Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:2]4[S:1][CH:5]=[N:4][N:3]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nncs1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nncs1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1,3,4-thiadiazol-2-ylcarbamate (247 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (161 mg, 53.2%) as a solid.
Reaction SMILES: P([O:5][C:6]1[C:7]([O:9][C@H:10]([C@H:13]([CH2:15][OH:16])[OH:14])[C:11]=1[O-:12])=[O:8])([O-])([O-])=O.[Mg+2].[K+].CO.C(O)C>CC(C)=O>[OH:12][C:11]1[C@@H:10]([C@@H:13]([OH:14])[CH2:15][OH:16])[O:9][C:7](=[O:8])[C:6]=1[OH:5]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1OP(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
the resulting potassium magnesium L-ascorbate 2-phosphate is isolated from the resulting aqueous solution by concentration and/or treatment with methanol, ethanol or acetone.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:15]([CH2:24][CH3:25])[CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O)[CH3:14].[NH2:26][C:27]1[CH2:33][N:32]=[C:31]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])[C:30]2[CH:42]=[C:43]([N+:46]([O-:48])=[O:47])[CH:44]=[CH:45][C:29]=2[N:28]=1>O1CCCC1.CN(C)C=O>[N+:46]([C:43]1[CH:44]=[CH:45][C:29]2[N:28]3[C:19]([CH2:18][CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[CH2:24][CH3:25])=[CH:20][C:21](=[O:23])[N:26]=[C:27]3[CH2:33][N:32]=[C:31]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])[C:30]=2[CH:42]=1)([O-:48])=[O:47]
Reactant: CCN(CC)CCCC#CC(=O)O
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2c(F)cccc2F)=NC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(CC)CCCc1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 21, carbonyldiimidazole, 6-diethylamino-2-hexynoic acid and 2-amino-7-nitro5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 9-nitro-1-(3-diethylaminopropyl)-7-(2,6-difluorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[OH:31][CH:32]1[CH2:37]OC(O)CO1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH2:37][CH2:32][OH:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Reactant: OC1COC(O)CO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(CCO)C1
Product: Cl
Reaction time: 0.17 h
Yield: 22 %

Procedure:
Dissolve 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (500 mg, 1.13 mmol) and 2,5-dihydroxy-1,4-dioxane (68 mg, 1.13 mmol) in dry 1,2-dichloroethane (6.66 mL). Add sodium triacetoxyborohydride (500 mg, 2.26 mmol) and stir overnight at room temperature. Add 1 N NaOH solution to the reaction mixture and extract with CH2Cl2 (2×25 mL). Combine the organic portions and wash with water (2×25 mL). Dry the organic layer with Na2SO4, filter, and concentrate in vacuo. Purify on HPLC, 4.6×75 mm XBridge® C18, Eluent: Reverse phase gradient 5-95% MeOH/water 0.1% TFA in 10 min, 2 mL/min. Re-dissolve the acquired material in CHCl3 and add 1 N HCl/Et2O solution (160 μL), followed by concentration in vacuo to give 65 mg (13%) of the title compound. ES/MS m/z (35Cl) 486.0 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([O:20][CH3:21])([CH3:19])[CH2:13][CH2:12]2)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([O:20][CH3:21])([CH3:19])[CH2:13][CH2:12]2
Reactant: COC1(C)CCc2cc(OCc3ccccc3)ccc2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC1(C)CCc2cc(O)ccc2O1
Reaction time: 9 h

