Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]([CH3:11])[OH:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12]([S:14](Cl)(=[O:16])=[O:15])=[CH2:13].C(N(CC)CC)C>O1CCCC1>[CH:12]([S:14]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([N:9]([CH3:11])[OH:10])=[O:8])(=[O:16])=[O:15])=[CH2:13]
Reactant: CN(O)C(=O)c1ccccc1
Reactant: C=CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)c1ccccc1C(=O)N(C)O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
130 ml of tetrahydrofuran was added to a mixture of 7.6 g of N-benzoyl-N-methylhydroxylamine and 6.3 g of vinylsulfonyl chloride and a solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added to the mixture over 2 hours with stirring while cooling the mixture so that the temperature was maintained at 25° C. or less. The reaction was continued for additional 2 hours at a temperature ranging from 15° to 25° C. and then the same procedures used in Preparation Example 4 were repeated to give 9.2 g of o-vinylsulfonyl-N-benzoyl-N-methylhydroxylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N#N.[H-].[Na+].[CH3:22]I>CN(C=O)C.O.CCCCCC.C(OCC)(=O)C>[CH3:22][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(C(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of tert-butyl (3-nitrophenyl)carbamate (6.0 g) in DMF (35 mL) in a 100 mL 3-neck RBF equipped with N2 Bubbler and thermo pocket was added NaH (1.21 g) portion wise and stirred 1.0 hr at room temperature. Methyl iodide (5.37 g in 15 mL DMF) was added dropwise to the reaction mixture at 0° C. The mixture was allowed to cool to room temperature and stirred for 2 hr. The reaction was monitored on TLC using hexane:ethyl acetate (9:1) as mobile phase. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. to give 6.0 g of tert-butyl methyl(3-nitrophenyl)carbamate 7. 1H NMR: DMSO-d6 (400 MHz): 1.43 (s, 9H), 3.26 (s, 3H), 7.62 (t, 1H, J=8.4), 7.77 (d, 1H, J=8), 8.00 (d, 1H, J=9.2), 8.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[C:20](O)([CH3:23])([CH3:22])[CH3:21].CC(=C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:12]
Reactant: Cc1ccccc1C(=O)CCC(=O)O
Reactant: CC(C)(C)O
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)CCC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A mixture of 4-(2-methylphenyl)-4-oxobutanoic acid (40 g), concentrated sulphuric acid (4 mL) and t-butanol (4 mL) in dichloromethane (200 mL) is cooled to 0° C., and isobutylene (about 400 mL) is condensed into the mixture. It is then stirred at 0° C. until t.l.c. shows reaction is complete. The excess isobutylene is allowed to evaporate, and then the mixture is treated carefully with saturated aqueous sodium bicarbonate solution (200 mL), with vigorous stirring. The organic layer is separated, filtered through a pad of silica gel with the aid of more dichloromethane, and concentrated in vacuo, to give t-butyl 4-(2-methylphenyl)-4-oxobutanoate (5 g), in the form of a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C[O-].[Na+].[C:10]([CH2:18][C:19]#[N:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:20][C:19]1[N:3]([C:4]([NH2:6])=[O:5])[N:2]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NNC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)n1nc(-c2ccccc2)cc1N
Reaction time: 0.17 h
Yield: 51.3 %

Procedure:
To a stirred solution of 6.0 g of semicarbazide hydrochloride in 100 ml of ethyl alcohol is added 2.8 g of sodium methoxide at room temperature. The reaction mixture is stirred for 10 minutes and 7.0 g of benzoylacetonitrile added. The reaction mixture is heated at reflux for 1 hour, cooled and concentrated in vacuo to a yellow solid. The yellow solid is suspended in water, filtered and dried. The dried solid is suspended in 100 ml of ethyl alcohol and 10 ml of triethylamine followed by heating at reflux for 1 hour. The reaction mixture is cooled and the volatiles removed in vacuo to a residue which is suspended in water, filtered, washed with water and dried to give 5.0 g of the desired product as a solid, m.p. 255° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:11](Br)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:11]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2][CH2:3]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCCN1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Product: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 76.3 %

