Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([F:14])[CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(F)c1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 4-acetyl-2-(fluoro)benzenesulfonamide from step1 (4.0 g, 18 mmol) in acetic acid (90 mL) was added dropwise a solution of bromine (2.9 g, 18 mmol) in acetic acid (10 mL) at 40° C. The mixture was heated at 70° C. for 4 h. After cooled to room temperature, the mixture was concentrated and the residual brown solid was rrecrystallized from ethyl acetate-hexane to give the title compound (3.2 g, 60%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:6][NH:7][C:8]1[S:12][C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][C:9]=1[C:19]([F:21])([F:20])[F:22]
Reactant: CN(C(=O)OC(C)(C)C)c1sc(-c2cccnc2)nc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CNc1sc(-c2cccnc2)nc1C(F)(F)F
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of DCE (4 mL) was added methyl-(2-pyridin-3-yl-4-trifluoromethyl-thiazol-5-yl)-carbamic acid tert-butyl ester (0.616 g, 1.7 mmol) and trifluoroacetic acid (4 mL) and the mixture was stirred for 15 min. The solvents were removed under reduced pressure and the resulting residue was re-dissolved in DCE and aqueous saturated NaHCO3. The biphasic mixture was separated and the aqueous layer was extracted three times with DCE. The organic extracts were combined, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an off-white solid (0.357 g, 80%): mp 152-157° C.; 1H NMR (300 MHz, CDCl3) δ 8.95 (d, J=2.3 Hz, 1H), 8.57 (dd, J=4.9, 1.7 Hz, 1H), 8.11 (dt, J=8.2, 2.3 Hz, 1H), 7.23 (ddd, J=7.9, 4.9, 0.7 Hz, 1H), 4.83 (br s, 1H), 3.05 (d, J=4.9 Hz, 3H); ESIMS m/z 260 (M+1), m/z 257.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[F:20])[CH3:11].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([F:20])=[CH:15][C:16]2[N:17]=[C:22]([NH2:23])[S:21][C:18]=2[CH:19]=1)[CH3:11]
Reactant: N#C[S-]
Reactant: CC(Oc1ccc(N)cc1F)c1c(F)ccc(Cl)c1Cl
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1F)c1c(F)ccc(Cl)c1Cl
Yield: 97.5 %

Procedure:
6-[1-(2,3-Dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 2 g of 4-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-3-fluoroaniline, 2.44 g of potassium thiocyanate and 0.322 cm3 of dibromine. We obtain 2.3 g of 6-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-amine in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.OO.C(OCC)(=[O:24])C.CCCCCC>O>[Cl:19][C:14]1[CH:13]=[C:12]([CH:9]2[O:8][C:5]3=[N:6][CH:7]=[C:2]([OH:24])[CH:3]=[C:4]3[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: Clc1ccc(C2CCc3cc(Br)cnc3O2)cc1Cl
Reactant: CCOC(C)=O
Agent: OO
Solvent: CCCCCC
Solvent: O
Product: Oc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -75 °C
Reaction time: 2 h

Procedure:
6-Bromo-2-(3,4-dichlorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine (1.5 g) was converted to the corresponding lithio intermediate according to the procedure described in Example 23 and then quenched at -90° C. with 1.3 ml of tri-n-butyl borate. The resulting dark solution was stirred at -75° C. for 2 hours and then allowed to warm to 0° C. The mixture was then acidified with 3N hydrochloric acid, the organic phase was separated, and the aqueous layer was extracted with ether. The combined organic layers were concentrated to give a light brown, tacky solid. To this material was added 25 ml of 30% hydrogen peroxide and the resulting mixture was warmed at 60° C. for 30 minutes. The mixture was then cooled and diluted with 75 ml of water and the resulting mixture was extracted with two 50-ml portions of methylene chloride. The methylene chloride extracts were combined, washed with aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography (silica gel, 3% ethyl acetate/hexane) gave 2-(3,4-dichlorophenyl)-3,4-dihydro-6-hydroxy-2H-pyrano[2,3-b]pyridine melting at about 218°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[CH:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1)([CH3:40])[CH3:39]
Reactant: CC(C)c1ccc(CBr)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: CC(C)c1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-isopropylbenzene following the procedure of Example 478: MS (ESI) m/z 526;
Reaction SMILES: O1CCCC1.Cl[Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCCCCC>[CH2:12]([Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(CCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.5 %

