Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].ClCCl.C(O)C>O>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: O=C(O)CO
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)O
Yield: 148.3 %

Procedure:
6 g of a lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 7,500 (lactic acid/glycolic acid=75/25 (mol %)) (Wako Pure Chemical Industries, Ltd.) was dissolved in a mixed solvent consisting of 60 ml of dichloromethane and 60 ml of ethanol. While thus obtained solution was cooled and stirred, 3.83 g of 1-ethyl-3-(3-dimethylaminoisopropyl)-carbodiimide hydrochloride was added and then the reaction mixture was stirred overnight. After 50 ml of water was added, dichloromethane phase was separated. The dichloromethane phase was washed 2 times with 40 ml of 10% ethanol-water and dried with magnesium sulfate. After magnesium sulfate was separated by filtration, the mixture was concentrated to dryness under reduced pressure to yield 5.2 g of the ethyl ester of lactic acid/glycolic acid copolymer.
Reaction SMILES: [Mg].[C:2]([CH2:21][CH2:22]I)([C:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3].Cl.C(Cl)(Cl)Cl>C(OCCC)CC.CI>[C:2]([CH2:21][CH2:22][CH2:22][CH2:21][C:2]([C:5]([C:8]([C:11]([C:14]([C:17]([F:18])([F:19])[F:20])([F:15])[F:16])([F:12])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3])([C:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])[F:3]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Agent: Cl
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: CCCOCCC
Solvent: CI
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 63.4 %

Procedure:
In accordance with K. von Werner, DE 39 25 525 Al (1989), in a four-necked flask of 250 cm3 capacity, which is equipped with a dropping funnel (with bypass for pressure equalization), vane stirrer, thermometer and reflux condenser with superimposed check valve, 1.82 g (0.075 mol) magnesium chips are placed under argon in 10 cm3 of anhydrous di-n-propyl ether and activated with a few drops of methyl iodide with gentle heating. The temperature is raised to 80° C. while a mixture of 23.7 g (0.05 mol) of C6F13CH2CH2I and 60 cm3 of anhydrous di-n-propyl ether is added drop by drop within one hour with vigorous stirring. Then the mixture is stirred with refluxing for 9 hours and then cooled to 10° C., hydrolyzed with 100 cm3 of 5 wt.-% aqueous hydrochloric acid until the excess magnesium has dissolved. Then the ether phase is separated and concentrated with a rotary evaporator. The oily residue thus obtained is treated with 30 cm3 of chloroform and let stand for 1 hour at 0° C. The solid product precipitated from the mixture is suction filtered and dried in the desiccator. 11.0 g of C6F13(CH2)4C6F13 is obtained as nearly colorless crystals which have a melting point of 48° C. The yield is 63.2% of the theoretical.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12]O)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:15]>C1COCC1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][Br:15])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrP(Br)Br
Reactant: Nc1nccc2ccc(CO)cc12
Solvent: C1CCOC1
Product: Nc1nccc2ccc(CBr)cc12
Reaction time: 1 h

Procedure:
1-Amino-7-hydroxymethylisoquinoline (0.2 g) was dissolved in dry THF (10 ml.) and phosphorous tribromide (0.03 ml.) added in one portion. A white precipitate was seen to form and the suspension was stirred for 1 hr. at room temperature. The mixture was evaporated to dryness and triturated with diethylether to give the product.
Reaction SMILES: [Mg].[Br-].[CH:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:4].C(C1C=C([Mg]Br)C=CC=1)=C.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].[Cl-].[NH4+]>O1CCCC1>[CH:3]([C:5]1[CH:10]=[C:9]([C:21]([OH:23])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])[CH:8]=[CH:7][CH:6]=1)=[CH2:4].[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: C=Cc1ccccc1
Agent: C=Cc1cccc([Mg]Br)c1
Agent: [Br-]
Agent: [Cl-]
Solvent: CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1cccc(C(C)(O)c2ccccc2)c1
Reaction time: 1 h

Procedure:
To a 2 liter three-neck flask equipped with a dropping funnel, a reflux condenser and a stirrer was added 25.5 g (1.05 mole) of metallic magnesium and it was dried sufficiently by supplying dry nitrogen gas. After that, 50 ml of tetrahydrofuran which had been dried with a molecular sieve 5A, was put into the flask and the contents were stirred vigorously. A solution of 183 g (1.0 mole) of 3-vinylbenzene bromide in 500 ml of dried tetrahydrofuran was then dropped little by little over 2 hours. The reaction temperature was maintained 75° to 80° C. and, after the addition of the solution, the stirring was continued for further 1 hour as it stands. Into the thus obtained Grignard reagent of 3-vinylphenylmagnesium bromide, a solution of 122.6 g (1.02 mole) of acetophenone in 500 ml of dried tetrahydrofuran was dropped little by little over 2 hours. The reaction temperature was maintained at 75° to 80° C. and, after the dropping, the stirring was continued for further 1 hour as it stands. The reaction mixture was then poured into 3 liter of an aqueous solution of 75 g of ammonium chloride and it was left to stand still for 20 hours and an oily layer was recovered to obtain 1-(3-vinylphenyl)-1-phenylethyl alcohol in a yield of 89% (acetophenone basis) by distilling off the tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO.ClCCl>[F:18][C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CC1CCN(c2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Yield: 93.9 %