Procedure:
1-Piperazinepropanol was reacted with benzhydryl bromide in the same manner as Reference Example 1-(1) to give crystals of 4-benzhydryl-1-piperazinepropanol, m.p. 126°-128° C. Yield 76.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C>[Br:16][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][Cl:17])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH:13]([CH3:14])[CH3:15])[N:7]=1
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(NC(=O)CCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a solution of 7-amino-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.5 g, 1.8 mmol) in DMF (8 ml), was added TEA (0.28 ml, 1.98 mmol). After 5 min, 4-chlorobutyryl chloride (0.22 ml, 2.0 mmol) was added and the solution was stirred at RT for 2 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was diluted with DCM (30 ml) and washed with HCl (1M, 20 ml). The organic layer was separated, dried (MgSO4) and concentrated under vacuum. The residue was subjected to flash column chromatography (elution: 60% heptane, 40% EtOAc) to give N-(1-bromo-3-isopropyl-4-oxo-3,4-dihydro-phthalazin-6-yl)-4-chloro-butyramide (0.46 g, 67% yield) as a white solid.
Reaction SMILES: C([O:4][C:5]1[C:14]([CH:15]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:16]2[O:18][CH2:17]2)=[CH:13][C:12]([CH3:28])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:29])[NH:10]2)(=O)C.Cl>O1CCCC1CO.[OH-].[Na+]>[Si:21]([O:20][CH2:19][CH:15]1[C:14]2[C:5](=[C:6]3[C:11](=[C:12]([CH3:28])[CH:13]=2)[NH:10][C:9](=[O:29])[CH:8]=[CH:7]3)[O:4][CH:16]1[CH2:17][OH:18])([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:23])[CH3:22]
Reactant: CC(=O)Oc1c(C(CO[Si](C)(C)C(C)(C)C)C2CO2)cc(C)c2[nH]c(=O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CO)C2CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
5-Acetoxy-6-[1-(tert-butyldimethylsilyloxy)methyl-2,3-epoxypropyl]-8-methylcarbostyril (6.10 g, 14.6 mmol) was dissolved in a solvent mixture (150 ml) of tetrahydrofuran methanol (1:1), to which aqueous 1N-NaOH solution (25 ml) was added. The mixture was stirred at 50° C. for 30 minutes. Concentrated HCl was added to adjust the pH to about 5. Extraction was carried out using chloroform--water. The organic phase was dried over sodium sulfate and condensed under reduced pressure. The resultant residue was recrystallized from chloroform--ether--n-hexane. As a result, 5.10 g the title compound (mixture of diasteromers, 3.1) was obtained as colorless powdery crystals (93.0%).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:30][CH2:29][C:24]5(OCC[O:25]5)[CH2:23][CH2:22]4)[C@@H:17]3[CH2:31][CH2:32][CH2:33][N:34]=[N+:35]=[N-:36])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>O>[N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C@H:16]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:30][CH2:29][C:24](=[O:25])[CH2:23][CH2:22]4)[C@@H:17]3[CH2:31][CH2:32][CH2:33][N:34]=[N+:35]=[N-:36])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC2(CC1)OCCO2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCCC[C@@H]1[C@@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)CCN1C1CCC(=O)CC1
Yield: 99.6 %

Procedure:
The compound 44 (1.24 g), water (2 mL) and trifluoroacetic acid (18 mL) were stirred at room temperature for 4 hours and then concentrated. The residue was added aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and obtained the title compound (1.13 g) having the following physical properties.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[N:9][N:10]=1)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:18])=[O:24])=[CH:15][CH:16]=2)=[N:9][N:10]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nnc(-c2ccc(SC)cc2)o1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ccc(S(C)=O)cc2)o1
Reaction time: 0.5 h

