Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:5]1[C:9]([CH:29]=[O:30])=[C:8]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:7]=[C:6]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCn1cc(C(OC)OC)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCn1c(-c2ccccc2)nc(C(OC)OC)c1C=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-butyl-4-dimethoxymethyl-2-phenyl-1H-imidazole 209 (2.74 g, 10 mmol) in anhydrous THF under nitrogen at −78° C., n-BuLi (1.6 M in hexane, 7.5 ml, 12 mmol) is added dropwise and the mixture is continued stirring at this temperature for 30 min. After anhydrous DMF (4 mL) is added, the mixture is stirred at room temperature for 16 h. Saturated ammonium chloride and ethyl acetate were added at 0° C. and the the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phase is washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography to yield the desired product as a white solid. Yield: 1.94 g; LC-MS (MH+): 303. 1H NMR (300 MHz, CDCl3) δ 10.18 (s, 1H), 7.60–7.56 (m, 2H), 7.51–7.46 (m, 3H), 5.63 (s, 1H), 4.32 (t, J=6.3 Hz, 2H), 3.47 (s, 6H), 1.73–1.63 (m, 2H), 1.28–1.16 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(=O)([O-])[OH:2].[Na+].[CH3:6][C:7]1([CH3:31])[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([NH:20][CH:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:19])[CH:13]=2)[O:8]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:6][C:7]1([CH3:31])[CH:16]2[O:2][CH:15]2[C:14]2[CH:13]=[C:12]([CH2:17][C:18]([NH:20][CH:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:19])[CH:11]=[CH:10][C:9]=2[O:8]1
Reactant: O=C([O-])O
Reactant: CC1(C)C=Cc2cc(CC(=O)NC3CCCc4ccccc43)ccc2O1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2C2OC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
950 ml of a saturated aqueous sodium hydrogen carbonate solution was added to a solution of 11 g of the 2-(2,2-dimethyl-2H-chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide obtained above in 600 ml dichloromethane. A total of 15 g m-chloroperoxybenzoic acid (=MCPBA) in three 5 g portions was added to this receiving solution at 5 min. intervals, and the mixture was stirred for 18 hours at room temperature. The organic phase was separated and substantially entirely evaporated on a rotary evaporator at 65° C. and 20 bar. 2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide was obtained as crude oil, which was used without further purification for the subsequent reaction.
Reaction SMILES: FC[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][NH2:12]>C(O)CO>[NH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:3]=[N:12]1
Reactant: O=C(CF)c1ccccc1
Reactant: NN
Solvent: OCCO
Product: c1ccc2[nH]ncc2c1

Procedure:
100 g of fluoro-acetophenone in 400 mL of ethylene glycol was stirred at room temperature with hydrazine (0.624 mol, 20 g) for 4 h after which the reaction mixture was heated to 150 C for 48 h. TLC analysis indicated complete reaction. Partitioned the reaction mixture into dichloromethane and brine. Dried organic phase over sodium sulphate and evaporated to a solid. Re-crystallized from hexane/dicholomethane gave indazole.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22](O)=[O:23])[C:17]=1[CH3:25].C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:23])[C:17]=1[CH3:25]
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(N3CCOCC3)CC2)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 0.080 g (0.24 mmol) of 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) in 1.5 ml of CH2Cl2 was treated at RT with 1 drops of DMF. 0.02 ml (0.29 mmol, 1.2 eq) of oxalyl chloride in 0.5 ml CH2Cl2 were added dropwise and stirring was continued for 1 h. The solution was evaporated, redissolved in 1 ml of CH2Cl2, cooled (0° C.) and treated with a solution of 0.041 g (0.24 mmol, 1 eq) of 4-(piperidine-4-yl)-morpholine and 0.07 ml (0.48 mmol, 2 eq) of triethylamine in 0.5 ml of CH2Cl2. The reaction was stirred for 3 h at this temperature, then partitioned three times between EtOAc and aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to give 0.134 g (quant.) of the title compound as light yellow foam. MS: 485.3 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>Cl.O1CCOCC1>[ClH:1].[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)C(CCCCl)C1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 212.4 %

