Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[Li+].CC([N-]C(C)C)C.[Cl-].[NH4+]>C1COCC1>[S:2]1[CH:1]=[C:5]([OH:6])[C:4]2[CH:9]=[CH:10][CH:11]=[CH:12][C:3]1=2
Reactant: COC(=O)c1ccccc1SC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1csc2ccccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-(methylthio)benzoate (4.0 g, 22.00 mmol) in THF (60 mL) was added to a solution of freshly prepared LDA (2M in THF, 17.5 mL, 35 mmol) placed at −78° C. The reaction mixture was stirred for 1 hour at −78° C., then overnight at room temperature. The reaction mixture was diluted by addition of a saturated solution of ammonium chloride (50 mL). The aqueous phase was separated and extracted with ethyl acetate (3×70 mL). The combined organic phases were washed with a saturated solution of sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (95:5 to 9:1) as eluent. The title product was obtained as a pink solid (1.74 g, 53%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([O:25]C(C)(C)C)=O)[CH:21]=[CH:22][C:5]=2[NH:4]1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH2:40][NH:41][CH3:42].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([N:41]([CH3:42])[CH2:40][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:25])[CH:21]=[CH:22][C:5]=2[NH:4]1
Reactant: CNCc1cc2ccccc2n1C
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 88.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-3-oxo-4-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.49 g, 1.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.23 g, 1.4 mmole), Et3N (0.37 mL, 2.62 mmole), HOBt.H2O (0.19 g, 1.4 mmole), and EDC.HCl (0.27 g, 1.4 mmole), the title compound (0.53 g, 82%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 497.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[N:5]([CH3:13])[N:4]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[N:5]([CH3:13])[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)nn1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(CO)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 3 (2 g, 0.01 mol) in THF (20 mL) was added lithium aluminum hydride (0.63 g, 0.02 mol) at 0° C. and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (2.0 mL) were added to the reaction mixture. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=1:1) to give the title compound as a colorless oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CI.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>ClCCl.[Cl-].[Na+].O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]([CH:22]=[O:23])([CH3:1])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CI
Product: CC1(C=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (2.80 g) and methyl iodide (3.60 mL) are added to an ice cold solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.00 g) in dichloromethane (24 mL). The mixture is stirred in the cooling bath for 30 min and then at room temperature overnight. Brine is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (MgSO4) and concentrated to give the crude title compound that is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12.[O-:23]Cl=O.[Na+].Cl>O.CC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([OH:23])=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:3]=12
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C=O)cnc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)c(C(=O)O)cnc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a stirred solution of NaH2PO4.2H2O (513 mg, 3.3 mmol) in water (3 ml), was added a solution of 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.50 mmol) in acetone (6 ml) at 0° C. A solution of NaClO2 (541 mg, 5.98 mmol) in water (3 ml) was added to the reaction mixture at 0° C. and the reaction mixture was warmed to room temperature spontaneously. After 2 hours, 1N HCl solution was added to reach pH=5. The produced solid was filtered and dried with nitrogen gas flow. The title product (440 mg, 84% yield) was used next reaction without further purification. MS m/z: 351 [M+1].
Reaction SMILES: [O:1]=[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[N:3]1[C@H:4]([C:11]([O:13]C)=[O:12])[CH2:5][CH2:6]2.[Li+].[OH-]>C1COCC1>[O:1]=[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[N:3]1[C@H:4]([C:11]([OH:13])=[O:12])[CH2:5][CH2:6]2
Reactant: COC(=O)[C@@H]1CCc2cccc(=O)n21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCc2cccc(=O)n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a stirred solution of 0.200 mg (1.00 mmol) of methyl (3S)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylate from step B above in 3 mL of THF was added 1.5 mL (1.5 mmol) of a 1.0 M aqueous LiOH solution. The resulting mixture was stirred for 2 h at ambient temperature then quenched with 2.0 mL (2.0 mmol) of a 1.0 M aqueous solution of hydrogen chloride. All volatiles were evaporated in vacuo and the aqueous phase was extracted with a 30% IPA in chloroform mixture (3×5 mL). The combined extract were washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to afford the title compound as a white solid (0.17 g, 92%). 1H NMR (500 MHz, CD3OD): δ 7.53 (dd, J=8.9, 7.1 Hz, 1H), 6.38-6.35 (m, 2H), 5.11 (dd, J=9.7, 2.7 Hz, 1H), 3.23-3.12 (m, 2H), 2.62-2.53 (m, 1H), 2.35-2.30 (m, 1H). LC-MS: m/z (ES) 180 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[N:10][N:11]=1)[OH:24]