Procedure:
In a 2 L 3-necked flask equipped with a nitrogen inlet, a 500 ml dropping funnel and a thermometer, was placed 500 ml of tetrahydrofuran. Chloro(chloromethyl)-dimethylsilane (100 ml, 0.744 mol) was added by syringe and the colorless solution cooled to 0° C. in an ice/acetone bath. Then benzylmagnesium chloride (2.0 M solution, 400 ml, 0.8 mol) was transferred to the dropping funnel by syringe and added dropwise over 2 hours. A slightly exothermic reaction was observed and the temperature was maintained below 10° C. After addition of the benzylmagnesium chloride was complete, the ice bath was allowed to warm up to room temperature without heating, and the reaction mixture was stirred overnight. Thereafter hexane (300 ml) was added and the reaction mixture was worked up by dropwise addition of saturated aqueous ammonium chloride (300 ml) and transferred to a 2 L separatory funnel with additional hexane (300 ml). After partitioning, the organic layer was washed with saturated aqueous ammonium chloride (200 ml) and saturated aqueous sodium chloride (200 ml). The combined aqueous layers were backwashed with hexane (2×500 ml). The combined organic layers were dried over magnesium sulfate, evaporated on a rotary evaporator, and finally evaporated with an oil pump to give a colorless oil 162.0 g (109.5% yield). A quantitative yield was assumed with a purity of the crude product as 91.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1.[N:22]([O-:24])=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:22]([O-:24])=[O:23])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1
Reactant: O=C(Nc1cncc2[nH]c3ccc(Cl)cc3c12)C(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
N-(6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (125 mg, 0.4 mmol, 1 equiv.) was dissolved in 2 ml TFA and NaNO2 (541 mg, 7.84 mmol, 2 equiv.) was added in one portion. The solution was stirred at room temperature for 4 hr. Volatiles were removed by rotovap, and the resulting oily orange solids were suspended in water, neutralized with a saturated aqueous sodium bicarbonate solution and filtered to give 132 mg (92%) of N-(6-chloro-8-nitro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide. 1H-NMR (300 MHz, DMSO-d6): δ 12.87 (s, 1H), 12.03 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.26 (s, 1H). Formic acid standard conditions. DAD RT=2.27 min. M+H=359.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:13])=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>O1CCCC1>[SH:15][C:14]1[NH:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]=2[N:13]=1
Reactant: CCOC(=O)c1cccc(N)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc2[nH]c(S)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
To a solution of 3-ethoxycarbonyl-1,2-phenylenediamine (790 mg) in tetrahydrofuran (10 ml) was added 1,1′-thiocarbonyldiimidazole (1.02 g) in ice water bath and the mixture was stirred for 20 hours at ambient temperature. The reaction solvent was concentrated in vacuo and the residue was washed with chloroform and collected by vacuum filtration to give ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (665 mg).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([OH:18])=O)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:15]=3[C:16]([NH:36][CH2:35][CH:34]([C:29]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)[CH3:37])=[O:18])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: CC(CNC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=12.51 min. MS (ESI−): mass calcd. for C22H16Cl4N4O3S2, 587.94; m/z found, 587/589/591 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.22 (s, 1H), 8.35 (d, J=7.0, 1H), 8.24 (d, J=8.8, 1H), 7.89 (s, 1H), 7.74-7.71 (m, 1H), 7.41 (d, J=8.2, 1H), 7.29 (d, J=2.0, 1H), 7.14 (s, 1H), 7.05 (dd, J=8.2, 2.0, 1H), 5.79 (s, 1H), 3.69-3.63 (m, 1H), 3.34-3.29 (m, 1H), 3.03-2.99 (m, 1H), 1.31 (d, J=7.0, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:40])[NH:12]2
Reactant: CC(=O)O
Reactant: Fc1ccccc1-c1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2F)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To the suspension of 4-(2-fluoro-phenyl)-1H-indole (1.30 g, 6.15 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (74 mL) was added pyridinium tribromide (5.90 g, 18.46 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(2-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.59 g, 42%) as a tan solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1>CN(C=O)C.O>[N:1]([CH2:6][N:7]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCn1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 12 h
Yield: 85.9 %

