Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[OH-].[K+:11].O>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O-:9].[K+:11]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: [O-]c1cc(Cl)ccc1Cl

Procedure:
A solution of 81.5 gm (0.50 mol) of 2,5-dichloro-phenol in 400 ml of xylene was boiled with 31.8 gm of 88% caustic potash (corresponding to 0.50 mol KOH) in a vessel equipped with an efficient water trap comprising a water-cooled phase separation tube until no more water separated out of the distillate. An anhydrous solution of potassium 2,5-dichlorophenolate in xylene was thus obtained. This solution was filtered and then charged into a shaker autoclave having a capacity of 2 liters, which had been warmed to 40° C. 104 gm (0.75 mol) of finely powdered, anhydrous potassium carbonate were then added to the contents, and the autoclave was flushed with carbon dioxide and then closed. The contents of the autoclave were now shaken for 25 minutes at 40° C. while introducing carbon dioxide at a pressure of 40 bars. Thereafter, the introduction of carbon dioxide was discontinued, and the contents of the autoclave were shaken at 140° C. for 15 hours, whereby the internal pressure rose to 70-80 bars. The contents of the autoclave were now allowed to cool to below 60° C., the pressure was released, and the autoclave was subsequently emptied by first rinsing it with xylene and then with a total of 700 ml of water. The xylene phases, including the solid matter contained therein, were combined. The solid matter was separated from the xylene mother liquor by suction filtration and then dissolved in the aqueous phase. The aqueous solution thus obtained was made strongly acid with concentrated hydrochloric acid, whereupon 3,6-dichloro-salicylic acid precipitated out. The precipitate was collected by suction filtration and, together with three liters of water, subjected to steam distillation. Any dichlorophenol and xylene still present passed over with the steam, whereas the desired product remained in the distillation vessel. When the distillate passing over was clear, the distillation was stopped. The contents of the distillation vessel were now filtered while still hot, and the filtrate was cooled, whereupon the product crystallized out. It was collected by suction filtration and dried (1st product fraction).
Reaction SMILES: [C:1]([N:20]=[N+:21]=[N-:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[C:24]#[CH:25]>CC(C)=O.CCOCC>[CH3:28][O:27][C:23]([C:24]1[N:22]=[N:21][N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=1)=[O:26]
Reactant: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(=O)OC
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a suspension of sodium azide (19.0 g: 0.283 Mol.) in dimethyl-formamide (130 ml) is added trityl chloride (76.0 g: 0.273 Mol.), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl azide. To a solution of this azide in acetone (300 ml) is added methyl propiolate (24 ml: 0.27 Mol.), and the mixture is heated under reflux for 6 days. The reaction mixture is cooled to the room temperature and diluted with ether. The separating crystals are collected by filtration to give 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (62.0 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][NH:18][CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](Cl)(Cl)=[O:38]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([CH:19]([CH:25]([CH3:26])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:37]2=[O:38])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NCCNc1ccc(OCc2ccccc2)cc1)C(C)C
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(C)C)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Ethyl 2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate (100 mg; 0.27 mmol) was dissolved in toluene (5 ml) and cooled to 0° C. DIEA (141 μl; 0.81 mmol) and phosgene (20% strength in toluene; 202 μl; 0.40 mmol) were added thereto. The mixture was allowed to reach RT over the course of 3 h, and then the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×; 5 ml). The combined organic phases were dried over MgSO4. After removal of the solvent whilst under reduced pressure, ethyl 2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (90 mg; 0.22 mmol) was obtained. MS: 397.15 (M+H); Rt: 1.90 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CCN=C=O
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CCNC(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanate (0.404 g, 0.0057 mole) is added to a solution of 1.64 g (0.005 mole) of 2,6 bis(1,1-dimethylethyl)-4-[(hydroxyamino)phenylmethyl]phenol in 50 mL toluene. After stirring at room temperature for 30 minutes the reaction mixture is concentrated to half its volume (rotary evaporator) and diluted with n-hexane. The solid is filtered off, washed with n-hexane, and recrystallized from Et2O-cyclohexane to give white crystals, 1.35 g (68%), m.p. 158°-159.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([CH3:13])=[CH:9]2)([CH3:3])[CH3:2].[CH3:14]N(C=O)C.[H-].[Na+].IC>CCOCC>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:14])[C:10]([CH3:13])=[CH:9]2)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc2cccc(C(C)C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: Cc1cc2cccc(C(C)C)c2n1C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 7-isopropyl-2-methyl-1H-indole (0.75 g, 4.33 mmol) and DMF (2 mL) is added 60% NaH (0.19 g, 4.76 mmol). After 30 minutes iodomethane (0.30 mL, 4.76 mmol) is added and the solution stirred for 1 hour. The solution is diluted with Et2O (30 mL), washed with water (2×20 mL), brine (20 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (2%-5% EtOAc gradient) to furnish the title compound (0.33 g, 1.76 mmol, 41%). 1H NMR (CDCl3), δ 1.42 (d, J=6.5 Hz, 6H), 2.43 (s, 3H), 3.84-3.91 (m, 1H), 6.24-6.27 (m, 1H), 3.93 (s, 1H), 6.29 (s, 1H), 7.01-7.14 (m, 1H), 7.38 (d, J=7.5 Hz, 1H) ppm. LC/MS (m/z): calcd. for C13H17N (M+H)+: 188.2. found: 188.1.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.[CH3:41][NH:42][CH3:43]>C1COCC1.O>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([S:23]([CH2:26][CH2:27][N:42]([CH3:43])[CH3:41])(=[O:24])=[O:25])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: CNC
Reactant: C=CS(=O)(=O)N1CCC(n2ncc3c(N4CCOCC4)nc(-n4c(C(F)F)nc5c(OC)cccc54)nc32)CC1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(=O)(=O)CCN(C)C)CC3)c2n1
Reaction time: 0.17 h
Yield: 93 %