Procedure:
tert-Butyl N′-[5-chloro-2-(tetrahydropyran-4-yl)-pentanoyl]-hydrazinecarboxylate (250 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane (2 ml), and the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain 215 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].CO[CH:8](OC)[CH2:9][CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:13][O:12][Si:11]([O:16][CH3:17])([O:14][CH3:15])[CH2:10][CH2:9][CH:8]1[S:5][CH2:1][CH2:2][CH2:3][S:4]1
Reactant: SCCCS
Reactant: COC(CC[Si](OC)(OC)OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CO[Si](CCC1SCCCS1)(OC)OC

Procedure:
The procedure and apparatus of Example 1 were used with 22.4 g (0.207 m) of propane-1,3-dithiol, 46.4 g (0.207 m) of (3,3-dimethoxypropyl)trimethoxysilane, 0.14 g of p-toluenesulfonic acid, and 100 ml of xylenes solvent. Methanol was removed by distillation as the contents of the flask were heated at reflux (143°) for 2 hours. The crude product, excluding solvent, contained 75% of the title product and 7.4% of the monosubstituted product, (MeO)3Si(CH2)2CH(OMe)S(CH2)3SH, as determined by GC/MS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:32])[C:11](=[O:31])[C:12]([CH3:30])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])=[O:16])=[C:4]([F:33])[CH:3]=1.Cl>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:32])[C:11](=[O:31])[C:12]([CH3:30])=[CH:13][C:14]=2[C:15]([NH:17][O:18][CH2:19][C@@H:20]([OH:22])[CH3:21])=[O:16])=[C:4]([F:33])[CH:3]=1
Reactant: Cc1cc(C(=O)NOC[C@H](C)O[Si](C)(C)C(C)(C)C)c(Nc2ccc(Br)cc2F)n(C)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NOC[C@H](C)O)c(Nc2ccc(Br)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(4-bromo-2-fluorophenylamino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (0.037 g, 0.0682 mmol) in THF (1.00 mL) was added 1 M HCl (0.682 mL, 0.682 mmol). The reaction mixture was stirred for one hour at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 (3×), saturated NaCl (1×), dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 30:1) gave 0.020 (69%) pure desired product as a yellow solid. MS ESI (+) m/z 428, 430 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 6.68 (t, 1H), 3.86 (m, 1H), 3.71 (m, 1H), 3.58 (m, 1H), 3.40 (s, 3H), 2.12 (s, 3H), 1.10 (d, 3H).
Reaction SMILES: [CH2:1]([S:4]([CH2:7][C:8]1[N:9]=[C:10]([NH:13]C(=O)OC(C)(C)C)[S:11][CH:12]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[ClH:21]>O1CCOCC1>[ClH:21].[CH2:1]([S:4]([CH2:7][C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1)(=[O:5])=[O:6])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Cc1csc(N)n1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(propylsulfonylmethyl)thiazol-2-ylcarbamate (16 mmol) in 1,4-dioxane (25 mL) was added 4N HCl in 1,4-dioxane (300 mL) and was stirred for 4 hours at 40° C. Removal of the volatiles afforded 4-(propylsulfonylmethyl)thiazol-2-amine HCl-salt (3.99 g, quant. yield) as a crème-colored solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>C1(OC)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.4 %

