Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]2[CH2:19][CH2:18][CH2:17][C@H:16]3[N:11]2[C:12](=[O:20])[CH2:13][CH:14]=[CH:15]3)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:9][C:6]1[CH:5]=[C:4]([C@@H:10]2[CH2:19][CH2:18][CH2:17][C@H:16]3[N:11]2[C:12](=[O:20])[CH2:13][CH2:14][CH2:15]3)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 88.4 %

Procedure:
Platinum oxide (162 mg) was added to a solution of (6S,9aR)-6-(3,4,5-trifluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (2.01 g) in methanol (50 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for seven hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.79 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:2]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CC(=O)Nc1cccc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)Nc1cccc(C=O)c1
Yield: 100.6 %

Procedure:
A solution of N-[3-(1,3-dioxolan-2-yl)phenyl]acetamide (50.0 g, 0.24 mole) and p-toluenesulfonic acid (1.0 g) in acetone (750 mL) was stirred at room temperature for 72 hours. The solution was filtered through a pad of neutral alumina and concentrated in vacuo to afford N-(3-formylphenyl)acetamide (39.4 g, 100%), mp 68°-70° C., used without further purification below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:4][C:5]([C:15](=[O:26])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH3:17])=[C:6]([CH:14]=1)[O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:39](O)[CH3:40]>O=S(Cl)Cl>[CH2:39]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:14]=[C:2]([Cl:1])[C:3]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:4][C:5]=1[C:15](=[O:26])[N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH3:17])[CH3:40]
Reactant: CCO
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCOc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid in ethanol (1 mL), 10 drops of SOCl2 were added. The mixture was stirred at rt for 24 hrs. The crude was purified via reverse phase preparative LCMS to afford 4-{5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid ethyl ester 43-1 (12.2 mg). MS: [M+H]+ 576.3; tR=6.33 min (method 3).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(OCC)(=O)C>CN(C=O)C.O>[Si:34]([O:33][CH2:32][CH2:31][N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][S:2](=[O:1])(=[O:23])[CH2:3][CH2:4]1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:13])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.400 g, 1.10 mmol) was combined with cesium carbonate (0.538 g, 1.65 mmol) in DMF (5 mL). The slurry was stirred at rt for 30 min, then to it was added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.527 g, 2.20 mmol). The resulting mixture was stirred at rt for 18 h. Dilution with ethyl acetate (60 mL) and water (40 mL) followed by shaking gave a separation of phases. The organic phase was isolated, washed with water (2×30 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. Purification by silica gel chromatography (gradient 100% DCM to 100:1 DCM:MeOH) gave the title compound as a yellow solid (0.560 g, 98% yield). LCMS: m/z 522 (M+H+), retention time 2.22 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.01 (s, 6H) 0.86 (s, 9H) 2.75 (t, J=5.95 Hz, 2H) 3.05 (s, 8H) 3.44 (t, J=5.49 Hz, 2H) 3.57 (t, J=6.41 Hz, 2H) 3.70 (t, J=5.49 Hz, 2H) 7.63-7.78 (m, 3H) 8.02-8.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[NH2:15].[CH3:20]CCCCC.C(O)C.C(O)(C(F)(F)F)=O>O.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[NH:15][CH3:20]
Reactant: N[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Reactant: CCCCCC
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h

Procedure:
(±)cis-1-(3,4-Dichlorobenzyl)-2-methylaminoindane (7.49 g) was prepared from (±)cis-1-(3,4-dichlorobenzyl)-2-aminoindane (Preparation 2, Method B, 13.95 g) as described in Preparations 3-5 , and then converted into the single enantiomers (+)cis-1-(3,4-dichlorobenzyl)-2-methylaminoindane hydrochloride(E1) and (-)cis-1-(3,4-dichlorobenzyl)-2-methylaminoindane hydrochloride(E2) as described above. In each case chiral purity was greater than 99.5% as judged by chiral HPLC analysis (Column: CHIRALPAK AD; Eluent: 99/1 hexane/ethanol+0.1% DEA). The level of other impurities was<0.3% as judged by HPLC (Column: Merck RP--Select B. Eluent A: 0.1% TFA in water; Eluent B 0.1% TFA in acetonitrile; Eluent composition increased linearly from 5%B to 80% B over 40min. and then held at 80% B for a further 10 min).
Reaction SMILES: COC1C=C(C=CC=1OC)C[NH:7][C:8]1[N:9]=[C:10]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:10]1[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]([NH2:7])[N:9]=1
Reactant: COc1ccc(CNc2nc(-c3ccco3)c3sccc3n2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2ccco2)c2sccc2n1
Yield: 92.1 %

Procedure:
A solution of N-(3,4-dimethoxybenzyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (199 mg, 0.54 mmol) in TFA (1 mL) was heated at 60° C. for 1 h, cooled, poured into sat. NaHCO3, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1 and MeOH:DCM, 1:19) to give the title compound (108 mg, 92%) as a cream solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(O)C>[NH2:9][C:7]1[N:6]([C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[N:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(C2CC2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CC2)nn1C(=O)Nc1ccccc1

