Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of 4-amino-3-nitrophenol (1.0 g, 6.5 mmol) and TBSCl (1.32 g, 8.8 mmol) in DMF (10 mL) was added imidazole (0.88 g, 13.0 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (300 mL), and washed with brine (100 mL) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EtOAc 2:1) to obtain the title compound (1.85 g, 100%) as gray solid. 1HNMR (600 MHz, CDCl3) δ 7.54 (d, J=2.7 Hz, 1H), 6.96 (dd, J=8.9, 2.7 Hz, 1H), 6.70 (d, J=8.9 Hz, 1H), 0.96 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[NH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O.CC(C)=O>[CH2:24]([O:23][C:21]([N:8]1[CH:9]([C:11]([OH:13])=[O:12])[CH2:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1CC(c2cccs2)=NN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1CC(c2cccs2)=NN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 9.8 g of (±)-4,5-dihydro-3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (see example 2B) and 13.8 g of potassium carbonate in 80 ml of water and 40 ml of acetone there is added slowly 9.3 g of benzyl chloroformate dissolved in 50 ml of acetone, maintaining the temperature of the mixture at 10°-15° C. with an ice bath. After stirring at room temperature for 2 hours, the mixture is diluted with an equal volume of water and washed twice with ether. The aqueous layer containing some solids, is adjusted to pH 3.0 with 6 N HCl and cooled and filtered to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=NC2CCCCC2)[CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)/C=C/C([O-])=[O:27]>C(O)(C)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:27])[CH:10]=[C:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: Clc1ccc(C(C=C2CCCN2)=NC2CCCCC2)cc1Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(C=C1CCCN1)c1ccc(Cl)c(Cl)c1

Procedure:
With the use of 76.8 g (0.3 mole) of 3',4'-dichloro-2-(2-pyrrolidinylidene)-acetophenone, there is obtained in an analogous manner 2-[2-(3,4-dichlorophenyl)-2-(cyclohexylimino)-ethylidene]-pyrrolidine-(1:1)-fumarate, m.p. 208°-209° (from isopropanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: Fc1ccc(S)c(F)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CSc1ccc(F)cc1F
Reaction time: 3 h

Procedure:
To a mixture of 2,4-difluorothiophenol (4.95 g) and chloroacetone (2.8 ml) in DMF (30 ml) was added potassium carbonate (9.67 g) at 0° C. The mixture was stirred for 3 hours, poured into water, and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid, water, and brine, dried over MgSO4, and concentrated to give 1-(2,4-difluorophenylthio)propan-2-one (6.80 g). This compound was dissolved in toluene and heated at reflux for 30 hours with polyphosphoric acid (24 g). The solvent was evaporated, and the mixture was heated at 150° C. for 1 hour, carefully neutralized with aqueous potassium carbonate with ice-cooling, and extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel using hexane as an eluent to give the titled compound as colorless crystals (2.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[CH:25](OCC)(OCC)OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:25]=[N:13][N:12]=[C:10]3[CH:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CC(C)CC1N=C(c2ccccc2)c2cc(Cl)ccc2-n2cnnc21

Procedure:
To a mixture of 1.7 parts of 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine prepared in Examples 8 and 11, 3.7 parts of triethyl orthoformate and 40 parts by volume of ethanol, is added 1 part of concentrated sulfuric acid with stirring and ice-cooling. The mixture is stirred for about 20 minutes at room temperature. After completion of reaction, the mixture is neutralized with sodium bicarbonate, followed by extraction with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane, whereby 8-chloro-4-isobutyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine is yielded as pale yellow crystals. Recrystallization from a mixture of benzene and n-hexane yields colorless needles melting at 140.5° C to 141.5° C.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C(O)(=O)C.[NH2:13][C:14]1[CH:34]=[C:33]([CH3:35])[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=1>C1(C)C=CC=CC=1>[CH3:7][C:6]1[N:13]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]3[O:18][C:19]4[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=3[CH:15]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1cc(N)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-n2c(C)ccc2C)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Yield: 51 %

