Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:15][C:14]2=[CH:38][CH:39]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH:27][C@H:16]2[CH2:15][C:14]3=[CH:13][CH:12]=[C:11]([CH:39]=[CH:38]3)[O:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([CH:3]=[O:2])[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:24])[CH3:25])[NH:18][C:17]2=[O:26])(=[O:29])=[O:30])=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(=O)(=O)c2ccc(F)cc2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1NC(=O)[C@@H](NS(=O)(=O)c2ccc(F)cc2)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 53 (100 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.98 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 16 mg, 17%. Rf=0.35 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][N:15]=2)=[N:5][N:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>ClCCl.CO>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[N:5][N:4]=2)=[CH:23][CH:22]=1
Reactant: Clc1nnc(Cc2ccncn2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Clc1ccc(Nc2nnc(Cc3ccncn3)c3ccccc23)cc1

Procedure:
A mixture of 100 mg (0.45 mmol) 1-chloro-4-(4-pyrimidinylmethyl)phthalazine hydrochloride and 149 mg (1.17 mmol) 4-chloroaniline is heated for 1.5 h to 100° C. The reaction mixture is distributed between dichloromethane/CH3OH, 19:1 and sat. NaHCO3solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4), and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH, 19:1) and crystallization from ethyl acetate/ether yield the title compound: m.p.: 174-176° C.; FAB MS (M+H)+=348. The starting material is prepared as follows:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl.CN(C1C=CC=CN=1)C>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=C1CCCCN1c1ccccc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2N2CCCCC2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
Dimethylaminopyridine (1.83 g, 15 mmol, 0.05 eq) and triethylamine (63.5 ml, 450 mmol, 1.5 eq) are added to a solution of 1-[2-(2-hydroxyethyl)phenyl]piperidin-2-one a2-2 (65.7 g, 300 mmol, 1 eq) in dichloromethane (250 ml) at 0° C. The mixture is stirred at 0° C. for 15 minutes, then a solution of 4-toluenesulfonyl chloride (63 g, 330 mmol, 1.1 eq) in dichloromethane (250 ml) is added dropwise. The reaction mixture is then warmed up to room temperature and stirred overnight. The reaction mixture is washed with water, 1N HCl, then dried over MgSO4, filtered and evaporated under vacuum. The residue is purified by chromatography over silicagel (gradient: CH2Cl2/MeOH from 100/0 to 98/2) to afford 99 g of 2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl 4-methylbenzenesulfonate a2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10]C(O)=O)=[C:4]([CH:14]=O)[CH:3]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][CH:10]=[CH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(Cl)cc(C=O)c1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc2ccoc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.4 %

Procedure:
A solution of [(4-chloro-2-formyl-6-methylphenyl)oxy]acetic acid (4.69 mmol) in acetic anhydride (20 mL) was treated with sodium acetate (14.07 mmol). The resulting solution was heated to reflux and stirred for three days. The brown reaction solution was allowed to cool to room temperature, and was diluted with toluene (10 mL). The solution was then treated with 1N aq NaOH (10 mL) and was stirred at room temperature for 20 min. The solution was then further diluted with water (50 mL) and was extracted using ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue was purified by flash chromatography (hexanes) to provide the title compound as a clear oil (120 mg, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=2.27 Hz, 1H) 7.55 (d, J=1.77 Hz, 1H) 7.20 (d, J=1.01 Hz, 1H) 6.94 (d, J=2.27 Hz, 1H) 2.47 (s, 3H).
Reaction SMILES: [BH4-].[Na+].F[C:4](F)(F)[C:5]([OH:7])=[O:6].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].C(O)(=O)CC(O)=O.N1CCCCC1>N1C=CC=CC=1.O1CCCC1.O1CCOCC1>[C:5](/[CH:4]=[CH:16]/[C:15]1[CH:18]=[CH:19][C:12]([CH2:10][NH2:11])=[CH:13][CH:14]=1)([OH:7])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=C(O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: NCc1ccc(/C=C/C(=O)O)cc1

Procedure:
Into a mixture of 0.946 g of sodium borohydride and 100 ml of tetrahydrofuran, a mixed solution of 2.850 g of trifluoroacetic acid and 20 ml of tetrahydrofuran, was dropwise added under stirring and cooling with ice. After the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was stirred for one hour. Then, a solution obtained by dissolving 4.325 g of 4-cyanociannamic acid obtained by heating and condensing 4-cyanobenzaldehyde with malonic acid in pyridine in the presence of a catalytic amount of piperidine, in 140 ml of tetrahydrofuran and 30 ml of 1,4-dioxane, was dropwise added to the reaction mixture, and stirred at room temperature for 2.5 hours. After cooling, ice pieces were added to decompose the excess reducing agent. Then, the reaction mixture was concentrated, and the precipitated powder was collected by filtration and subjected to vacuum drying to obtain 3.50 g of the above identified compound as a colorless powder.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:34]=[C:35]([S:54][CH3:55])[N:36]2[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][C:37]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:34]=[C:35]([S:54][CH3:55])[N:36]2[CH:40]=[C:39]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:38][C:37]=12)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(SCCN=[N+]=[N-])c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CSc1nc(SCCN=[N+]=[N-])c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 53.4 %

