Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C([N:17](CC)CC)C.COC(Cl)=O.O>CC(C)=O.CC1C=CC(CCN)=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][C:10]=2[C:12]([NH2:17])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Cl)cc2cccnc12
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: Cc1ccc(CCN)cc1
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1cccc2cccnc12

Procedure:
5.2 g of 6-chloro-quinoline-8-carboxylic acid in 150 ml of acetone were combined, while stirring and cooling with ice, with 2.8 g of triethylamine and 2.6 g of chloroformic acid methyl ester. The whole was stirred for about 10 minutes, a solution of 3.4 g of 2-(4-methylphenyl)-ethylamine in 50 ml of 2-(4-methylphenyl)-ethyl-amine in 50 ml of acetone was added and the mixture was again stirred for 1 hour at room temperature. Then, water was added, the precipitate was filtered off with suction, treated with a dilute ammonia solution, undissolved matter was filtered off and recrystallized from dilute methanol. The 6-chloro-N-(2-<4-methylphenyl>-ethyl)-quinoline-8-carboxylic acid amide so obtained was found to melt at 102°-104° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(O)C.CN(C=O)C>[CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[C:34]([CH3:42])[CH:35]=3)=[O:39])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To tert-butyl 8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600 mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4.028 mL of 4 M in dioxane, 16.11 mmol) and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, then DMF (4 mL), 4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) and HATU (613 mg, 1.61 mmol) were added and the reaction mixture was stirred for 10 minutes. Triethylamine (898 μL, 6.44 mmol) was added and the reaction mixture was stirred for 16 hours, The reaction mixture was concentrated in vacuo, diluted with DCM (5 mL), washed with 1 N aq. NaOH (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% EtOAc/hexanes eluent to give (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (715 mg, 99%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H), 5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14 (m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz, 1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0 Hz, 6H); ESI-MS m/z calc. 448.6. Found 449.5 (M+1)+; Retention time: 1.48 minutes (3 min run).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1>C(C#N)(C)=O>[Cl:4][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Agent: CC(=O)C#N
Product: COc1cc(NC(C)=O)c(Cl)c(OC)c1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Sulfurylchloride (26.9 ml, 325 mmol, 1.93 eq.) is added (in 7 min) to a cold (0° C.) suspension of N-(3,5-dimethoxyphenyl)-acetamide (32.9 g, 169 mmol) in AcCN (500 ml), under an inert atmosphere. The resulting yellowish is allowed to stir 30 min and quenched by dropwise addition of a saturated aqueous solution of sodium bicarbonate (250 ml). The resulting precipitate is collected by vacuum filtration, washed with water (300 ml) and dried to afford 20 g of the desired product (batch 1). The filtrate is diluted with a saturated aqueous solution of sodium bicarbonate (300 ml) and extracted with EE (2×300 ml). The organic phase is washed with water and brine, dried (sodium sulphate), filtered and concentrated. The residue is purified by silica gel column chromatography (EE/Hx, 1:1→2:1) to provide 8.8 g of product (batch 2). Batch 1 and 2 are combined and stirred in hexane. The solid is collected by filtration, washed with hexane and dried to afford 25.8 g of the title compound as a white solid. ESI-MS: 264.0/266.0 [MH]+.
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCC[C@@H]1C(O)=O)=O)(C)(C)C.[F:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[C:46]([CH2:48][CH2:49][C:50]([OH:52])=O)=[O:47]>>[F:42][C:43]1[CH:44]=[C:45]([C:46](=[O:47])[CH2:48][CH2:49][C:50]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:17]3[CH2:18]2)=[O:52])[CH:53]=[CH:54][C:55]=1[O:56][CH3:57]
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCC[C@@H]3C2)cc1F