Procedure:
A suspension of the above vinylsulfonamide (140 mg, 0.243 mmol) in 100 mL THF was treated with 10 mL of 40% aq. dimethylamine to give a clear solution. After 10 min, the mixture was diluted with water and the THF was removed under vacuum to give 140 mg (93% yield) of N-[2-({4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl}sulfonyl)ethyl]-N,N-dimethylamine as a white solid: 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.98 (m, 1H), 3.91 (m, 4H), 3.18-3.07 (m, 4H), 2.80 (dd, J=8.3, 6.4 Hz, 2H), 2.41 (dq, J=11.7, 4.2 Hz, 2H), 2.29 (s, 6H), 2.14 (dd, J=12.5, 2.5 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]([Cl:27])=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)=[CH:15][CH:14]=[CH:13][CH:12]=2.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:27][C:9]1[C:8]([NH:7][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:17]([NH:18][CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere butyryl chloride (322 μL, 3.11 mmol) was added dropwise was added to a suspension of 4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol (0.92 g, 2.83 mmol) in dichloromethane (28 mL). After 2 hours triethylamine (0.79 mL, 5.66 mol) was added and the reaction mixture was stirred for 2 hours. More butyryl chloride (0.2 mL) and triethylamine (0.30 mL) were added. The reaction mixture was stirred for an additional hour and then diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (3×60 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (40 mL) and brine (30 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide N-(2-chloro-4-{[(4-hydroxytetrahydro-2Hthiopyran-4-yl)methyl]amino}quinolin-3-yl)butanamide as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:26])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[CH:8]=1)=[O:3].ClC1C=CC=C(C(OO)=[O:35])C=1>>[CH3:1][S:2]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:26])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[CH:8]=1)(=[O:35])=[O:3]
Reactant: CS(=O)c1cc(C(=O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)c1cc(CC(=O)c2c[nH]c(S(C)(=O)=O)c2)cc(C(C)(C)C)c1O