Procedure:
To a solution of the (±)-6-benzyloxy-2-methoxy-2-methylchroman prepared in Example 45 in 250 ml. of ethanol was added 2.5 g. of 10% palladium on carbon catalyst, and the resulting mixture was hydrogenated at atmospheric pressure and room temperature. After 9 hours, the uptake of hydrogen (3100 ml.) had ceased. The catalyst was removed by filtration and the filtrates were stripped of solvent at reduced pressure. Crystallization of the solid residue from ether-30°-60° petroleum ether gave (±)-6-hydroxy-2-methoxy-2-methylchroman as white needles, m.p. 128°-130°.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[C:9]([N:13]=[C:14]=[S:15])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([NH:13][C:14]([NH:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4])=[S:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)N=C=S
Reactant: CCCC[C@@H](N)CO
Solvent: CCO
Product: CCCC[C@H](CO)NC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
The process is performed as in Example 2, starting with 1.14 g of (2R)-2-amino-2-butyl-1-ethanol and 1.36 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol, with stirring for 18 hours at a temperature in the region of 20° C. and then for 3 hours in the region of 60° C. After concentration of the reaction medium under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.38 g of N-(tert-butyl)-N′-[(1R)-1-butyl-2-hydroxyethyl]thiourea are obtained in the form of a yellow oil. Infrared spectrum (CH2Cl2): 3620; 4430; 4410; 2960; 1560; 1500; 1395; 1375 and 1205 cm−.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]1([P:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:9]1([P:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH:18]=[N:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[N:8]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[P:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=Cc1ccccc1P(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C(=N[C@@H]1CCCC[C@H]1N=Cc1ccccc1P(c1ccccc1)c1ccccc1)c1ccccc1P(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
7.5 g of granulated molecular sieves (4A) are baked in a Schlenk tube. After addition of 50 ml of dichloromethane, 1.75 g (15 mmol) of trans-1,2-diaminocyclohexane and 8.7 g (30 mmol) of o-diphenylphosphinobenzaldehyde, the reaction mixture is stirred for 24 hours. After filtration through Celite, the solvent is removed and the residue is recrystallized with 50 ml of ethanol, giving the product in the form of a light-yellow powder in a yield of 8.6 g (13 mmol, 87%). 1H-NMR (400 MHz, CDCl3): δ=8.71 (d, J=4 Hz, 2H, N═C—H), 7.78–6.64 (m, 28 H, aromat. H), 3.16 (m, 2H, C—H), 1.66–1.31 (m, 8H, (CH2)4) ppm.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]1([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[OH:38][C@@H:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:27]([C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:22]=1)[C:28]([OH:30])=[O:29]
Reactant: O=Cc1ccccc1
Reactant: O=C(O)Cc1cccc(C#Cc2ccccc2)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)[C@@H](c1cccc(C#Cc2ccccc2)c1)[C@@H](O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To diisopropylamine (0.241 mL, 1.693 mmol) in tetrahydrofuran (10 mL) under nitrogen at −78° C. was added n-BuLi (0.677 mL, 1.693 mmol). After 60 min, the colorless solution was warmed to −20° C. and a solution of 2-(3-(phenylethynyl)phenyl)acetic acid (200 mg, 0.847 mmol; Araldi, G. L.; Liao, Y.; Brugger, N. Hydrazide Deriviatives as Prostaglandin Receptor Modulators. WO 2005/012232 A2, 2005) in tetrahydrofuran (5 mL) was added resulting in a red solution which was allowed to stir for 45 min as the cooling bath temperature rose to 5° C. The reaction was recooled to −30° C., benzaldehyde (0.103 mL, 1.016 mmol) was added dropwise resulting in immediate disappearance of the red color and the cooling bath was removed. After 48 h, the reaction mixture was quenched with 1N HCl (20 mL), extracted with ethyl acetate (3×20 mL), washed with brine, dried over MgSO4, filtered and concentrated providing (2S,3R)-3-hydroxy-3-phenyl-2-(3-(phenylethynyl)phenyl)propanoic acid as an amber oil which was used in the next step without further purification or characterization.
Reaction SMILES: CC1(C)[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([N:11]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]([NH:34][C:35]([C:37]5[N:38]=[C:39]([CH:42]6[CH2:44][CH2:43]6)[O:40][CH:41]=5)=[O:36])=[C:16]([N:21]5[CH2:26][CH2:25][N:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])[CH2:23][CH2:22]5)[CH:17]=4)[C:12]3=[O:45])[C@H:4]2[O:3]1.Cl>CO.ClCCl>[OH:3][C@H:4]1[C@@H:5]([OH:6])[CH2:7][CH2:8][CH2:9][C@@H:10]1[N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:34][C:35]([C:37]3[N:38]=[C:39]([CH:42]4[CH2:43][CH2:44]4)[O:40][CH:41]=3)=[O:36])=[C:16]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:17]=2)[C:12]1=[O:45]
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2coc(C4CC4)n2)C(=O)N([C@H]2CCC[C@@H]4OC(C)(C)O[C@@H]42)CC3)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2coc(C4CC4)n2)C(=O)N([C@H]2CCC[C@H](O)[C@@H]2O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-cyclopropyl-oxazole-4-carboxylic acid [(S)-2-((3aR,7aS)-2,2-dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide (0.165 g, 0.26 mmol) in anhydrous methanol (2 mL) was added methanolic HCl (5 mL) at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 1 h. The progress of the reaction was monitored by the TLC. Upon completion of the reaction, the reaction mixture was concentrated in vacuo, residue obtained was diluted with dichloromethane (100 mL); and was washed with 10% NaHCO3 solution, water followed by brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) by eluting 3.25-3.5% methanol in dichloromethane to afford the title compound. Finally, the title compound 2-cyclopropyl-oxazole-4-carboxylic acid [(S)-2-((2R,3S)-2,3-dihydroxy-cyclohexyl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide was purified again by preparative HPLC to afford the pure compound. Yield (0.110 g, 65%, off white solid).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].C([SiH](CC)CC)C.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Temperature: 2.5 °C
Yield: 181.7 %

