].[BH4-].[Na+]>CO.O1CCCC1>[OH:8][CH2:7][C:6]1[N:1]=[C:2]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=[CH:4][CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A suspension of dimethyl 2,6-pyridine-dicarboxylate (100 g, 513 mmol) in methanol (800 mL) and tetrahydrofuran (300 mL) was heated to dissolve and while the solution was still hot, it was treated in portions with sodium borohydride (18.2 g, 479 mmol) over 1 hour. The mixture was stirred for 1 hour at room temperature, cooled to 0-5° C., and quenched with 10% citric acid (160 mL), stirred for another 15 minutes, and filtered. The filtrate was concentrated, dissolved in dichloromethane, dried (sodium sulfate), filtered, and concentrated to a white solid. The solid was heated to dissolve in ethyl acetate (100 mL), stirred for 16 hours at room temperature, filtered and concentrated to give the title compound (44.5 g, 56% yield). 1H NMR (CDCl3) δ ppm 3.50(s, 1H), 4.00 (s, 3 H), 4.86 (s, 2 H), 7.52 (d, 1 H), 7.85 (t, 1 H), 8.04 (d, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.O=[C:13]([CH2:19][CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C1(C)C=CC=CC=1.C(O)(=O)C>O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:13]([CH2:19][CH3:20])=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)CC(=O)OC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 4.5 h
Yield: 72.8 %

Procedure:
In a IL-flask were placed 4-trifluoromethylaniline (161 g, 1.00 mol), methyl 3-oxopentanoate (130 g, 1.00 mol) and toluene (160 mL). To this solution was added acetic acid (16 g, 0.27 mol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 19 kPa for 3.5 hours, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. Acetic acid (16 g, 0.27 mol) was then added, and reflux was continued for 4.5 hours. Acetic acid (8 g, 0.13 mol) was then added again, and reflux was continued for another 2.5 hours. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. After distillation of the solvent and acetic acid under reduced pressure, the residue was distilled under reduced pressure to give 199 g of the title compound. The yield was 72.8%. The 1H-NMR spectrum was identical to that of Example 1.