Procedure:
A suspension of p-methoxybenzyl dl-3-acetoxymethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylate (13.8 mg., 0.027 mMol) in anisole (70 μl.) is cooled in an ice-bath. Ice-cold trifluoroacetic acid (350 μl.) is added and the mixture is swirled to make it homogeneous. The resulting solution is kept at 0°C. for 5 minutes, then evaporated in vacuo at 0°C. to remove excess trifluoroacetic acid. The oily residue is allowed to warm to room temperature under vacuum, then diluted with anisole (0.5 ml.) and evaporated in vacuo at 35°C. The resulting semi-solid is taken up in water (5 ml.) containing sodium bicarbonate (23 mg., 0.27 mMol) and the solution is extracted with methylene chloride (3 × 2 ml.). The aqueous phase (pH 8.65) is acidified to pH 2.6 with 1 M pH 2 phosphate and is extracted with ethyl acetate (4 × 3 ml.). The combined extracts are dried over magnesium sulfate, filtered, and evaporated in vacuo to yield dl-3-acetoxymethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (10.1 mg.) as a white solid: ir (neat) 2.8-4.5, 5.60, 5.76, 5.91, 6.50, 7.23, 8.10 and 9.63μ; nmr (Me2CO-d6) τ 7.96 (s, 3, CH3CO), 6.58, 6.20 (dd, 2, J=19Hz, 2-CH2), 6.08 (s, 2, ArCH2), 5.20, 4.83 (dd, 2, J=13Hz, CH2OAc), 4.86 (d, 1, J=4.5Hz, H6), 4.13 (d of d, 1, J=4.5Hz and J-9Hz. H7), 2.85 (m, 3, ArH), and 1.96 (d, 1, J=9Hz, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[CH:12]1([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(Cl)(Cl)Cl>[CH:12]1([CH2:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][OH:11])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)CC1CCCCC1
Reactant: Nc1ccccc1CCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(CC1CCCCC1)Nc1ccccc1CCCO
Temperature: 25 °C
Reaction time: 113 h
Yield: 51.9 %

Procedure:
To a solution of 3-(2-aminophenyl)propan-1-ol (180 mg) and cyclohexylacetic acid (203 mg) in dichioromethane (12mL) were added 1-hydroxybenzotriazole (193 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (274 mg) under ice cooling. The solution was stirred at room temperature for 113 hours. Chloroform was then added to the solution and it was washed in turn with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane: ethyl acetate=1:1) to give the title compound (170 mg).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13].[ClH:21]>C(#N)C>[Cl:21][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: Cl
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Temperature: 60 °C

Procedure:
9.3 g of anhydrous cuprous chloride and 8.8 g of tert-butyl nitrite were added to 150 ml of acetonitrile and under stirring and heating at 60° C. 11 g of 3-amino-2,4,5-trifluorobenzoic acid 26 (a commercial product) was added. The mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Finally the residue was subjected to silica gel (100 g) column chromatography using chloroform as an eluent. The procedure gave 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17](=O)[C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.CS(C)=[O:40]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([N:16]=[C:17]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])[CH:19]=3)[NH:15][C:14]2=[O:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCOc1cc(C(=O)NC2(C#N)CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCOc1cc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
4-(3-But-3-enyloxy-5-trifluoromethyl-benzoylamino)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (3.0 g) was dissolved in ethanol, and a 5 N aqueous sodium hydroxide solution (6.9 ml, 34.5 mmol) and a 30% aqueous hydrogen peroxide solution (3 ml) were added. After stirring at room temperature for two hours, DMSO (19 ml) was added to the reaction solution, and the mixture was stirred at 50° C. for four hours. The reaction solution was cooled, and then quenched with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (2.39 g, 67% in two steps).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8]>CO>[CH3:3][O:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
1N Sodium hydroxide was added to a solution (50 ml) of methyl 2-methoxy-3-nitrobenzoate (4.96 g, 23.5 mmol) in methanol and the mixture was stirred at 50° C. for 2 hrs. Methanol was evaporated under reduced pressure and water was added. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from hexane-ethyl acetate to give the title compound (4.37 g) as pale-yellow crystals. melting point: 224–226° C.
Reaction SMILES: Cl.[C:2]([NH2:11])(=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[NH2:5].[C:12](OC(=O)C)(=O)[CH3:13]>>[CH3:12][C:13]1[NH:11][C:2](=[O:10])[C:3]2[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccccc1N
Agent: Cl
Product: Cc1nc2ccccc2c(=O)[nH]1
Reaction time: 8 h
Yield: 42 %