Procedure:
3-Nitro-1-(4-octylphenyl)propan-1-one (37 g) and dichloromethane (185 mL) are charged into a round bottom flask at 25-30° C. and stirred. Triethylsilane (36.87 g) is charged into the flask and the reaction mixture is cooled to 0-5° C. Titanium tetrachloride (28.9 g) in dichloromethane (185 mL) is added to the reaction mixture over the period of 30 minutes at temperature below 5° C. and the reaction mixtures is stirred at a temperature of 25-30° C. for about 1 hour. The reaction mixture is added to water (370 mL) precooled to 0-5° C., stirred, and the organic layer is separated. The organic layer is washed with aq. sodium bicarbonate (2×370 mL), followed by water (370 mL), and brine solution (370 mL). The organic layer is dried over sodium sulphate and evaporated under reduced pressure at about 45° C. to give 64.0 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([OH:31])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:19]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([O:31][C:16]1[CH:15]=[C:14]([Cl:13])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH:17]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(CCOc2cc(O)cc(Cl)c2)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(CCOc2cc(Cl)cc(OS(=O)(=O)c3ccc(F)cc3Cl)c2)cc1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
2-Chloro-4-fluorobenzenesulfonyl chloride (1.16 g; 5.0 mmol) was added to a cold solution (ice:water temperature) of 3-chloro-5-[2-(4-cyanophenyl)-ethoxy]phenol (0.689 g; 2.5 mmol; from step (ii) above) in pyridine (8 mL). The temperature was allowed to rise (slowly) to ambient overnight. The mixture was re-cooled (ice:water temperature) and ice was added to the reaction flask. After stirring for 4 hours, the pyridine was removed in vacuo. CH2Cl2 was then added and the organic layer was washed with aqueous KHSO4 and water. Drying (MgSO4), evaporation of the solvent and purification by flash chromatography (SiO2; CH2Cl2) afforded 0.84 g (72%) of the sub-title compound.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=2[O:12]1.C[O-:23].[Na+].CO>C(OC)(OC)OC>[OH:23][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH:2]=[CH:16][C:15]1[CH:18]=[CH:19][C:20]2[O:21][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: C[O-]
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Reaction time: 0.5 h

Procedure:
A mixture of 2-hydroxyacetophenone on Wang resin (2.0 g, 1.76 mmol) was swelled in trimethyl orthoformate (20 mL) for 10 min. 3,4-Methylenedioxybenzaldehyde (6.0 mmol) was added and 25% NaOMe in MeOH (0.86 g, 4.0 mmol) was added to the mixture dropwise over 30 min. The mixture was then stirred for an additional 0.5 h. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 2.23 g of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:7]1[C:8](=[O:13])[CH2:9][CH2:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:6]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Product: O=C1CCC(=O)N(Cc2ccccc2)c2cc(Cl)ccc21
Yield: 38 %

Procedure:
In a manner similar to that described for Method W, 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione and benzyl bromide were converted to the title compound (38%): MS m/z=300 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[C:22]4=[O:29])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[C:22]4=[O:29])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: CCCN1CCN(c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)C1=O
Agent: Br
Product: CCCN1CCN(c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)C1=O
Yield: 89 %