Procedure:
To 0.4 g (3.2 mmol) of 3-cyclopropyl-5-amino-1H-pyrazole in 10 ml of 95% ethanol containing 0.3 g of sodium hydrogencarbonate 0.35 ml (3 mmol) of phenylisocyanate were added dropwise over several minutes. After 30 min water was added, and the solid was filtered, washed with 10% HCl and then with water. The filtrate was concentrated in vacua. The crude was recrystallized from methanol/water to give white peddles of 5-amino-3-cyclopropyl-N-phenyl-1H-pyrazole-l-carboxamide,
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1)#[N:14]>C(O)(=O)C>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][N:31]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:32][CH:33]=1)#[N:14]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 95 mg of the title compound (89%) as a orange powder in 94.7% purity by HPLC (Rt: 4.37, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34]>>[CH:23]1([C:22]2[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:33][CH2:32][CH2:31][C:30]5=[O:34])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=[C:20]([CH:26]3[CH2:28][CH2:27]3)[CH:21]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCCN1
Reactant: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: Cc1nc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 103 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 251 and pyrrolidin-2-one (29 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (104 mg) was obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)S(C1C=CC(C)=CC=1)(=O)=O)C.O1CCOCC1.Cl>O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([CH:4]=[CH:5][N:6]=[CH:17]2)=[CH:22][CH:21]=1
Reactant: CCOC(CN(Cc1cccc(OC)c1)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2ccncc2c1
Yield: 102.4 %

Procedure:
To a 2 liter round bottom flask equipped with a magnetic stir bar, condenser and nitrogen inlet is added (75 g, 0.184 mole) of N-(2,2-diethoxyethyl)-N-[(3-methoxyphenyl)methyl]-4-methyl-benzenesulfonamide, 1.0 liter of dioxane and 200 ml of 6N HCl. This slurry is stirred and heated at reflux under nitrogen for 18 hours. The reaction solution is then slowly poured into 1 liter of H2O and stirred for an additional 30 minutes then extracted with ether (2×500 ml). The pH of the aqueous layer is adjusted to 8 with ammonium hydroxide, the product is extracted with dichloromethane. The combined organics extracts are dried over MgSO4, filtered and evaporated to yield 30 g of an oil. The crude product is purified by chromatography with 12.0% acetone in dichloromethane to provide the product (19.7 g) in a 67% yield.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH2:33]Br)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:35][C:36]1[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=1>>[C:1]([C:9]1[C:10]([CH2:33][S:35][C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)=[CH:16][C:15]([O:29][CH3:30])=[C:14]([O:31][CH3:32])[CH:13]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: Cn1ccnc1S
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 4, 3-benzoyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with 2-mercapto-1-methylimidazole to give 3-benzoyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-[(1-methylimidazol-2-yl)thiomethyl]quinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 185°-186° C.
Reaction SMILES: [CH:1](=[N:8][NH:9][CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C(=O)=O.C(O[CH:24]=[C:25]([C:28]#[N:29])[C:26]#[N:27])C>C1COCC1>[CH:1](=[N:8][N:9]([CH:24]=[C:25]([C:28]#[N:29])[C:26]#[N:27])[CH:10]([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)NN=Cc1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N(C=C(C#N)C#N)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of Intermediate 1-benzylidene-2-isopropylhydrazine (12.9 g, 0.079 mol) in 200 ml anhydrous THF was cooled in a dry ice/acetone bath under an argon atmosphere. To this solution was added n-butyllithium (1.6 M in hexanes, 66 ml, 0.106 mol) via syringe. Following completion of the addition, the mixture was stirred at dry-ice temperature for an additional 5 minutes. A solution of (2-(ethoxymethylene)malononitrile (13.6 g, 0.11 mol) in THF (30 ml) was added. The mixture was stirred at dry-ice temperature for 0.5 h, and then was quenched with saturated aqueous sodium bicarbonate solution. The quenched reaction mixture was allowed to warm to rt and was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was suspended in ethanol with sonication. The resulting precipitate was collected via filtration and washed with a small amount of cold ethanol to obtain 2-((2-benzylidene-1-isopropylhydrazinyl)methylene)malononitrile as a yellow solid. The mother liquor was concentrated and the residue purified by silica gel column chromatography (1:1 hexanes/ethyl acetate eluant) to afford additional 2-((2-benzylidene-1-isopropylhydrazinyl)methylene)malononitrile. MS m/z 239.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: NCc1ccc(F)cc1
Product: N#Cc1ccc(N(CC(=O)NCc2ccc(F)cc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and 4-fluorobenzyl amine: MS (APCI) m/z 406 (M+1).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:5]2[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]2=[O:9])=[O:24])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1COC(=O)N1C(=O)Cc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 106 %

