Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:25]=[O:26])=[CH:12][NH:13]2)=[CH:9][C:8]=1[C:16]([F:19])([F:17])[F:18]
Reactant: FC(F)(F)c1cc2cc[nH]c2cc1Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)c(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Phosphorus oxychloride (1.83 ml) was added dropwise to dimethylformamide (16 ml) under ice-cooling, and the mixture was stirred at 0° C. for 20 min. 6-Chloro-5-(trifluoromethyl)-1H-indole (3.24 g) dissolved in dimethylformamide (10 ml) was added to the reaction mixture, and the mixture was stirred at 0° C. for 3 hr. Water was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hr, and the mixture was alkalified with a 1N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water and dried to give 6-chloro-5-(trifluoromethyl)indole-3-carbaldehyde (3.25 g, yield 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9](Cl)[CH3:10].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])[CH3:10]
Reactant: Cc1ccc(C)c(C(C)Cl)c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: Cc1ccc(C)c(C(C)Sc2cccc[n+]2[O-])c1
Yield: 83 %

Procedure:
The intermediate 2-(1-[2,5-dimethylphenyl]-ethylthio)pyridine N-oxide is prepared from 1-(2,5-dimethylphenyl)ethyl chloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 118° - 120°C. Structure confirmed by IR and NMR.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH2:7]([OH:11])[CH:8]([CH3:10])[CH3:9].CCOCC>>[CH2:7]([O:11][C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)CO
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CC(C)COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chloro-oxo-acetic acid isobutyl ester was prepared by adding oxalyl chloride (21 μL, 252 μmol) to a solution of isobutanol (21 μL, 226 μmol) in ether (206 μL, 2.0 mmol). The mixture was stirred at room temperature for 15 min and then evaporated.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC#N>[CH2:29]([N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CN2C(=O)CCC2N1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: O=C1CCC2N1CC(=O)N2Cc1ccccc1
Yield: 86.9 %

Procedure:
A solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994), BEMP (2 ml, 7 mmol) and benzylbromide (0.6 ml, 5 mmol) in CH3CN (20 ml) was refluxed for 1 hour. The reaction mixture was concentrated to dryness; the residue was then re-dissolved in ethyl acetate and washed with a saturated solution of NaCl, dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by flash chromatography over silica gel (CH2Cl2/MeOH/NH4OH 95/5/0.5) to afford 0.7 g of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CC(C)([O-])C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.O>CS(C)=O>[NH2:4][CH2:3][CH2:1][O:2][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:16][CH:17]=1
Reactant: O=C1CCC(c2ccc(F)cc2)=NN1
Reactant: NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 65 °C
Yield: 34.4 %

Procedure:
In a flame-dried, round-bottomed flask, ethanolamine (1.7 ml, 28.1 mmol) was dissolved in dimethylsulfoxide (9.5 ml), and potassium tert-butoxide (95%, 3.3 g, 28.1 mmol) was added to the solution. This mixture was stirred at about 65° C. for about ten minutes, and then 6-(4-fluorophenyl)-4,5-dihydro-2H-pyridazine-3-one (3.6 g, 18.7 mmol) was added. This dark-colored solution was heated to about 80° C. for about twelve hours, and was then cooled to room temperature. Water was added, and the resulting tan solid was removed by filtration. This crude solid was then purified by column chromatography (silica gel; 5% methanol/dichloromethane to 15% methanol/dichloromethane) to afford the product as a white solid (1.5 g, 34% yield). LRMS ([M+H]+)=234.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:5]2=1.C1C(=O)N([Br:40])C(=O)C1>C(#N)C.O>[Br:40][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[C:9]3[C:4]([C:5]=2[CH:17]=1)=[CH:3][C:2]([CH3:1])=[N:11][CH:10]=3
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(Br)cc21
Yield: 39.1 %