Procedure:
The procedure of Example 1a) was repeated, except that 300 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 485 mg of 7-(2-azidoethyl)thio-5-methylthio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 272 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-azidoethyl)thio-5-methylthioimidazo-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:27]2[CH2:28][CH2:29][C@H:25]([F:24])[CH2:26]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: F[C@H]1CCNC1
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CC[C@H](F)C2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 352 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.88 mmol) and (S)-3-fluoro-pyrrolidine (165 mg, 1.32 mmol). MS: [M+H]+=392.
Reaction SMILES: [F:1][C:2]([F:6])([S:4]Cl)[CH3:3].[P:7]([O:16]CC)([O:13][CH2:14][CH3:15])[S:8][CH:9]([CH2:11][CH3:12])[CH3:10]>ClCCl>[P:7]([S:4][C:2]([F:6])([F:1])[CH3:3])([O:13][CH2:14][CH3:15])([S:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:16]
Reactant: CC(F)(F)SCl
Reactant: CCOP(OCC)SC(C)CC
Solvent: ClCCl
Product: CCOP(=O)(SC(C)CC)SC(C)(F)F

Procedure:
The compounds of the general formula (I) obtainable according to the invention are useful precursors and intermediates for organic syntheses, for example for the preparation of insecticidal phosphoric acid esters (compare DE-A 3,903,409). Thus, for example, the 1,1-difluoroethanesulphenyl chloride obtainable according to the invention can be reacted with S-s-butyl O,O-diethyl thiophosphite in dichloromethane as a solvent to give the insecticidally active O-ethyl S-s-butyl S-(1,1-difluoroethyl) dithiophosphate (b.p. 75° C./1.3 mbar). This phosphoric acid ester can be formulated in a customary manner to give a plant protection agent which can be employed as an insecticide in a customary manner.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][OH:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29](O)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(N(CC)CC)C>[O:20]=[C:21]1[C:26]2[CH:27]=[CH:28][C:29]([O:14][CH2:13][CH2:12][O:11][C:1]3[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[CH:4]=[CH:3][CH:2]=3)=[C:30]([CH2:31][CH2:32][CH3:33])[C:25]=2[O:24][C:23]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:22]1
Reactant: OCCOc1cccc2c1CCCC2
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1c(OCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of 202 mg (1.05 mmol) of the title product of Example 59 in 10 ml of CH2Cl2 was cooled with stirring to 0° C. and treated sequentially with 370 mg (3.70 mmol) of triethylamine and 362 mg (3.15 mmol) of methanesulfonyl chloride. After one hour, the mixture was treated with another 370 mg of triethylamine and 362 mg of methanesulfonyl chloride. After one-half hour, the mixture was washed successively with water, aqueous sodium bicarbonate solution, dilute aqueous hydrochloric acid, and water. The organic phase was dried (MgSO4), filtered, and the solvent removed under reduced pressure. The residue was taken up in 10 ml of dimethylformamide. To the resulting solution was added 406 mg (1.00 mmol) of the title product of Example 1 and 290 mg (2.10 mmol) of anhydrous potassium carbonate. The mixture was stirred overnight at room temperature. Another 290 mg of potassium carbonate was then added, and stirring was continued at 60° C. for six hours. The mixture was allowed to cool, and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed successively with water and with brine, dried (Na2SO4), filtered, and the solvent removed under reduced pressure. The residue was chromatographed over silica gel. Elution with 15% ethyl acetate/toluene produced 152 mg of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N+:15]([O-:18])([OH:17])=[O:16].[S:19](=[O:23])(=[O:22])([OH:21])[OH:20]>O>[Cl:1][C:2]1[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[S:19](=[O:21])(=[O:20])([OH:23])[OH:22].[N+:15]([O-:18])([OH:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
A 4-chloro-3, 5-dinitrobenzotrifluoride product is prepared by adding 1 mole of 4-chloro-3-nitrobenzotrifluoride to a nitrating mixture containing 3.04 moles nitric acid, 10.13 moles sulfuric acid, (59.9 mole percent sulfuric acid) and 3.72 moles water based on the mixture formed by mixing 94 percent (by weight) sulfuric acid in water obtained from a reconcentration process for sulfuric acid with 98 percent (by weight) nitric acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1>CN(C=O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:16][C:11]1[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: Brc1ccccn1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Oc2ccccn2)c1

Procedure:
General procedure A (110° C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 292 μl of 2-bromopyridine (3 mmoles), 244 mg of 3,5-dimethylphenol (2 mmoles), 600 mg of ground and activated 3 Å molecular sieve and 1.2 ml of DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(Cl)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 83 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): 3.24 (s, 4H), 3.81-3.86 (m, 12H), 4.15 (s, 3H), 6.21 (s, 2H), 7.36-7.45 (m, 1H), 7.27 (s, 1H), 7.36-7.45 (m, 1H), 7.64-7.75 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]1[C:36](O)=[O:37])=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]1[CH2:36][OH:37])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CO)C1
Reaction time: 3 h
Yield: 68.7 %