Procedure:
Anthranilamide hydrochloride was prepared by adding 20 ml of concentrated hydrochloric acid (37% by weight) to a solution of 27.3 g of anthranilamide in 200 ml of methanol. This mixture was cooled in an ice bath to precipitate the hydrochloride which was then collected and dried to obtain a product melting at 234°C with decomposition. A 17.4 g (0.1 mole) portion of the hydrochloride obtained above was refluxed for 3 hours with 100 ml acetic anhydride and allowed to stand overnight. The mixture was then cooled in an ice bath and the solids collected by filtration on a Buchner funnel. The filter cake was slurried in 100 ml of water, and warmed to aid solution and then 28% aqueous ammonia was added until the mixture was alkaline. After cooling the 2-methyl-4-(3H)quinazolinone precipitated as a solid, was then collected, washed with a small amount of cold water and dried at 70°C to obtain 6.72 g of the desired product. The 2-methyl-4-(3 H)quinazolinone melted at 236°-8°C and was obtained in a 42% yield.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[C:12]1([CH2:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.[OH-].[Na+].C(Cl)Cl>[CH2:18]([NH:19][CH:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a suspension of 1,4-dioxaspiro[4.5]decan-8-one (10 g, 64.0 mmol) in DCE (200 mL) was added phenylmethanamine (7.34 mL, 67.2 mmol), AcOH (3.67 mL, 64.0 mmol) and sodium triacetoxyborohydride (19.00 g, 90 mmol). The reaction was stirred at RT for 16 hours and then the mixture was diluted with 1N NaOH (100 mL) and DCM (250 mL). The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in acetone (66.7 mL) and treated with HCl (2N aqueous) (64.0 mL, 128 mmol), and the mixture was stirred at RT for 16 hours. The reaction mixture was concentrated to half its volume and diluted with 1 N aqueous NaOH (100 mL) and DCM (300 mL). The layers were separated, and the organic portion was dried over sodium sulfate and concentrated under reduced pressure to afford a white solid. The solid was purified by silica gel chromatography (5-10% MeOH/DCM) to afford 4-(benzylamino)cyclohexanone (9.1 g, 69.9% yield). MS m/z=204.2 [M+H]. Calc'd for C13H17NO: 203.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[S:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:20]2[CH2:21][CH2:22][S:17][CH2:18][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCSCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCSCC2)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
In a 3-neck round-bottomed flask equipped with a condenser and a nitrogen inlet, TiCl4 (0.51 mL, 4.67 mmol) was slowly added to a suspension of zinc powder (0.63 g, 9.60 mmol) in anhydrous THF (13 mL) at room temperature. The reaction was heated at reflux for 2.5 h. The reaction was taken out of the oil bath then a solution of (4-bromophenyl)(4-hydroxyphenyl)methanone (2) (0.35 g, 1.26 mmol) and tetrahydrothiopyran-4-one (0.44 g, 3.79 mmol) in anhydrous THF (13 mL) was added and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and water (10 mL) added, via syringe, followed by addition of 10% aqueous K2CO3 (10 mL). The reaction mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oil. The crude product was purified by flash column chromatography on silica gel using a hexanes:EtOAc gradient (100:0 to 75:25) to give compound 36 as a white powder (0.323 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 2.38-2.41 (m, 2H), 2.45-2.47 (m, 2H), 2.62-2.66 (m, 4H), 6.67 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 9.39 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(=O)[O:29][C:27](=[O:28])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][N:16]2[C:27](=[O:28])[C:26]3[C:25](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:24]2=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(CN2C(=O)c3ccccc3C2=O)c2ccccc2Cl)CC1
Temperature: 130 °C
Yield: 93.8 %

Procedure:
To 4-2[-amino-1-(2-chloro-phenyl)-ethyl]-1-Boc-piperazine (201) (4.34g, 12.7 mmol) was added phthalic anhydride (1.89 g, 12.7 mmol). The mixture was heated at 130° C. for 1 h and then allowed to cool to room temperature. The resulting solid was recrystallized from MeOH. The enantiomers of the phthalimide-protected product were separated by chiral chromatography, using a Chiralcel OD (4.6×250 mm) column, eluting with 5% 3A alcohol in heptane at 1 mL/min. The first eluting isomer was labeled isomer #1 and the second eluting isomer #2. 5.6 g (95%) of the mixture was isolated and separated.