Reactant: COc1ccc(Cn2cnnn2)cc1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2C(O)c2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 1-(4-methoxybenzyl)tetrazole (6.12 g; Y. Satoh and N. Marcopulos, Tetrahedron Letters, 1995, 36, 1759-1762), and N,N,N'N'-tetramethylethylenediamine (10 ml) in dry tetrahydrofuran (10 ml) under nitrogen was cooled to -95° C. and treated dropwise with n-butyl lithium (2.5M solution in hexanes) over 15 minutes. The reaction mixture was left at -80° C. for 15 minutes when 2-chlorobenzaldehyde (4.53 g) was added dropwise over 10 minutes maintaining the reaction temperature at or below -80° C. The mixture was stirred at or below -80° C. for 30 minutes, allowed to warn to room temperature, quenched with ammonium chloride solution (50 ml) and the organic phase separated. The aqueous phase was extracted three times with ethyl acetate (50 ml), the combined organics dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:1, v/v) then with a mixture of ethyl acetate and pentane (2:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (1.33 g) as a white solid, m.p. 128-130° C. [Elemental analysis:- C,58.22; H,4.74; N,17.15%. Calculated:- C,58.1; H,4.57; N,16.94%].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([N:13]([CH2:2][CH2:3][CH2:4][Cl:5])[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCBr
Reactant: CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCCCl)Cc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
260 ml of 1-bromo-3-chloropropane were dissolved in 400 ml of acetone. 230 g of potassium carbonate were added to the solution. A solution of 115 ml of N-methyl-N-benzylamine in 115 ml of acetone was added dropwise to the reaction mixture with stirring at a bath temperature of 40° C., the addition being distributed over a period of 30 minutes. The reaction mixture was subsequently stirred at a temperature of 40° C. for 4 hours. The precipitated salts were then filtered out. The filtrate was concentrated under reduced pressure at a temperature of 40° C. The residue was acidified to a pH of 1 using 16% strength aqueous hydrochloric acid solution and was washed 3 times with tert-butyl methyl ether in order to remove unreacted 1-bromo-3-chloropropane. The aqueous phase was subsequently brought to a pH of 8 by addition of 16% strength sodium hydroxide solution and was extracted repeatedly with ethyl acetate. The combined ethyl acetate phases were dried with magnesium sulfate and concentrated. 71 g of 3-(N-benzyl-N-methyl-amino)-propyl chloride were obtained.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>CCOCC>[CH:2]1([NH:1][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: CCOCC
Product: O=C(CCCCC(=O)NC1CCc2ccccc21)NC1CCc2ccccc21
Reaction time: 0.75 h
Yield: 60 %

Procedure:
Racemic 1-aminoindan (5.7 g, 43 mmole) in ether (20 ml) stirred in ice, was treated dropwise with adipoyl chloride (1.83 g, 10 mmole) in ether (10 ml). After 30 min. the solid was filtered and slurried with water for 45 min. The insoluble solid was collected, air dried (2.82 g) and crystallized from HOAc/H2O, washed with acetic acid/water (1:1), ethanol and ether and then dried to give 2.26 g (60% title compound. Melting point: 227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]#[N:14])[NH:6][C:5]2=[O:15].[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][CH2:12][C:13]#[N:14])[NH:6][C:5]3=[O:15])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: N#CCCn1[nH]c(=O)c2cc(N)ccc21
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2c(c1)c(=O)[nH]n2CCC#N
Temperature: 60 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To a solution of 3-(5-amino-3-oxo-2,3-dihydro-indazol-1-yl)-propionitrile (0.08 g) in pyridine (1 mL) was added 3-chloro-2-methylbenzenesulfonylchoride (0.089 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired 3-Chloro-N-[1-(2-cyano-ethyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl]-2-methyl-benzenesulfonamide (0.087 g) as a light brown solid. MS (ESI+): 391.0 [M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([NH2:8])=[O:7].[N:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.[I-].[K+].C(O)(C)C>[C:6]([CH2:5][O:4][CH2:3][CH2:2][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]1)(=[O:7])[NH2:8]
Reactant: CCOC(=O)N1CCNCC1
Reactant: NC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)N1CCN(CCOCC(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
15.13 g of (2-chloroethoxy)acetamide (0.11 mol), 14.6 ml of ethyl piperazine carboxylate (0.1 mol), 23.3 g of sodium carbonate (0.22 mol) and 1.0 g of potassium iodide in 25 ml of toluene are introduced into a round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is heated at the reflux temperature for 4 hours and is allowed to cool to room temperature. The reaction is continued, still with stirring, for a further 16 hours. 100 ml of isopropanol are added and the solid materials formed are filtered off. The solvent is evaporated from the filtrate under reduced pressure to dryness. The product obtained after evaporation of the solvents is recrystallized from toluene. 21.35 g of ethyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate are obtained.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[NH:5][C:6]([N:8]([CH3:10])[CH3:9])=[O:7].Cl>>[CH3:10][N:8]([CH3:9])[C:6]([NH:5][C@H:4]([C:3]([OH:20])=[O:2])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)N(C)C
Agent: Cl
Product: COc1ccc(C[C@H](NC(=O)N(C)C)C(=O)O)cc1

Procedure:
Prepared according to the procedure of Example 130 from the resultant compound of Example 131 with the modification that the product was isolated by pouring the reaction mixture into 2 M HCl and extracting with ethyl acetate which was dried over Na2SO4 and evaporated. EI-MS: M+ =266.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C=C(N)OCC