Procedure:
93 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (R)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1>[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Into a solution of 14.6 g (52.6 mmol) of tert-butyl 4-[3-(amino)phenyl]-1-piperidinecarboxylate and 14.7 mL (105 mmol) of triethylamine in 120 mL THF at 0° C. was slowly added 4.5 mL (63.1 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 16.6 g (52.1 mmol, 99%) of desired product: 1H NMR (400 MHz, CDCl3) δ 7.41–7.20 (m, 3H), 6.94 (d, 1H, J=7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16 (s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([CH:23]=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1.[OH:26]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([C:23]([OH:26])=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C(=O)O)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
3-(3-methyl-isoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (16 mg, 0.05 mmol) was dissolved in tert-butanol (2 mL) followed by the sequential addition of saturated aqueous sodium phosphate monobasic solution (0.25 mL), 2-methyl-2-butene (0.05 mL), and sodium chlorite (NaClO2) (7 mg, 0.08 mmol). The mixture was stirred at room temperature for 3.5 h and concentrated. The residue was dissolved in ethyl acetate (15 mL), dried (MgSO4), filtered, and concentrated to give 3-(3-methylisoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydroquinoline-6-carboxylic acid (b) as a white solid (17.3 mg, 100%). 1H NMR (300 MHz, CD3OD) δ 8.19 (dd, J=6.4, 8.0 Hz, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.51-7.43 (m, 4H), 7.31-7.23 (m, 2H), 6.33 (s, 1H), 2.18 (s, 3H). MS: 347.2 (M+H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]([NH:16][CH:17]([CH3:19])[CH3:18])[C:10]=1[NH2:20])[CH2:2]2.[CH3:21][N:22]([CH3:28])[CH2:23][CH2:24][C:25]([O-])=[O:26].CN(C)CCC(O)=O.C(OC1C=CC2C(=CC=CC=2)N1C(OCC(C)C)=O)C(C)C>CN(C)C=O>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:10]([NH:20][C:25](=[O:26])[CH2:24][CH2:23][N:22]([CH3:28])[CH3:21])=[C:11]([NH:16][CH:17]([CH3:18])[CH3:19])[N:12]=[C:13]([Cl:15])[N:14]=1)[CH2:2]2
Reactant: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1N
Reactant: CN(C)CCC(=O)[O-]
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Agent: CN(C)CCC(=O)O
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(Cl)nc(N2CC3CCC(C2)O3)c1NC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N4-isopropylpyrimidine-4,5-diamine 3-(dimethylamino)propanoate (48, 0.500 g, 1.68 mmoles) was dissolved in dimethylformamide and 3-dimethylaminopropionic acid (0.310 g, 2.02 mmoles) and isobutyl 2-isobutoxyquinoline-1(2H)-carboxylate (IIDQ, 0.699 mL, 2.35 mmoles) were added. The reaction mixture was allowed to stir at room temperature for 18 hours, concentrated, and purified by silica gel column chromatography (5-10% ethanol in dichloromethane) to provide N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49) as a tan solid. Yield: 0.350 g (53%). LCMS (Waters walk-on); 2.43 min., 397.2, M+H.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].Cl.CONC.Cl.CN(C)[CH2:31][CH2:32]CN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](=[O:14])[CH:31]=[CH2:32])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Agent: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)CC)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of 2-[4-(ethylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (1.30 g) in N,N-dimethylformamide (20 mL) were added N-methoxymethanamine hydrochloride (582 mg), triethylamine (1.67 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (840 mg) and 1-hydroxybenzotriazole (670 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50-0:100, volume ratio) to give a colorless oil. A solution of the obtained oil in tetrahydrofuran (40 mL) was purged with nitrogen, and a 1.0M vinylmagnesium bromide tetrahydrofuran solution (12 mL) was added under ice-cooling. The reaction solution was warmed to room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio) to give the title compound (1.20 g, yield 90%) as a colorless oil. MS: 337 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[N:19]=[C:18]([CH:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:31]([CH3:33])[CH3:32])=[N:19][N:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ccc3ccccc3n2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
N-bromosuccinimide (21.03 g, 118 mmoles) was added in one portion to a solution of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (39.16 g, 118 mmoles) in 400 mL DMF at 0° C. under an inert atmosphere. The mixture was warmed to room temperature and stirred for 16 hours, then poured into 500 mL H2O and the resulting precipitate was collected. The precipitate was air dried on a vacuum filter for 16 hours to give 47.20 g (97%) of the title compound as a white solid, mp 110°-114° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([O:16]C)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CCC(C(=O)OC)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
1.075 Ml. of 1.6 molar n-butyllithium in hexane is added to a solution of 0.242 ml. of diisopropylamine in 15 ml. of dry tetrahydrofuran. 0.300 Ml. of hexamethylphosphoric triamide is added and the mixture is cooled to about -60° C. 0.465 G. of methyl (5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)acetate is added, and after 15 minutes, 0.137 ml. of ethyl iodide is added. The mixture is warmed slowly to room temperature and a further 0.05 ml. of ethyl iodide is added. After 30 minutes an additional 0.05 ml. of ethyl iodide is added. After 30 minutes, a few drops of methanol are added, and then ether and water are added. The organic layer is washed with water, dilute hydrochloric acid and saturated sodium chloride solution, then dried and evaporated to yield the impure product, which, after chromatography on 40 g. silica gel, eluting with hexane:ether (5:1) affords methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate. 0.326 G. of methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate is refluxed for 4 hours in 10 ml. of methanol and 20 ml. of water containing 0.5 g. of sodium hydroxide. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid. The product is extracted with ether and the extract washed, dried and evaporated to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyric acid (m.p. 147°-148° C).
Reaction SMILES: [CH:1]1[CH:6]=CC(/C=C/CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[CH:3][CH:2]=1.[O-]O.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1C(C)C)(C)[CH3:25]>>[CH2:6]=[CH:1][CH:2]=[CH2:3].[CH2:25]=[CH:24][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)c1ccccc1C(C)C
Agent: [O-]O
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
1.0 wt. parts of rosin salt as an emulsifier was added after 3 hours from the addition of diisopropylbenzene hydroperoxide as an oxidant at an initial reaction step, and thereafter 1.5 wt. parts of rosin salt were added after 8 hours.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[S:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.CCOCC>[OH:17][CH2:16][CH2:15][S:14][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: OCCSCCO
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CCc1ccc(OCCSCCO)cc1
Temperature: 22 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (30.0 g, 0.166 mol), 2,2′-thiodiethanol (61.0 g, 0.50 mol) and triphenylphosphine (48.0 g, 0.183 mol) in dry benzene (450 ml) was treated at 22° C. with diethyl azodicarboxylate (33.2 g, 0.19 mol) added dropwise over 10 min and the resulting mixutre was stirred at 22° C. for 5 h. The reaction mixture was then diluted with ether (300 ml) washed with water, saturated sodium bicarbonate and brine. After drying (magnesium sulfate) the solvent was evaporated in vacuo and the residue was chromatographed on silica gel (elution toluene-ethyl acetate 85:15) to give 37.64 g (79%) of the starting material as a white solid: mp 47-48° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:15]=1C=O.Cl.O.[CH3:26]O>>[CH3:23][O:22][C:18]1[CH:15]=[C:14]([O:13][CH3:12])[CH:21]=[CH:20][C:19]=1[CH:26]=[C:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8]1
Reactant: COc1cccc(OC)c1C=O
Reactant: CO
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: O
Product: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)c(OC)c1
Temperature: 25 °C