Procedure:
Acetonylacetone (0.040 g, 0.35 mmol)) and acetic acid (0.1 mL, 1.7 mmol) were added to a solution of the methylester of Example 36j in toluene (10 mL). The reaction mixture was refluxed for 6 h, concentrated and triturated with PE60-80° C. The organic extract was concentrated and the crude obtained was purified using flash chromatography (silica gel, EtOAc/PE60-80° C.). It was then subjected to hydrolysis as described in Example 11 to obtain the title compound (J. Chem. Soc., Chem. commun, 800-801, (1982)). Yield: 51%; 1H NMR (DMSO-d6): δ 2.0 (s, 6H, 2CH3), 2.40 (s, 3H, CH3), 2.65 (s, 3H, CH3), 5.20 (s, 2H, CH2), 5.70 (s, 2H, pyrrolyl), 7.30 (s, 1H, Ar), 7.35 (s, 1H, Ar), 8.20 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (ES+) 411 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[BrH:19]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][Br:19])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OCCC1CCC(c2cc(F)c(F)c(F)c2)CC1
Reactant: Br
Solvent: O
Product: Fc1cc(C2CCC(CCBr)CC2)cc(F)c1F

Procedure:
4-(3',4',5'-Trifluorophenyl)-1-(2'-hydroxyethyl)cyclohexane (10.4 g) was added to an aqueous solution of 47% HBr (15 ml), followed by stirring the mixture under reflux for 2 hours, adding the reaction solution to water (50 ml), extracting with ethyl acetate (100 ml), washing the organic layer with water, drying over anhydrous MgSO4, and concentrating the solvent under reduced pressure, to obtain 4-(3',4',5'-trifluorophenyl)-1 -(2'-bromoethyl)cyclohexane (10.4g).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH3:13])[CH3:12])[CH3:3].[C-:14]#[N:15].[Na+]>CS(C)=O>[C:14]([CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:3])#[N:15]
Reactant: [C-]#N
Reactant: CC(C)Cc1ccccc1C(C)Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Cc1ccccc1C(C)C#N
Temperature: 80 °C

Procedure:
Crude 1-chloro-1-(isobutylphenyl)ethane containing 47g of 1-chloro-1-(isobutylphenyl)ethane was added to a mixture of 17g of sodium cyanide in 126g of dimethyl sulfoxide (DMSO). The reaction mixture was heated to 80° C. with agitation for 10 hours, after which the DMSO and inorganic salts were removed by water washing to yield 1-cyano-1-(isobutylphenyl)ethane. The crude nitrile was reacted with excess 50% sodium hydroxide at 135.C for four hours to form the sodium salt of 2-(isobutylphenyl)propionic acid, which was then acidified and crystallized from hexane at -10.C. The para/ortho ratio of the resultant 2-(isobutylphenyl)propionic acid in hexane solution was approximately 200/1.
Reaction SMILES: O[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.P(Cl)(Cl)([Cl:26])=O.CN(C)C1C=CC=CC=1>O1CCOCC1>[Cl:26][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(CSc2nc(O)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CSc2nc(Cl)c3nc[nH]c3n2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
6-hydroxy-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine (14.67 g, 44 mmol) was suspended in dioxane (30 ml), phosphorus oxychloride (12.3 ml, 132 mmol) and dimethylaniline (8.3 ml, 66 mmol) were added and heated and stirred at 100° C. for 2 hours. The reaction solution was poured into ice water and extracted twice with ethyl acetate. After combining the ethyl acetate layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (dichloromethane: methanol=20:1) to obtain 5.45 g (35% yield) of 6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9H-purine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:41][O:42][Si](C)(C)C)[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>ClCCl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:41][OH:42])[C:8]([O:39][CH3:40])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:38])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]([C@@H:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(CO[Si](C)(C)C)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
270 mg of (S)-1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carboxylic acid-(5-tert-butyl-2-methoxy-3-trimethylsilanyloxymethyl-phenyl)-amide are dissolved in 5 ml dichloromethane, mixed with 833 μl of a 5 M solution of hydrogen chloride in isopropanol and stirred for 30 minutes at ambient temperature. The mixture is divided between dichloromethane and saturated aqueous sodium hydrogen carbonate solution, the aqueous phase is extracted twice with dichloromethane and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the product thus obtained is purified by preparative HPLC (method 3).
Reaction SMILES: [NH2:1][CH:2]([C:5]1([C:8]([O:10]CC)=O)[CH2:7][CH2:6]1)[C:3]#[N:4].N.[H][H]>[Ni]>[NH2:1][CH:2]1[C:5]2([CH2:7][CH2:6]2)[C:8](=[O:10])[NH:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(N)C#N)CC1
Agent: [Ni]
Agent: N
Product: NC1CNC(=O)C12CC2
Yield: 92.3 %