Procedure:
To a solution of (4R)-4-isopropyl-1,3-oxazolidin-2-one (5.3 g, 41.1 mmol) in dry THF (100 mL) at −78° C. under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at −78° C. for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 30 min and 0° C. for 15 min, quenched with saturated NH4Cl (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%–15% EtOAc/hexane) to give 6.48 g (23.1 mmol, 56%) of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.31–7.22 (m, 4H), 4.45–4.41 (m, 1H), 4.35–4.16 (m, 4H), 2.39–2.29 (m, 1H), 0.89 d, 3H, J=7.2 Hz), 0.80 (d, 3 H, J=7.2 Hz); ESMS m/e: 282.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2.Cl.[CH3:37][NH:38][CH3:39].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([N:38]([CH3:39])[CH3:37])=[O:22])[CH2:16][C@H:15]1[NH:23][C:24]([C:26]1[S:27][C:28]3[CH2:29][N:30]([CH3:35])[CH2:31][CH2:32][C:33]=3[N:34]=1)=[O:25])=[O:12])=[CH:5]2
Reactant: CNC
Reactant: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)O)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 153.7 %

Procedure:
The compound (900 mg) obtained in Example 58 was dissolved in N,N-dimethylformamide (50 ml), to which dimethylamine hydrochloride (304 mg), 1-hydroxybenzotriazole monohydrate (262 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (369 mg) and diisopropylethylamine (1.83 ml) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to conduct extraction with methylene chloride. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (methylene chloride:methanol=47:3). The thus-obtained white solids were dissolved in methylene chloride, to which 1N ethanol solution (1.49 ml) of hydrochloric acid was added. The solvent was distilled off under reduced pressure, and methanol and diethyl ether were added to the residue to collect precipitate formed by filtration, thereby obtaining the title compound (777 mg).
Reaction SMILES: [Mg].[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1Br)([CH3:5])[CH3:4].[CH2:17]1[O:19][CH2:18]1>O1CCCC1>[CH3:2][C:3]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[CH2:17][CH2:18][OH:19])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(Br)c(C(C)(C)C)c1
Reactant: C1CO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 243 mg (10 mmoles) of magnesium turnings in 10 ml of tetrahydrofuran is added dropwise a solution of 2.69 grams (10 mmoles) of the title product of Example 9 in 5 ml of tetrahydrofuran. After the addition is complete, the mixture is refluxed for one hour. Ethylene oxide (440 mg, 10 mmoles) is then added, and refluxing continued for one hour. The mixture is cooled to room temperature and partitioned between saturated ammonium chloride and diethyl ether. The aqueous layer is further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using mixtures of ethyl acetate and hexane as eluents gives the title compound.
Reaction SMILES: C(=O)(OCC)O[CH:3]([C:6]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:7]=1[Br:13])[CH:4]=[CH2:5].[F:18][C:19]([F:39])([F:38])[C:20]1[CH:21]=[C:22]([C@H:30]2[O:34][C:33](=[O:35])[NH:32][C@H:31]2[CH:36]=[CH2:37])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C1C=C2C=CC3C(C=CC2=CC=1)=CC=CC=3.C(Cl)Cl>[F:39][C:19]([F:18])([F:38])[C:20]1[CH:21]=[C:22]([C@H:30]2[O:34][C:33](=[O:35])[N:32]([C@H:3]([C:6]3[CH:11]=[C:10]([C:19]([F:39])([F:38])[F:18])[CH:9]=[CH:8][C:7]=3[Br:13])[CH:4]=[CH2:5])[C@H:31]2[CH:36]=[CH2:37])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C=CC(OC(=O)OCC)c1cc(F)ccc1Br
Reactant: C=C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C1=C\c2ccccc2/C=C\c2ccccc2/1
Agent: C1=Cc2ccccc2C=Cc2ccccc21
Solvent: ClCCl
Product: C=C[C@@H](c1cc(C(F)(F)F)ccc1Br)N1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C=C
Temperature: 33 °C
Reaction time: 48 h
Yield: 124.4 %

Procedure:
To a 500 mL RBF was added 1-(2-bromo-5-fluorophenyl)prop-2-en-1-yl ethyl carbonate (10.4 g, 29.5 mmol), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-ethenyl-1,3-oxazolidin-2-one (4 g, 12.3 mmol), DCM (20 mL), and the Helmchen dibenzo[a,e]cyclooctatetraene (dbcot) iridium phosphoramidite catalyst complex (407 mg, 0.369 mmol) (Helmchen et al, Chem. Eur. J., 2010, 16, 6601-6615). The reaction was stirred at 33° C. for 2 days open to air. The reaction was filtered over Celite and purified by column chromatography to yield (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]prop-2-en-1-yl}-4-ethenyl-1,3-oxazolidin-2-one (4.5 g, 7.65 mmol). 1H NMR (500 MHz, CDCl3) δ7.86 (m, 2H), 7.68 (s, 2H), 7.64 (s, 1H), 7.54 (d, J=6.5 Hz, 1H), 6.22 (m, 1H), 5.75 (m, 2H), 5.43 (m, 2H), 5.20 (m, 1H), 5.03 (d, J=5.0 Hz, 1H), 4.8 (d, J=8.5 Hz, 1H), 4.1 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.00 g of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate in CHCl3 (20 ml) was added TFA (10 ml) under ice cooling, the reaction mixture was warmed to room temperature, then was stirred for 3 hours at the same temperature. Thereafter, the reaction solution was concentrated under reduced pressure to obtain 3.82 g of the title compound (crude form, colorless oil). The present compound was used in the next reaction without purification.