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 2,6-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. After the solution was cooled to room temperature, water 400 ml was added. The precipitated crystals were filtered, and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.95 g.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1>C(#N)C>[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[C:18]([N+:7]([O-:8])=[O:6])=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nn(C(=N)N)c(C)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2 g of nitronium tetrafluoroborate were added little by little to a suspension of 2.01 g of 3,5-dimethyl-1H-pyrazole-1-carboxamidine nitrate in 150 ml of absolute acetonitrile, with cooling with ice in argon atmosphere, and the reaction mixture was stirred for 30 minutes with cooling with ice. The solvent was removed by distillation under reduced pressure, and the residue was washed with chloroform to obtain 2.43 g of 3,5-dimethyl-4-nitro-1H-pyrazole-1-carboxamidine nitrate.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>ClCCl.CO>[C:1]([NH:9][CH2:10][CH:11]([CH:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)c1ccccc1)C(C)O
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Into a 200-ml stainless steel-made autoclave was placed 3.56 g (0.0143 mole) of methyl 2-benzamidomethyl-3-oxobutyrate. After nitrogen replacement, 7 ml of a separately prepared dichloromethane/methanol (7/1 by volume) mixed solvent solution containing 0.01 g (0.00894 mmole) of [RuI(p-Cymene)((-)-OcH-BINAP)]I as obtained in Example 5 was added. The resulting mixture was stirred at a hydrogen pressure of 50 kg/cm2 and a temperature of 65° C. for 20 hours. After the reaction, the reaction mixture was analyzed- by high-speed liquid chromatography. As a result, it was found that 2.79 g (percent yield: 78%) of methyl 2-benzamidomethyl-3-hydroxybutyrate had been formed and that the conversion was 80%, diastereomer selectivity 91.6%, and optical percent yield 99% ee.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18](O)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([F:17])[CH:8]=1.[O:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([C:18]([NH:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[C:9]([F:17])[CH:8]=1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Reactant: NC1CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (45 mg, 0.145 mmol), tetrahydro-2H-pyran-4-amine (14.7 mg, 0.15 mmol) and triethylamine (61.3 μl, 0.44 mmol) in dichloromethane (2 mL) a 50 wt % solution of 1-propanephosphonic acid cyclic anhydride (64.9 μl, 0.22 mmol) in ethylacetate was added. After stirring for 1 hr, the reaction mixture was diluted with dichloromethane (10 mL) washed with NaHCO3 solution (10 mL) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with dichloromethane to 20% methanol in dichloromethane to afford the title compound: (18 mg, 0.046 mmol).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[BrH:11].[OH-].[Na+]>C(O)(=O)C>[NH2:2][C:1]1[N:10]=[C:9]([Br:11])[C:8]2[CH:7]=[CH:6][S:5][C:4]=2[CH:3]=1
Reactant: N#CCc1sccc1C#N
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc2sccc2c(Br)n1
Yield: 70 %

Procedure:
2-Cyanomethyl-3-cyanothiophene (823 mg) was added to a solution (30 ml) of 25% hydrogen bromide in acetic acid, and the resulting mixture was stirred under ice-cooling for 90 min, which was neutralized with a 8N-aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with water, dried (over MgSO4) and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow solid (894 mg, yield; 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](O)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:27]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:31]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C(CCc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CCc2ccccc2)NS(=O)(=O)c2ccc(Br)cc2)cc1
Yield: 27 %

Procedure:
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-4-phenylbutanoic acid (310.3 mg) and ethyl 4-aminophenylacetate hydrochloride (201.6 mg) were condensed in THF (5 ml) in the presence of triethylamine (421.2 μl) and pivaloyl chloride (153.6 μl), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (117.6 mg).