Procedure:
To the stirred solution of (S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (40 mg, 0.069 mmol) in acetonitrile (3 mL) at room temperature was added NBS (12 mg, 0.069 mmol). The reaction mixture was heated to reflux for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-tert-butyl (1-((9-bromo-2,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (30 mg, 0.027 mmol, 40% crude yield) as a yellow oil. The material was carried forward without further purification. LC/MS (ESI) m/e 518.2 [(M+H)+, calcd for C25H33BrN3O4 518.2]; LC/MS retention time (method E): tR=1.25 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved in methylene chloride (100 ml), and thereto are added with stirring triethylamine (8.66 g) and tosyl chloride (16.3 g) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated, and the residue is dissolved in a mixture of water and ethyl acetate. The organic layer is separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=O)[CH2:8]2)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:21][OH:22]>C(O)C>[CH:1]([N:4]1[CH:9]2[CH2:10][CH2:11][CH2:12][CH:5]1[CH2:6][C:7](=[N:21][OH:22])[CH2:8]2)([CH3:3])[CH3:2]
Reactant: CC(C)N1C2CCCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N1C2CCCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-isopropyl-9-aza-bicyclo[3.3.1]nonan-3-one (CAS no: 56258-85-6) (5.0 g, 28 mmol) in ethanol (125 mL) and pyridine (3.3 mL, 41 mmol) with hydroxylamine hydrochloride (2.03 g, 29 mmol) was refluxed for 6 h. Cooled to 23° C., the precipitate was filtered off, washed with diethyl ether leaving a solid, which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (4.43 g, 82%); MS: m/e=197.1 (M+H−).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24][CH3:25])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1>O.C(O)C>[Br:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[CH:16]=[C:17]([C:27]([NH2:29])=[O:28])[N:18]3[C:23]([S:24]([CH3:25])=[O:1])=[CH:22][C:21]([CH3:26])=[N:20][C:19]=23)=[C:10]([CH3:30])[CH:9]=1
Reactant: CSc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(S(C)=O)n2c(C(N)=O)cc(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 0 °C
Yield: 2180.4 %

Procedure:
To a solution of Oxone (9.12 g) in water (50 mL) was added a solution of 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-methylsulfanyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (3.00 g) in ethanol (50 mL) in an ice-cooling bath. The reaction mixture was stirred under ice-cooling for 30 minutes, poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: ethyl acetate) to give 8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (1:68 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C(C(O)=O)CCC1=O.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:25][S:26]([O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(CO)N1
Agent: O=C1CCC(C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
An ice cold solution of 5-(hydroxymethyl)pyrrolidin-2-one (1.5 g, 13 mmol) prepared from 2-pyrrolidone-5-carboxylic acid (Valesinas et al., J. Org. Chem. 1992, 57, 2156-2160) in 20 mL of dichloromethane was treated with triethylamine (2.4 g, 23.5 mmol) and methylsulfonyl chloride (2.2 g, 19 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated under reduced pressure. The crude, oily material was purified by chromatography (silica gel; 10% methanol in chloroform) to give 2.1 g of 5-(methanesulfonyloxymethyl)pyrrolidin-2-one as an oil which solidified upon addition of ether.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][N:11]=[C:10]([NH2:30])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:6][C:7](=[O:31])[C:8]1[C:13]([S:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:12][N:11]=[C:10]([NH:30][S:40]([C:34]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=2[Cl:32])(=[O:42])=[O:41])[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: CCCCCOC(=O)c1cc(N)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCOC(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 29.3 %

Procedure:
A solution of the 2-amino-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester (500 mg, 1.1 mmol), 2,4-dichlorobenzenesulfonylchloride (327 mg, 1.33 mmol) and 4-dimethylaminopyridine (134 mg, 1.1 mmol) in pyridine (10 ml) was stirred at 40° C. overnight. The pyridine was removed under reduced pressure and the residue purified by flash column chromatography using ethyl acetate 1/2 hexane as eluent to afford 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinic acid pentyl ester as a yellow foam (217 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C([N:24](CC)CC)C.N>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([NH2:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)nc2)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic from Step 4 (1.0 g) in chloroform (50 mL) were slowly added isobutyl chloroformate (800 μL) and triethylamine (920 μL). The reaction mixture was stirred at 0° C. for 2 hours. Then it was saturated with ammonia gas and stirred at 0° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then poured into water (80 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2×80 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](Cl)(=[O:43])[C:34]1[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:36](Cl)=[O:37]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([N:25]2[C:36](=[O:37])[C:35]4[C:34](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:33]2=[O:43])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N)nccc3c2)C1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ccc3c(N4C(=O)c5ccccc5C4=O)nccc3c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of (S)-3-(1-amino-isoquinolin-6-yloxy)piperidin-1-carboxylic acid tert-butyl ester (380 mg, 1.11 mmol) and triethylamine (1.5 ml, 11.1 mmol) in anhydrous tetraydrofuran (1.5 ml) was added phthaloyl dichloride (170 μL, 1.16 mmol). The mixture was stirred at ambient temperature for 2 h and then poured into quickly stirring water. The mixture was extracted with dichloromethane (3×50 ml) and concentrated in vacuo to give a residue. Flash chromatography of the residue on silica (eluent: 0-100% ethyl acetate in heptane) gave (S)-3-[1-(1,3-dioxo-1,3-dihydroisoindol-2-yl)isoquinolin-6-yloxy]piperidine-1-carboxylic acid tert-butyl ester (390 mg) E1l-MS: m/z=474.3 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:10])[CH2:5][CH:6]([OH:9])[CH2:7]O.CS([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH:5]([N:4]([CH3:10])[CH3:3])[CH:6]([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:7])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Reactant: CN(C)CC(O)CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(C)C(OCCCCCCCC/C=C\C/C=C\CCCCC)N(C)C
Reaction time: 14.5 h