Procedure:
To a solution of 2-ethoxycarbonyl-5-(4-methylthiophenyl)-1,3,4-oxadiazole (0.7 g) in chloroform (14 ml), m-chloroperoxybenzoic acid (0.57 g) was added dropwise at 4°-6° C. with stirring. After 30 minutes, the reaction mixture was extracted with chloroform (50 ml), washed with a sodium iodide aqueous solution, a sodium thiosulfate aqueous solution, a sodium hydrogencarbonate aqueous solution and brine successively and dried over magnesium sulfate. After evaporating the solvent, the residue was crystallized from diethyl ether to afford 2-ethoxycarbonyl-5-(4-methylsulfinylphenyl)-1,3,4-oxadiazole.
Reaction SMILES: C(O)(=O)C.O.[NH2:6]N.C[N:9]([CH:11]=[C:12]1[C:17](=O)[C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14][C:13]1=[O:21])C>C(O)CCC>[CH3:19][C:16]1([CH3:20])[C:17]2[NH:6][N:9]=[CH:11][C:12]=2[C:13](=[O:21])[CH2:14][CH2:15]1
Reactant: NN
Reactant: CN(C)C=C1C(=O)CCC(C)(C)C1=O
Solvent: CCCCO
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCC(=O)c2cn[nH]c21
Yield: 51.1 %

Procedure:
According to Scheme 2 Step 2: At 0° C., acetic acid (8.55 mL) followed by hydrazine monohydrate (150 mmol, 7.25 mL), were added slowly to a solution of 2-((dimethylamino)methylene)-4,4-dimethylcyclohexane-1,3-dione (150 mmol, 29.2 g) in butanol (400 mL). The reaction mixture was stirred under reflux for 16 hours. After evaporation of the filtrate, the crude residue was purified by flash chromatography over silica gel cyclohexane/AcOEt (100:0 to 50:50) and then over C18 gel using water/MeOH (100:0 to 50:50) as eluent to yield 7,7-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (76.7 mmol, 12.6 g, 51%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)=[N:6]2.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH3:33])[N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)=[N:8][C:7]([C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1)=[N:6]2
Reactant: [H][H]
Reactant: COc1cc(Oc2nc(-c3ccc([N+](=O)[O-])cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc(Oc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
70 mg (0.17 mmol) of 5,7-dimethyl-2-(4-nitrophenyl)-4-(3,4,5-trimethoxyphenoxy)-imidazo[5,1-f][1,2,4]triazine from example 14A are dissolved in methanol under argon. The mixture is treated with 20 mg of palladium on carbon (10% strength). It is hydrogenated for 5 h at a hydrogen pressure of 3 bar. The catalyst is then filtered off from the reaction mixture and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography. (Eluent:dichloromethane/methanol 80:1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][NH:13][C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1([C:30]2[CH:47]=[CH:46][CH:45]=[CH:44][C:31]=2[C:32]([NH:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=2)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][N:17]2[C@H:11]([CH2:12][N:13]([C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:32](=[O:33])[C:31]4[CH:44]=[CH:45][CH:46]=[CH:47][C:30]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:43][CH:42]=3)[C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CNc3ccccc3C(=O)N2C1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3C(=O)N2C1
Yield: 95 %

Procedure:
The same procedures used in Example 25 were repeated using (2R, 11aS)-2-(tert-butyldimethylsilyloxy)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo [2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 26 and 4-[(2-phenylbenzoyl)amino]benzoic acid to give the title compound. Yield 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-:26])=O)=[CH:22][CH:21]=1>>[C:24]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:24](=[O:26])[C:23]4[CH:22]=[CH:21][C:20]([N:19]([CH3:18])[CH3:29])=[CH:28][CH:27]=4)=[CH:10][CH:9]=3)[CH:5]=[N:6]2)=[CH:12][CH:13]=1)(=[O:26])[C:23]1[CH:27]=[CH:28][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(cnn3-c3ccc(NC(=O)c4ccccc4)cc3)c2)cc1