Procedure:
The procedure of Example 4, step (b) was followed using 88 mg (0.19 mmol based on 60% purity by 1H-NMR) of 1-(5-chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the previous step) and 105 μL (0.950 mmol) of 1-methylpiperazine at 150° C. for 16 h. Chromatography on a 10-g silica SPE column with 24% MeOH-dichloromethane afforded 60 mg (94%) of the title compound as a crystalline orange solid: Mass spectrum (ESI, m/z): Calcd. for C17H25FN4O2, 337.2 (M+H), found 337.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][NH:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][N:12]([C:23](=[O:24])[C:22]4[CH:21]=[C:20]([O:19][CH3:18])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCC1(c2ccc3c(c2)OCO3)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc4c(c3)OCO4)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-(3-benzo[1,3]dioxol-5-yl-pyrrolidin-3-yl)-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=2)[C:9]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18].C([O-])(O)=O.[Na+]>CO>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=2)[C:9]([NH:17][OH:18])=[NH:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C#N)cc(C2CCCC2)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=N)NO)cc(C2CCCC2)n1
Temperature: 60 °C
Reaction time: 18 h
Yield: 113.1 %

Procedure:
To a solution of 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g, 10.3 mmol) in methanol (100 mL), hydroxylamine hydrochloride (2.15 g, 31.0 mmol) and NaHCO3 (3.04 g, 36.2 mmol) are added. The mixture is stirred at 60° C. for 18 h before it is filtered and the filtrate is concentrated. The residue is dissolved in EA (300 mL) and washed with water (30 mL). The washings are extracted back with EA (4×100 mL) and DCM (4×100 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried under HV to give the title compound (2.74 g) as a white solid; LC-MS**: tR=0.47 min, [M+1]+=236.24; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.92-2.01 (m, 2H), 3.04-3.13 (m, 1H), 3.84 (s, 3H), 5.90 (s, 2H), 6.86 (s, 1H), 7.13 (s, 1H), 9.91 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[CH:10](C(OCC2C=CC=CC=2)=O)[CH:9]1[C:25]([O:27]CC1C=CC=CC=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[C:11](=[O:14])[CH2:10][CH:9]1[C:25]([OH:27])=[O:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1C(=O)C(C(=O)OCc2ccccc2)C(C(=O)OCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: CC1C(=O)CC(C(=O)O)N1C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
To a suspension of 600 mg of 10% Pd—C in 25 mL of 2-propanol was added a solution of 8.9 g of crude 5-methyl-4-oxo-pyrrolidine-1,2,3-tricarboxylic acid 2,3-dibenzyl ester 1-tert-butyl ester in 100 mL of 2-propanol. The reaction was shaken under 60 psi of H2 for 1.5 h, then filtered and concentrated to an oil. This was taken up in 20 mL of 2M NaOH(aq.) and extracted with diethyl ether (3×15 mL) to remove the mineral oil introduced in the previous step. The ether layers were set aside, and the aqueous layer was cooled with an ice bath, then acidified with 10 mL of 6M HCl(aq.). The suspension was extracted with diethyl ether (3×15 mL), then the ether layers were extracted with brine (1×15 mL), dried over MgSO4, filtered, and concentrated to an oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([CH:16]=[CH2:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])C=C>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:9]([O:8][CH2:7][C@H:6]1[O:5][C:1](=[O:4])[CH:17]=[CH:16]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=CC(=O)O[C@@H](C=C)COCc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: O=C1C=C[C@@H](COCc2ccccc2)O1
Yield: 98.5 %