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(C)cc1

Procedure:
Upon heating a solution of 6 g of 4-methylbenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 6 hours, 2-amino-4-(4-methylphenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119°C (ethyl acetate/petroleum ether) is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[O:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][O:10][CH2:11][CH2:12]2)[CH:7]=1
Reactant: C1CNCCOC1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(N2CCCOCC2)ncn1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (20.1 mmol) of 4,6-dichloropyrimidine, 2.8 g (20.1 mmol) of 1,4-oxazepane hydrochloride and 6.4 g (60.4 mmol) of sodium carbonate in 45 ml of water is stirred under reflux for 16 h. After cooling to RT, the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. Under reduced pressure, the filtrate is concentrated to dryness. The product is obtained as an oil. Yield: 3.9 g (86% of theory)
Reaction SMILES: [N-]=C=S.N1CCC(N2C3C=CC=CC=3N(CCC[N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])C2=O)CC1>C(Cl)Cl.O>[C:26]1(=[O:27])[NH:22][C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Agent: [N-]=C=S
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Di(2-pyridyl)thionocarbonate (0.286 g, 1.2 mM) was added to a cold (0° C.) solution of 1,1-di(p-anisyl)methyl amine (0.3 g, 1.2 mM) and triethylamine (0.17 ml) in methylene chloride (10 ml). The resulting mixture was slowly warmed up to RT over a 4 hour period then stirred at RT for additional 1 hour to provide the 1,1-di(p-anisyl)methyl isothiocyanate. The prepared isothiocyanate was added to Compound 53 (0.94 g, 0.43 mM), prepared in Example 53, dissolved in methylene chloride (10 ml). The mixture was stirred at RT overnight, diluted with water (20 ml) and the layers were separated. The aqueous layer was again extracted with methylene chloride (2×20 ml). The combined CH2Cl2 extracts were dried over MgSO4, evaporated in vacuo and chromatoraphed (EM silica gel 60, 10% EtOAc in CH2Cl2) to give the pthalimide intermediate. This intermediate, substituted for Compound 54, was treated as described in Example 55 to give the HCl salt of the product. m/z (MH+) 560
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]([SH:15])[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:23][CH:24]=[O:25]>C1COCC1.O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:25][CH:24]1[CH2:23][S:15][C:12]2=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:14][N:13]12
Reactant: O=CCCl
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
5-(3-Nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (prepared as described in Example 1) (3.92 g, 13.14 mmol) was dissolved in a 1:1 THF/water mixture (130 mL). Chloroacetaldehyde (55% in water, 2.31 mL, 19.71 mmol, 1.5 eq) was added and the solution was stirred at room temperature overnight. The reaction mixture was diluted with AcOEt and saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried and evaporated to dryness. 3.25 g of crude product were obtained as yellow solid (72%), which was used in the following step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][NH2:47])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.O>C1COCC1>[F:48][C:14]([F:13])([F:49])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][NH:47][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (109 μl) and methanesulfonyl chloride (36.4 μl) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (200 mg) in THF (4 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex; eluent; ethyl acetate) and recrystallized from ethyl acetate-hexane to give the titled compound (126 mg) as colorless needle crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH2:2][C:3]12[CH2:8][O:9][C:10]([CH3:11])([O:7][CH2:6]1)[O:5][CH2:4]2
Reactant: OCC(CO)(CO)CO
Reactant: CCOC(C)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC12OCC(CO)(CO1)CO2
Temperature: 125 °C
Yield: 93 %

Procedure:
To a suspension of pentaerythritol (13.6 g, 0.100 mol) in 10 mL of toluene was added freshly distilled triethyl orthoacetate (16.2 g. 18.3 mL, 0.100 mol) and p-toluenesulfonic acid monohydrate (50 mg). The mixture was slowly heated in an oil bath and ethanol was distilled from the mixture over a period of 12 hrs. After removal of the ethanol, the bath temperature was raised to 125° C. and toluene was distilled off until the solution was homogeneous (about 30 mL). The residue was sublimed (bulb to bulb, ~130--C, 2.5 mmHg) to give 4-(hydroxymethyl)-1-methyl-2,6,7-trioxabicyclo[2.2.21octane (15.0 g, 0.093 mol, 93%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl.O>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH3:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A 300 gallon glass lined reactor was charged with p-toluene sulfonyl chloride (2) and methylene chloride. A second 300 gallon glass lined reactor was charged with USP water, sodium hydroxide, methylene chloride, triethyleneglycol monomethyl ether (TEG) (1), and benzyltriethyl ammonium chloride. The p-toluene sulfonyl chloride solution was slowly added over 2 hours to the TEG solution while maintaining a temperature of 0-25° C. The reaction mixture was agitated for 1 hour and sampled for reaction completion analysis by HPLC. The product was isolated by separating the methylene chloride layer (product layer) from the aqueous layer. The organic layer was washed twice with water and the methylene chloride was replaced with toluene by vacuum distillation to yield 2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (Ts-TEG) (3).