Procedure:
For example, using 2-methylsulfinyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)-1-oxo-ethyl]pyrrole in this general reaction together with one molar equivalent of m-chloroperbenzoic acid yields 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)-1-oxo-ethyl]pyrrole (a compound according to Formula X wherein: m is 1; n is 1; R is H; and X is SO2CH3 ; and Y and Z are each H).
Reaction SMILES: S(O)(=O)(=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14]O)[CH2:12][C:11]2=[CH:16][CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH:13]([CH2:14][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][C:11]2=[CH:16][CH:17]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)C(CO)C2
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(CN1CCCCC1)C2

Procedure:
A solution of 5-methoxy-1-hydroxymethylbenzocyclobutene mesylate (38 g) and piperidine (45 ml) in toluene (180 ml) is refluxed under nitrogen for about 12 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo leaving a liquid residue which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C([C:23]2[O:27]N=C(C(=O)C)C=2)C=CC=1.[BH4-].[Na+]>CO>[CH3:23][O:27][C:13]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)=[O:15]
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(Cl)c2)on1

Procedure:
A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) in MeOH (60 ml) was heated at 80° C. for 4 h. After cooling, the mixture was filtered and washed with cold methanol to afford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (2.0 g, 71%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). Step 2: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw cap vial equipped with stir bar was mixed methyl magnesium iodide (3M in Et2O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39 ml, 4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to 0° C. a solution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300 mg, 1.19 mmol) in toluene (5 ml) was added, followed by stirring at 0° C. for 5 h. The mixture was then quenched with aq 1N HCl (6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentially washed with water, sat. aq. sodium bicarbonate,water and brine. The organic phase was concentrated in-vacuo. The isolated residue was dissolved in MeOH (8 ml) and 20% aq. KOH (1 ml) was added, followed by stirring at 45° C. for 30 min and then concentrated in-vacuo. The residue was dissolved in toluene (60 ml), sequentially washed with water, sat. aq. sodium bicarbonate and water. The organic phase was concentrated in-vacuo. The crude residue was purified on silica gel using 2% EA in hex. to isolate the desired compound (156 mg, 60%). 1H-NMR: 7.77 (m, 1H), 7.66 (m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vial equipped with stir bar was mixed 1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol), sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed by stirring at r.t for 3 h and the quenched with water and brine, extracted with DCM. The combined organic phase was dried (Na2SO4), filtered and concentrated in-vacuo to isolate the title compound. 1H-NMR: 7.69 (m, 1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br. s, 1H), 1.58 (d, 3H).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=O)=[C:11]([O:23][CH3:24])[C:10]=1[O:25][CH3:26])=[O:8])([CH3:5])[CH3:4].S(Cl)(Cl)=O>CCOCC>[CH3:26][O:25][C:10]1[C:11]([O:23][CH3:24])=[C:12]([C:15]2[O:20][CH2:19][C:18]([CH3:21])([CH3:22])[N:17]=2)[CH:13]=[CH:14][C:9]=1[C:7]1[O:8][CH2:5][C:3]([CH3:2])([CH3:4])[N:6]=1
Reactant: COc1c(C(=O)NC(C)(C)CO)ccc(C(=O)NC(C)(C)CO)c1OC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1c(C2=NC(C)(C)CO2)ccc(C2=NC(C)(C)CO2)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
To 6.00 g (16.3-mmol) of N,N'-bis(2-hydroxy-1,1-dimethylethyl)-2,3-dimethoxy-1,4-phenylenedicarboxamide, was added 7.0 mL (96.0 mmol) of thionyl chloride. The mixture was stirred at room temperature for 3 hours. Further thereto, 7.0 mL (96.0 mmol) of thionyl chloride was added, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into 50 mL of ether. The supernatant liquid was removed by decantation. Aqueous 10% sodium hydroxide solution was added to the residue to bring the pH to 8. It was extracted with ether, and was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by silca gel column chromatography (methylene chloride:ethanol=20:1) to obtain 2.52 g (47%) of 2,2'-(2,3-dimethoxy-1,4-phenylene)-bis (4,4-dimethyl-2-oxazoline) in a colorless crystal state.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)C.[S-2:27].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([SH:27])[N:10]=[C:9]([CH3:17])[C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: [S-2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(S)c([N+](=O)[O-])c1NCCCN(C)C