Procedure:
To a solution of acrylate (12) (1.87 g, 8.05 mmol) in CH2Cl2 (700 mL) was added second generation Grubbs' catalyst (4 mol %, 170 mg, 0.322 mmol). The reaction mixture was refluxed for 5 hours, and the solvent then was removed under reduced pressure. Column chromatography on silica gel (30% EtOAc in hexanes as the eluent) yielded the furanone (13) (1.62 g, 98%) as a brown oil, Rf=0.15 (30% EtOAc in hexanes), [α]25D −81.3° (c 1.09, MeOH); 1H-NMR (500 MHz, CDCl3) δ: 3.66 (dd, 1H, J=5.0, 5.5 Hz), 3.71 (dd, 1H, J=5.0, 5.2 Hz), 4.57 (s, 2H), 5.17 (m, 1H), 6.16 (dd, 1H, J=1.9, 3.8 Hz), 7.29-7.37 (m, 5H), 7.48 (dd, 1H, J=1.4, 4.3 Hz); 13C-NMR (125.8 MHz, CDCl3) δ: a 69.86, 74.18, 82.61, 123.03, 128.42, 128.95, 137.69, 154.32, 173.19.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH2:26])=[CH:19][CH:18]=1>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([NH:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(OCCN)cc1
Reactant: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(OCCNc2nc(C(C)(C)C)cn3c(=O)[nH]nc23)cc1
Temperature: 80 °C

Procedure:
To a solution of 60 mg of 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one and 100 mg of 2-p-tolyloxy-ethylamine hydrochloride in DMF (2.0 mL) was added 60 mg of TEA. The mixture was heated to 80° C. for three h and then was cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was washed with sat. sodium chloride solution and then dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford the title compound as a white solid. MS (M+H+)=342.5.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH3:33])=[N:28][O:29][C:30]=2[CH2:31][OH:32])=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:27]([CH3:33])=[N:28][O:29][C:30]=2[CH:31]=[O:32])=[O:19])=[CH:16][CH:17]=1
Reactant: Cc1noc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
To a round bottomed flask was added CH2Cl2 (15 mL) and oxalyl chloride (0.24 mL, 2.75 mmol). The solution was cooled to −78° C. before addition of DMSO (0.29 mL, 4.13 mmol) and the reaction stirred at −78° C. for 15 minutes before addition of (4-chlorophenyl)(2-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)phenyl)methanone (0.451 mg, 1.38 mmol) dissolved in CH2Cl2 (5 mL). The reaction was stirred an additional 15 min at −78° C. before addition of Et3N (0.959 mL, 6.88 mmol) and removal of the cold bath. After warming to room temperature water was added and the layers separated. The aqueous was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazole-5-carbaldehyde (0.448 g, 1.38 mmol). LC/MS m/z 326 [M+H]+.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1.C(#N)C.C([O-])(=O)C.[K+]>O.ClCCl>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[C:6]3[C:7]([O:11][CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=2)[CH:41]=[CH:40][N:39]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Temperature: 100 °C
Yield: 66.5 %

Procedure:
To a microwave vial was charged 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.00 g, 1.70 mmol), 2-chloropyridin-4-ylboronic acid (0.281 g, 1.79 mmol) and bis(diphenylphosphino)ferrocenepalladium chloride (139 mg, 0.170 mmol). Acetonitrile (11 mL, 210 mmol) and 1.0 M of potassium acetate in water (4.1 mL) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100° C. under microwave irradiation for 30 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite® and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-100% EtOAc in heptane to give the title compound (0.648 g, 66%). LC-MS (Method H): m/z=573.4 [M+H]+; 1.56 min. 1H-NMR (400 MHz, CDCl3): δ 8.37 (d, J=5.2, 1H), 8.13 (s, 1H), 7.80 (d, J=5.2, 1H), 7.54 (d, J=6.2, 1H), 7.35-7.27 (m, 9H), 7.22-7.14 (m, 6H), 5.90 (d, J=6.2, 1H), 5.55-5.46 (m, 1H), 4.01-3.92 (m, 2H), 3.69-3.60 (m, 2H), 2.23-2.13 (m, 2H), 1.99-1.87 (m, 2H).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:26]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:12][CH:13]=1)([CH3:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(SC)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
Anhydrous dimethylformamide (7 ml) was added to 256 mg of methyl α-methylthio[p-(1-oxo-2-isoindolinyl)phenyl]acetate. With ice cooling and stirring, 35 mg (65% content) of sodium hydride was added. The mixture was stirred for 10 minutes at room temperature and again cooled with ice. Methyl iodide (0.1 ml) was added, and the mixture was stirred for 5 minutes. Addition of an aqueous solution of ammonium chloride (100 mg/30 ml) resulted in the precipitation of colorless crystals. The crystals were collected by filtration, washed with 20 ml of water and then with 10 ml of n-hexane, and dried to afford 191 mg of methyl α-methylthio-α-[p-(1-oxo-2-isoindolinyl)phenyl]propionate. The filtrate and the washing were combined and extracted three times with 20 ml of methylene chloride. The extract was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with 10 ml of n-hexane to afford 39 mg of methyl α-methylthio-α-[p-(1-oxo-2-indolinyl)phenyl]propionate. The total amount of the product was 230 mg (yield 86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([CH:17]([O:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[I-].[Na+].P(O)([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:13][O:12][C:10]([CH:9]([NH:14][C:15]([CH:17]([O:22][C:23](=[O:31])[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:28][CH:29]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:16])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][CH:4]=1)=[O:11]
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(=O)C(OC(=O)c1ccc(O)cc1)C(=O)OC
Agent: O=P([O-])([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CC(NC(=O)C(OC(=O)c2ccc(OCC(=O)OC)cc2)C(=O)OC)C(=O)OC)cc1