Procedure:
An autoclave was charged with 1.0 g of 1-(1-amino-1-cyanomethyl)-1-ethoxycarbonylcyclopropane, 0.4 ml of Raney nickel and 4.0 ml of ammonia-saturated ethanol, and the contents were stirred at 80° C. for 4 hours in an atmosphere of hydrogen under a pressure of 20 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 692 mg (92%) of the title compound in the form of colorless crystals. The thus obtained product was recrystallized from ethyl acetate and diethyl ether and used as a sample for analyses.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[Br:10]Br>C(O)(=O)C>[Br:10][CH:5]1[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1CC(=O)C(Br)C(=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 5-methyl-1,3-cyclohexanedione (23) (45.4 g, 360 mmol) in acetic acid (540 mL) was added bromine (19.4 mL, 378 mmol) over 5 min. After 30 min of stirring (with mechanical stirrer), the reaction mixture was filtered. The solid was left under high vacuum overnight and used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]C)=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of methyl 3-amino-6-(2,6-difluorophenyl)picolinate (1.0 equiv) in THF (0.5 M), was added 1M LiOH (4.0 equiv). After stirring for 4 hours at 60° C., 1N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered and rinsed with cold H2O (3×20 mL) to yield 3-amino-6-(2,6-difluorophenyl)picolinic acid (90%). LCMS (m/z): 251.1 (MH+); LC Rt=2.1 min.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[ClH:12]>C1(C)C=CC=CC=1>[CH2:1]([Cl:12])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Cl
Solvent: Cc1ccccc1
Product: ClCc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In a 500-ml flask were placed 30 g (0.2 mol) of piperonyl alcohol, 102.8 g (1.0 mol) of a 35% aqueous hydrochloric acid solution and 150 ml of toluene. They were stirred in a nitrogen stream at 90° C. for about 2 hours. The stirring was stopped and phase separation was made to remove the aqueous phase. The toluene phase was washed with water and an aqueous NaHCO3 solution in this order, and then with water several times. The toluene phase was concentrated under reduced pressure to obtain 32.28 g of piperonyl chloride. In a 500-ml flask were placed 8.4 g (0.21 mol) of sodium hydride and 100 ml of toluene, and they were stirred under refluxing in a nitrogen stream, in a 120° C. oil bath. Thereto was dropwise added, in 20 minutes, 29.6 g (0.19 mol) of 1-menthol dissolved in 30 ml of toluene. 30 minutes later, 32.3 g (0.19 mol) of the piperonyl chloride dissolved in 32 ml of toluene was added dropwise, followed by stirring for about 1 hour. The stirring was stopped and 110 ml of a 2 N aqueous hydrochloric acid solution was added to terminate a reaction, after which phase separation was made. The toluene phase was washed with water three times and then concentrated. The resulting concentrate was distilled for purification to obtain 35.6 g (yield: 30.6%, purity: 97.2%) of piperonyl 1-mentyl ether as a transparent oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[SH:16][C:17]1[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=1>>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:16][C:17]2[S:21][C:20]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:19][N:18]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCSc1nnc(S)s1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Product: CCCc1c(CSc2nnc(SCCCCCC(=O)OCC)s2)ccc(C(C)=O)c1O
Yield: 92.4 %

Procedure:
Using as starting materials 0.30 g of 4-acetyl-3- hydroxy-2-propylbenzyl chloride and 0.46 g of ethyl 6-[(5- mercapto-1,3,4-thiadiazol-2-yl]thio]hexanoate, 0.59 g of oily ethyl 6-[[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4- thiadiazol-2-yl]thio]hexanate was obtained in a manner similar to Example 9.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CN(C)C=O>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([C:3]3[C:4]([O:8][CH2:25][CH:26]4[CH2:28][CH2:27]4)=[N:5][N:6]([CH3:7])[C:2]=3[NH2:1])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(OCC2CC2)c(-c2ccc3c(c2)OCO3)c1N
Reaction time: 8 h