Procedure:
A mixture of 7 parts of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone and 225 parts of a hydrobromic acid solution 48% was stirred and refluxed for 5 hours. After cooling, the precipitated product was filtered off, washed with 2-propanol and dissolved in a mixture of methanol and water. The solution was neutralized with a sodium hydrogen carbonate solution. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was triturated in dichloromethane. The product was filtered off and dried, yielding 6 parts (89%) of 1-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3-propyl-2-imidazolidinone (46).
Reaction SMILES: C([Si:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15]C=2)[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)CCCC.Br[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1.Br[CH2:35][C:36]([F:39])([F:38])[F:37]>>[CH2:13]([Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:24][CH:25]=2)[CH2:10][CH2:11]1)[CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: FC(F)(F)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(OCC(F)(F)F)cc2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4-n-pentyl-4-phenyl-4-silacyclohexanone, 4-bromo-1-(t-butyldimethylsiloxy)benzene and 1-bromo-2,2,2-trifluoroethane, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:19]([OH:22])(=[O:21])=[O:20].Cl.C[O-].[Na+:26]>C(Cl)(Cl)Cl>[S:19]([O-:22])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:21])=[O:20].[Na+:26]
Reactant: CCCCCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methylpentadecanol (119 g, 0.496 mol), prepared as an intermediate in Example II. Chlorosulfonic acid (61.3 g, 0.52 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with an ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until a aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added methanol (1 L) and 300 ml of 1-butanol. Vacuum filter off the inorganic salt precipitate and remove methanol from the filtrate on a rotary evaporator. Cool to room temperature, add 1 L of ethyl ether and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (82 g, 90% active by cat SO3 titration).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH:17]([OH:20])([CH3:19])[CH3:18]>O1CCCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:20][CH:17]([CH3:19])[CH3:18])=[O:16])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)O
Reactant: CC(C)OC(=O)c1cc(N=C=O)ccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Reaction time: 8 h

Procedure:
NMR (CDCl3): 1.39 (6H,d), 5.26 (1H,m), 6.98-7.52 (3H,m). 1-Methylethyl 2-chloro-5-isocyanatobenzoate (3 g, 0.013 mole) in tetrahydrofuran (5 ml) was added to isopropyl alcohol (5 ml) in tetrahydrofuran (5 ml). A few drops of triethylamine were added and the reaction mixture left at ambient temperature overnight. Removal of the solvent and crystallization from isopropyl alcohol gave the title compound, m.p. 108°-109° C. (2.7 g).
Reaction SMILES: [NH3:1].CC(O)C.Cl[C:7]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)([C:28]1[N:32]([CH3:33])[C:31]([S:34][CH3:35])=[N:30][N:29]=1)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]1[N:18]=[N:19][N:20]=[C:13]1[N:12]=[C:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]([C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)([C:28]4[N:32]([CH3:33])[C:31]([S:34][CH3:35])=[N:30][N:29]=4)[NH2:1])[CH:9]=3)[N:14]3[N:18]=[N:19][N:20]=[C:13]3[N:12]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: N
Reactant: CSc1nnc(C(Cl)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CSc1nnc(C(N)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
NH3/iPrOH saturated solution (40 ml) was added dropwise at 0° C. to a solution of 7-[chloro(4-chlorophenyl)[4-methyl-5-(methylthio)-4H-1,2,4triazol-3-yl)methyl]-5-(3-chlorophenyl)-tetrazolo[1,5-a)quinazoline (0.0036 mol) in THF (80 ml). The mixture was stirred from 0° C. to room temperature then at room temperature for 2 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue (2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 98/2/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.35 g (18%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-tetrazolo[1,5-a]quinazoline-7-methanamine. A sample (0.15 g) was crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.05 g of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 150° C.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6]([C:20]([O:22][CH2:23][CH3:24])=O)=C2S(Cl)(=O)=O.Cl[S:30]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35](S(C2C=CC=CC=2)(=O)=O)[C:34]=1[C:53]([O:55]CC)=O)(=[O:32])=[O:31].Cl.CN.[NH:61]1CCOCC1>C(N(CC)CC)C>[CH3:43][O:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:53]([NH2:61])=[O:55])=[C:33]2[S:30]([N:7]1[CH2:6][CH2:20][O:22][CH2:23][CH2:24]1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride and triethylamine with morpholine, the title compound was obtained. HRMS (ES) exact mass calculated for C14H18N3O5S (M+H+): 340.0962. Found 340.0960.