Procedure:
To a mixture of 4-hydroxy-benzoic acid [2-(4-hydroxy-phenyl)-1-methoxycarbonyl-ethyl carbamoyl]-methoxycarbonylmethyl ester 17 (10.7 grams, 24.82 mmol) anhydrous potassium carbonate (17.5 grams, 126.62 mmol), sodium iodide (3 grams, 20.01 mmol), and disodium phosphate (3 grams, 21.13 mmol) in anhydrous acetone (100 mL) is added methyl chloro acetate (7 grams, 64.5 mmol). The mixture is refluxed for 10 hours. Acetone is distilled off, and water (100 mL) is added. Crude 18 is filtered, dried, and can be purified in appropriate solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.[OH-].[Na+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH2:12][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([OH:11])[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: CCCC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 25 °C
Yield: 61.9 %

Procedure:
A solution of 20.5 g (0.077 mol) of 2-(4-chlorophenylethyl)-2-(1,1-dimethylbutyl)-oxirane, 5.3 g (0.077 mol) of 1,2,4-triazole, 1.0 g (0.025 mol) of sodium hydroxide, 1 ml of water and a spatula tipful of α,α'-azoisobutyronitrile in 50 ml of N-methylpyrrolidone is heated at 120° C. for 5 hours. After this, the solution is cooled to room temperature and concentrated by stripping off the solvent under reduced pressure, the remaining residue is dissolved in acetic acid and washed three times with water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel; dichloromethane:ethyl acetate=4:1). In this manner 16.0 g (61.9% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-3-(1,2,4-triazol-1-yl-methyl)-3-heptanol are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:1][C:2](=[O:3])[CH2:4][CH2:5]2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1CCc2cc(C(=O)c3ccccc3)ccc2N1

Procedure:
A mixture of 2.2 g of 3,4-dihydrocarbostyril, 3.21 g of benzoyl chloride and 13 g of aluminum chloride in 50 ml of carbon disulfide was refluxed for 2 days. The reaction mixture was poured onto ice water and the resulting solid filtered off, washed with water and dried under reduced pressure to yield 6-benzoyl-3,4-dihydrocarbostyril, m.p. 205°-207° C.
Reaction SMILES: O=O.[CH3:3]C(C)([O-])C.[K+].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].CI>C1COCC1.O>[CH3:3][CH:10]([C:11](=[O:12])[CH3:13])[C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: O=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)C(C)=O
Reaction time: 1 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere free of water and oxygen, to a three-necked flask equipped with a dropping funnel were successively added 0.15 mol of potassium tert-butoxide and 150 ml of THF, then stirrer was started. 0.12 Mol of ethyl acetoacetate was slowly dropped to the reactor cooled in an ice-water bath. Upon completion of the dropping, the reaction was continued at room temperature for further 1 hr. Then 0.18 mol of methyl iodide was slowly dropped at room temperature, and then the reaction was continued at room temperature for further 24 hrs. At the end of the reaction, solvent was evaporated by using a rotatory evaporator, and saturated saline was added to just dissolve the solid. Organic phase was separated, and aqueous phase was extracted with a suitable amount of diethyl ether for three times. The combined organic phase was washed well with saturated saline, then dried over anhydrous sodium sulfate. Solvent was removed by using a rotatory evaporator, and the residue was distilled under reduced pressure to give 0.084 mol of product. Yield 70%.
Reaction SMILES: [ClH:1].P([O-])([O-])([O-])=O.[CH2:7]([O:14][C:15]([N:17]([CH2:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=2)[CH2:29][CH2:28][N:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+]>C(O)C>[ClH:1].[CH2:7]([O:14][C:15]([N:17]([CH2:25][CH:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH3:39])=[C:33]([O:36][CH3:37])[CH:34]=2)[CH2:29][CH2:28][NH:27]1)[C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc2c(cc1OC)C(CN(C(=O)OCc1ccccc1)c1ccc(C)cc1)=NCC2
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(CN(C(=O)OCc1ccccc1)c1ccc(C)cc1)NCC2

Procedure:
A mixture of hydrochloride and phosphate of 1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline (4.6 g) was dissolved in 99% ethanol (45 ml). To the solution was added sodium borohydride (0.8 g) with stirring under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure and to the residue was added water. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The oil obtained was treated with ethanol containing hydrochloric acid to give 1-(N-benzyloxycarbonyl-p-toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.3 g), mp 189° to 190° C.