Procedure:
In a nitrogen atmosphere, dehydrated toluene (30 ml) and potassium hydroxide (4.9 g, 87.0 mmol) were added to a four-necked flask, and 3-(dimethylamino)-1,2-propanediol (0.57 g, 4.78 mmol: DAP) was dropped under agitation. Thereafter, linoleyl methane sulfonate (5.0 g, 14.5 mmol) was added, and reaction was effected at room temperature for 14.5 hours. The reaction was terminated because isomers increased to 0.079%, although remaining linoleyl methane sulfonate was 51.1% and, therefore, 5.0% or less was not satisfied (degree of conversion: 28.9%, integrated value of isomer: 0.079).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:38])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:38])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC(=O)N1CCNCC1)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (37) (2.05 g; 3.93 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1 hour at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as an oil. ESMS: MH+ 422.2
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH2:34]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:35]#[CH:36].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7](/[C:10](/[C:27]3[CH:32]=[CH:31][C:30]([C:36]#[C:35][CH2:34][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:29][CH:28]=3)=[CH:11]/[CH2:12][O:13][C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:16]([CH3:26])[CH:15]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C3CC3)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C3CC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a degassed solution of the above ester (392 mg, 0.707 mmol), N-propargylmorpholine (176 mg, 1.41 mmol) and diisopropyl amine (0.466 mL, 3.3 mmol) in anhydrous tetrahydrofuran (11 mL), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and copper(I) iodide (12.0 mg, 0.063 mmol) were added. The reaction mixture was stirred at ambient temperature for 7 h under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5) yielding methyl (Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(OCc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-benzyloxyaniline (97 mg, 0.486 mmol) similar to Example 13 and isolated as a yellow oil (161 mg, 90%). 1H NMR (CDCl3): 8.78–8.76 (m, 1H), 8.48–8.45 (m, 1H), 7.79–7.74 (m, 1H), 7.68 (s, 1H), 7.42–7.29 (m, 6H), 7.24 (t, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J=0.8, 8.0 Hz, 1H), 6.77–6.74 (m, 1H), 6.58 (s, 1H), 5.04 (s, 2H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][NH:11][C:10]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:20]=[S:21]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11]([C:20](=[S:21])[NH:19][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C:10]1=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C=S
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNC(=S)N1C[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-3-[[(t-butyloxy)carbonyl]amino]-2-azetidinone (186 mg, 1 mmol) in 6 ml of dry tetrahydrofuran at -75° C. was treated with 0.65 ml (1.1 mmol) of 1.68N n-butyl lithium. After 30 minutes, a solution of t-butyl isothiocyanatoacetate (0.17 ml, 1.1 mmol) in 1 ml of dry tetrahydrofuran was added to the reaction mixture. After stirring at -75° C. for 2 hours, the reaction mixture was placed at -70° C. overnight.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=1.O[CH2:47][CH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:47][CH2:48][CH:49]2[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:53][CH2:54]2)=[C:37]([C:42]([F:43])([F:44])[F:45])[CH:36]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
DIAD (33.5 g) was added dropwise to the solution of triphenylphosphine (43.5 g), 4-bromo-2-trifluoromethylphenol (40 g) and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate (31.7 g) in DCM (200 ml) at 0° C. during 15 minutes. The mixture was then stirred at room temperature for 20 hours. After removal of DCM under reduced pressure, to the residue was added ether (100 ml) and heptane (300 ml), solid was then filtered off. Filtrate was then washed with 1M sodium hydroxide (100 ml×3). Organic layer dried over sodium sulphate, solvent removed under vacuum, residue was then columned on silica gel using heptane:EtOAc (5:1) as eluant to give tert-butyl 4-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate as a colorless oil as product (61.3 g).