Procedure:
Triethylamine (6.06 g) and isobutyl chloroformate (7.51 g) were added to a solution of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester (16.52 g) in tetrahydrofuran (200 ml) at −10° C., and the mixture was stirred for 3 hours. The reaction solution was filtered, and treated with 20 ml aqueous solution of sodium borohydride (7.72 g) at −10° C. After the mixture was stirred for 1 hour, ethyl acetate (500 ml) and water (200 ml) were added thereto, and excessive sodium borohydride was quenched with 1 N hydrochloric acid. The organic layer was washed with water (200 ml), followed by saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.87 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][N:17]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[CH2:28][CH:24]2[CH:23]=[CH:22]3)[C:18]1=[O:19])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (6.5 g, 23 mmole) in methylene chloride (20 ml), a solution of N-hydroxy-bicyclo[2,2,1]-hept-5-ene-2,3-dicarboximide (3.6 g, 20 mmole) and pyridine (1.6 g) in methylene chloride (10 ml) was added dropwise at 0°-5° C. and continued to stir for 15 minutes at the same temperature. The reaction mixture was washed with H2O (20 ml×3), dried over anhydrous Mg SO4 and evaporated. The residue was recrystallized from ethanol to give 6.1 g of N-trifluoromethanesulfonyloxy-bicyclo[2,2,1]-hept-5-ene-2,3-dicarboximide as white needles. m.p. 89°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[Br:25]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1ncc2c(Oc3ccc(OC)cc3)cccc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(Br)c2c(Oc3ccc(OC)cc3)cccc2c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A mixture of 4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (1.17 mmol, 381 mg), N-bromosuccinimide (1.3 mmol, 234 mg), benzoyl peroxide (0.06 mmol, 15 mg), and CCl4 (8 mL) was refluxed with stirring for 2.5 h. After cooling to ambient temperature silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a chromatography column filled with silica gel. Elution with CH2Cl2 gave the title compound as a tan solid (403 mg); MS-(+)-ion: M+1, 79Br/81Br=404.3 and 406.3.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:13]N>NCCCCO>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[NH:13][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: NNc1nc2ccccc2c(=O)n1N
Agent: NCCCCO
Product: Nn1c(NCCCCO)nc2ccccc2c1=O
Reaction time: 8 h
Yield: 116 %

Procedure:
16 g of 3-amino-2-hydrazinoquinazolin-4(3H)-one were stirred in 48 ml of 4-aminobutanol at 160° C. for 3 days and the majority of the 4-aminobutanol was then distilled off under vacuum. The residue was diluted with water and the mixture was seeded and stored at 0° C. overnight to crystallize the product. The mixture was filtered and the recovered product was washed and dried to obtain 12.05 g of 3-amino-2-(4-hydroxybutylamino)-quinazolin-4(3H)-one.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8](OC)=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[OH-:13].[K+]>C(O)C.O.CCOCC>[NH2:2][CH2:1][CH2:3][CH2:4][O:13][C:6]12[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]1[CH2:4][CH:3]2[CH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:10][CH2:9]1
Reactant: COc1ccc2c(c1)C(C#N)C2
Reactant: [OH-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 25 °C

Procedure:
1-Cyano-5-methoxybenzocyclobutene (29 g) is stirred with saturated KOH in ethanol (180 ml) for about 12 hours under nitrogen at RT. Water (60 ml) is added to the reaction mixture which is refluxed for about 3 hours. The mixture is cooled to RT, diluted with water, washed with ether and the aqueous layer acidified forming an oil. The oil is dissolved in ether and the ethereal solution washed, dried over Na2SO4, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].C1(C)C=CC=CC=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[C:26]([O:18][CH:15]1[CH2:14][CH2:13][N:12]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:17][CH2:16]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.6 %

Procedure:
5-Nitro-2-(4-hydroxypiperidin-1-yl)benzonitrile (20 g) was dissolved in pyridine (100 ml). To the solution was added dropwise toluene solution (50 ml) containing benzoyl chloride (12.8 g) under ice-cooling, and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water. The obtained crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g), melting point: 143–145° C.
Reaction SMILES: ClC1C=C2NC(=O)C3(C(CC(C)(C)C)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)C2=CC=1.C(OC([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([Cl:44])[CH:42]=2)/[C:37](=[CH:45]/[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)/[C:36]1=[O:52])=O)C.CO.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:44][C:41]1[CH:42]=[C:43]2[NH:35][C:36](=[O:52])[C:37]3([CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:14][C:13](=[O:21])[NH:12][CH:11]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:38]2=[CH:39][CH:40]=1
Reactant: CCOC(=O)N1C(=O)/C(=C\c2ccccc2)c2ccc(Cl)cc21
Reactant: CC(C)(C)CC1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CC(c2ccccc2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)N1
Temperature: 140 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1c in toluene (30 mL) was added E/Z-3-benzylidene-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester prepared in Example 12b (0.4 g, 1.22 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 1 h. After the solution was cooled to room temperature, methanol (40 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in methanol (30 mL) and 1N of NaOH solution (5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h, then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:4) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-phenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow oil (Yield 0.5 g, 100%).