Procedure:
To 5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (500 mg) (Preparation 46) in anhydrous dimethylformamide (21 ml) under an atmosphere of nitrogen at room temperature was added solid potassium carbonate (980 mg) and bromomethylcyclopropane (230 μl). The mixture was stirred overnight then quenched by the addition of water (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The solution was extracted with ethyl acetate (3×40 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with hexane:ethyl acetate (1:2) to yield the title compound as a colourless oil (365 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5](=O)[CH2:4][CH2:3]1.[C:25]([Si](C)(C)C)#[N:26]>B(F)(F)F.CCOCC>[C:25]([C:5]1[C:6]2[CH:7]=[C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=3)[CH:9]=[CH:10][C:11]=2[C:2]([CH3:24])([CH3:1])[CH2:3][CH:4]=1)#[N:26]
Reactant: CC1(C)CCC(=O)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: CCOCC
Product: CC1(C)CC=C(C#N)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 80 °C

Procedure:
To 76 mg (0.24 mmol) of 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoic acid (Compound 8) was added 0.06 ml (0.48 mmol) of cyanotrimethylsilane and 6 drops of boron trifluoride etherate. The resulting dark mixture was heated at 80° C. for 45 minutes, cooled to room temperature and purified by flash chromatography (silica, 50% EtOAc-hexane) to yield the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:6]3[C:7]4[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=4[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[N:10][CH2:11][C:5]3=[N:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: Brc1nnc2n1-c1ccccc1C(c1ccccn1)=NC2
Reactant: CN1CCNCC1
Product: CN1CCN(c2nnc3n2-c2ccccc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-methylpiperazine to give 1-(4-methyl-piperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:22][CH2:23][CH3:24])[N:15]=1.Cl>O.C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2](=[O:10])[N:22]([CH2:23][CH3:24])[C:16]2[C:17]([C:18]=1[NH2:19])=[CH:20][CH:21]=[C:14]([Cl:13])[N:15]=2)=[O:5])[CH3:8]
Reactant: CCNc1nc(Cl)ccc1C#N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(N)c2ccc(Cl)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2.07 g. (0.09 g. atom) of sodium in 75 ml. of ethanol is added 14.4 g. (0.09 mole) of diethyl malonate. The solution is stirred at room temperature for 5 minutes and then 5.4 g. (0.03 mole) of 6-chloro-2-ethylaminonicotinonitrile is added. The mixture is heated under reflux for about 6 hours. The mixture is cooled and diluted with 75 ml. of water and acidified with conc. hydrochloric acid. The precipitate which forms is collected and air dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:26]([O:28][CH2:29][CH3:30])=[CH2:27])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12

Procedure:
To a solution of 7-bromo-4-trifluoromethanesulfonyloxycoumarin (5.1 g, 13.7 mmol) in dioxane is added tributyl(1-ethoxyvinyl)tin (4.8 mL, 14.2 mmol), (Ph3P)4Pd (0.790 g, 0.7 mmol) and LiCl (1.74 g, 41 mmol). The mixture is refluxed for 4 h, cooled and partitioned between aqueous NH4Cl and EtOAc. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed on silica gel (CH2Cl2/EtOAc; 95:5) and triturated in hexane/Et2O to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)[CH:2]=[CH2:3].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=CCc1cccc2c1NCC2
Solvent: c1ccncc1
Product: C=CCc1cccc2c1N(C(=O)OCC)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
The product from Example 113 (0.8 g) was dissolved in pyridine (3 ml), cooled to 0° C. and ethyl chloroformate (0.77 ml) was added. After 10 minutes, the reaction was quenched with water and extracted with diethylether. The organic layer was separated and washed with cold 2% hydrochloric acid, 5% sodium bicarbonate, brine and dried. The solvent was evaporated in vacuo affording the desired compound in 90% yield as an oil.