Procedure:
Compound 375 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-dimethylaminobenzoate. 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.01 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.33 (d, J=1 Hz, 1H), 8.01-7.78 (m, 11H), 7.55 (t, J=8 Hz, 2H), 6.77 (d, J=9 Hz, 2H), 3.00 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:21])([CH3:20])[C:4](=[O:19])[C:5]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)(C)C>[Cl:1][CH2:2][C:3]([CH3:21])([CH3:20])[CH:4]([OH:19])[C:5]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: CC(C)(CCl)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(C)O
Product: CC(C)(CCl)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
2.0 g (6.13 moles) of the E-isomer of 1-chloro-5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-penten-3-one (the compound of Example 2) and 0.467 g (4.11 mmoles) of calcium chloride were dissolved in 30 ml of isopropanol, and a solution of 0.167 g (4.3 mmoles) of sodium borohydride was added dropwise at -5° C. After 6 hours, the reaction mixture was warmed to 25° C. and concentrated in vacuo. The residue was poured onto water and the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulphate and concentrated in vacuo. The oily residue crystallised on trituration with diisopropyl ether. 1.1 g (55% of theory) of 1-chloro-5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-penten-3-ol of melting point 170° C. were obtained as the E-isomer.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:13][N:12]=[C:11]2[C:7]=1[CH2:8][CH:9]1[C:14]([CH3:16])([CH3:15])[CH:10]12)=[O:5])C.CO.[OH-].[Li+]>C1COCC1>[CH3:15][C:14]1([CH3:16])[CH:9]2[CH2:8][C:7]3[C:11]([CH:10]12)=[N:12][NH:13][C:6]=3[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]nc2c1CC1C2C1(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C2Cc3c(n[nH]c3C(=O)O)C21

Procedure:
(±)-1,1-Dimethyl-1a,3,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (0.0390 g, 0.177 mmol) was stirred for 18 hours at room temperature in a solution of 1:5:1 methanol:THF: 1M aqueous lithium hydroxide (14 mL). Solvent was removed under reduced pressure, the residue was taken up in 1M aqueous hydrochloric acid (5 mL) and extracted into ethyl acetate (40 mL). Solvent was removed under reduced pressure and the residue purified by preparative HPLC to give a white solid. m/z (ES+): 215 [N+Na]+, 193 [M+H]+, 175 [M−OH]+; 1H NMR (CD3CN): δ 2.91 (dd, 1H, J1=17.4, J2=6.8), 2.66 (d, 1H, J=17.4), 2.11 (dd, 1H, J1=6.3, J2=1.2), 2.05-1.95 (m, 1H), 1.19 (s, 3H, exo-CH3), 0.77 (d, 3H, J=2.0, endo-CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:13][CH:14]([C:20]1([CH3:25])OCC[O:21]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH2:13][CH:14]([C:20](=[O:21])[CH3:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]2=[O:26]
Reactant: CCOC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C(C)=O