Procedure:
34.5 g. of 4-[[3-(dimethylamino)propyl]amino]-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester are dissolved in 100 ml. of ethanol. 15 g. of sodium sulfide in 10 ml. of water are added and the mixture is stirred without cooling for 1 hour. After this time, the precipitated 4-[[3-(dimethylamino)propyl]amino]-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is filtered off and recrystallized from methanol, yield 18 g. (53%), m.p. 131°-132°.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8]>CN(C)C=O>[OH:4][CH2:3][CH:2]([NH:1][CH:8]=[CH:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH3:5]
Reactant: CC(N)CO
Reactant: C#CC(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=CNC(C)CO
Reaction time: 6 h

Procedure:
3.76 g (50 mmol) of 2-amino-1-propanol (III: R=methyl) was added to 100 ml of dimethylformamide and cooled. To this, 4.91 g (50 mmol) of ethyl propiolate (II, R1 =ethyl) was slowly added dropwise. The reactant mixture was stirred at not more than 5° C. for 6 hours and further stirred at room temperature for 2 hour.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[S:5][CH:6]=[C:7]([C@@H:9]2[CH2:13][C@@H:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[N:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:3]([C:4]1[S:5][CH:6]=[C:7]([C@@H:9]2[CH2:13][C@@H:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[N:8]=1)=[O:2]
Reactant: COC(OC)c1nc([C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(C=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Yield: 95.7 %

Procedure:
To a solution of (2S,4R)-2-[2-(dimethoxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.6 g) in acetone (100 ml) was added p-toluenesulfonic acid (0.49 g) at room temperature. After stirring under reflux for 1 hour, the mixture was evaporated. The residue was dissolved in ethyl acetate, washed in turn with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The organic layer was evaporated to give (2S,4R)-2-(2-formylthiazol -yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl) -pyrrolidine (2.26 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:6]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: Cc1ccc(-n2cnnn2)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4C)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C@H:7]([O:10]C(=O)CCCCCCCCCCC)[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].CO.S(=O)(=O)(O)O>O>[CH3:1][CH:2]([C@H:7]([OH:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCC(=O)O[C@H](CC)C(C)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC[C@@H](O)C(C)C(=O)OC
Yield: 38.5 %

Procedure:
A mixture of 3.5 g of methyl (3R )-2-methyl-3-dodecanoyloxypentanoate, 12 ml of methanol and 0.5 ml of concentrated sulfuric acid was refluxed for 8 hours, and 20 ml of water was added thereto followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate and ether was distilled away, and then the residue was distilled to give 0.6 g of methyl (3R)-2-methyl-3-hydroxypentanoate of the following formula, b.p. 52.5° C. (2.5 mm Hg), [α]D30 =-10.7° (C=0.61, CHCl3). ##STR97## This compound was converted to (+)-MTPA ester according to a procedure similar to Example 1-(5) and the optical purity determined by 1H-NMR was 95% ee. The NMR chart is shown in FIG. 4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1>CN(C=O)C>[NH2:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: NCc1cccc2c(Cl)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Temperature: 100 °C

Procedure:
A mixture of C-(4-chloroquinolin-8-yl)methylamine (Preparation 89) (129 mg, 0.67 mmol), K2CO3 (186 mg, 1.34 mmol) and 4-hydroxybenzamide (110 mg, 0.81 mmol) in DMF (4 mL) were heated in a microwave at 100° C. for 40 min (150 W). Solvent removed in vacuo. The mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the aqueous phase was further extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (20 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (0.25% to 0.75% NH4OH(aq), 2% to 8% MeOH in DCM) to give the title compound: RT=2.15 min; m/z (ES+)=294.1 [M+H]+.