Procedure:
Ethyl 2-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (264 mg, 26%) in the same manner as described in the above example 6 (20) from ethyl 3-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (1.13 g, 2.80 mmol) and p-toluenesulfonic acid monohydrate (100 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[NH2:30][C:31]1[N:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:32]=1[CH:51]=O>O1CCCC1.C(OCC)(=O)C>[NH2:30][C:31]1[C:32]([CH:51]=[CH:2][O:3][CH3:4])=[C:33]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[C:34]([C:40]([O:42][CH3:43])=[O:41])=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(C(C)C)nc(N)c(C=O)c1-c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=Cc1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (methoxymethyl)triphenyl-phosphonium chloride (260 mg, 0.75 mmol) in tetrahydrofuran (0.3 mL) was added, dropwise, a solution of potassium tert-butoxide (0.75 mL, 1.0 M in tetrahydrofuran). After 15 min, a solution of methyl 6-amino-4-(4-fluorophenyl)-5-formyl-2-(1-methylethyl)-3-pyridinecarboxylate (95 mg, 0.3 mmol) in tetrahydrofuran (0.3 mL) was added to the above mixture. The resulting mixture was stirred at room temperature for 2.5 h, diluted with ethyl acetate (15 mL) and washed with brine, dried (Na2SO4) and evaporated. The residue was purified by a silica gel chromatography (45 g column), eluting with 15% to 20% of ethyl acetate in hexanes to provide methyl 6-amino-4-(4-fluorophenyl)-2-(1-methylethyl)-5-(2-methoxyethenyl)nicotinate as a E/Z mixture (80 mg, 77%): LCMS (ESI, pos. ion spectrum) m/z 345 (M+H); HPLC (method 3) tR=2.4 min.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3]O.S(Cl)([Cl:16])=O>>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][Cl:16]
Reactant: CC(CO)CC(C)c1ccccc1
Reactant: O=S(Cl)Cl
Product: CC(CCl)CC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
219 g of 2,4-dimethyl-4-phenyl-butan-1-ol are added dropwise to 161 g of thionyl chloride, the mixture is stirred overnight at room temperature and then for 2 hours at 140° C., and the crude product is distilled to give 150 g of 2,4-dimethyl-4-phenylbutyl chloride of boiling point 84°-86° C./0.1 mm.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+].Cl>CO.O>[CH3:16][O:17][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(Sc2ccc(O)cc2)n1

Procedure:
A solution of 11.05 grams (0.05 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol (prepared as above in Example VI) and 8.10 grams (0.15 mole) of sodium methoxide in 200 milliliters of methanol was heated at reflux overnight. The resulting solution was acidified with concentrated hydrochloric acid and thereafter diluted with water. The solid 4-((6-methoxy-2-pyridyl)thio)phenol product was recovered by filtration, water washed and dried. The product was recovered in a yield of 10 grams (86 percent of theoretical) and melted at 88.5°-94.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16](C(O)=O)=[C:4]2[CH2:3]1.C(=O)=O>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Agent: O=C=O
Product: CN1Cc2cncn2-c2ccccc2C1=O

Procedure:
8.2 g of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are heated to 300°. After completion of the carbon dioxide evolution, the residue is left to cool and the material is recrystallized from chloroform/hexane. After drying, there is obtained 4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 212°-213°.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Li].[C:7]12[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12]C(=O)O[C:8]2=[O:9].Cl>CS(C)=O.C(OCC)C>[CH3:1][S:2]([NH:5][C:8]([C:7]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:12])=[O:9])(=[O:4])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: [Li]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CS(=O)(=O)NC(=O)c1ccccc1N
Temperature: 25 °C

Procedure:
Lithium methanesulfonamidate (1.0 g, 10 mmol) and isatoic anhydride (1.63 g, 10 mmol) in dimethyl sulfoxide (5 mL) were heated at 80° C. for 30 min. The reaction was cooled down to room temperature and acidified with hydrogen chloride in diethyl ether. The ether was evaporated and water added. The precipitated oil was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (95:5). The desired material was obtained in a yield of 0.52 g.
Reaction SMILES: [CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([O:24]CC)=[O:23])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+].O1CCCC1>O.C(OCC)(=O)C>[CH2:1]([NH:10][C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([OH:24])=[O:23])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Mix 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloroindole (300 mg, 0.79 mmol), lithium hydroxide monohydrate (2.39 mmol), tetrahydrofuran (2 mL) and water (2 mL). Stir at room temperature overnight. Dilute with water and ethyl acetate. Acidify the aqueous phase and separate the organic phase. Dry (MgSO4), evaporate the solvent in vacuo, and recrystallizethe residue (ethyl acetate/hexane) to give the title compound (175 mg, 64%).