Procedure:
0.70 g (0.010 mol) of sodium azide is added, at room temperature, to a solution of 1.85 g (0.005 mol) of 1-chloromethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole in 25 ml of DMF. The reaction mixture is stirred for 12 h, diluted with 100 ml of H2O and extracted with ether. After drying the organic phase and concentration under vacuum, the residue is triturated with 20 ml of heptane, filtered and dried. We obtain 1.30 g of 1-azidomethyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 74° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nc(Cl)cc(-c2cc(Cl)ccc2C)n1
Product: Cc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2C)n1
Yield: 97 %

Procedure:
Following the method described in Example 38 (alternate method), 4-chloro-6-(5-chloro-2-methyl-phenyl)-2-methyl-pyrimidine and 4-chloroaniline provided the title compound (97% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 2.53 (s, 3H, CH3), 6.71 (s, 1H, Ar), 7.35-7.44 (m, 4H, Ar), 7.49 (d, 1H, J=2.2 Hz, Ar), 7.78 (d, 1H, J=8.8 Hz, Ar), 9.72 (s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:37].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6,6′-trimethyl-[2,2′]bipyridine (compound 446) (75 mg) was dissolved in methylene chloride (2 ml) to prepare a solution. The solution was brought to 0° C., trifluoroacetic acid (1 ml) was added thereto, and the mixture was stirred at 0° C. for 30 min and then at room temperature for 4 hr. The reaction solution was brought to 0° C., was stirred and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N:32]1[S:36][N:35]=[C:34]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:33]=12>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[C:34]5=[N:35][S:36][N:32]=[C:33]5[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc5nsnc45)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and benzo[1,2,5]thiadiazole-4-sulfonyl chloride. Purity (ELSD, based on MW=619.7)=80%.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:15][CH:14]=1
Reactant: OCCCCCCOc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCCCOc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
To a suspension of 32 g (0.15 mol) of pyridinium chlorochromate in 450 ml of methylene chloride is added 23 g (0.1 mol) of 6-(4-chlorophenoxy)-1-hexanol. The mixture is maintained under a nitrogen atmosphere for 2 hours, is diluted with 1000 ml of ethyl ether and is stirred for 1.5 hours.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[OH2:16]>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:6]([C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][C:9](=[O:16])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: O
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc(-c2ccc(F)cc2)cc1=O

Procedure:
25 gms of ethyl 4-fluorobenzoylacetate was dissolved in 250 gms of 1:10 P2O5 /methanesulfonic acid and heated at 45° for 4 days. The mixture was cooled, poured into 1200 mls of water and extracted with (3×100 mls) methylene chloride. Evaporation of the solvent and chromatography of the resulting oil (silica gel/ether) provided 12.9 gms of crystalline 2,6-di(4'-fluorophenyl)-3-ethoxycarbonyl-pyr-4-one. mp=113-114.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:34]1[CH:33]=[CH:32][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)(=[O:13])=[O:14])(=[O:22])=[O:23]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccc4ccccc4c3)c2c1
Yield: 29 %

Procedure:
2-Methylsulfonyl-N-(3-naphthalen-2-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 298 mg of 2-naphthaleneboronic acid, 20 ml of dimethylformamide, 1.88 ml of a saurated aqueous sodium hydrogencarbonate solution and 24.5 mg of tetrakis(triphenylphosphine)palladium[0]. 120 mg of 2-methylsulfonyl-N-(3-naphthalen-2-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 221° C. (analysis C24H19N3O4S2 % calculated C, 60.36; H, 4.01; N, 8.80; O, 13.40; S, 13.43. % found C, 60.09, H, 4.06; N, 8.55; S, 13.51).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])=[S:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: COC(CN)OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=S)NCC(OC)OC)cc1

Procedure:
A solution of 10 g (0.06 mole) of p-methoxyphenylisothiocyanate in 100 ml of CHCl3 was treated with 6.3 g (0.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-(β,β-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated H2SO4 and 20 ml of H2O was refluxed for 3 hr. The mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptomidazole, 4.9 g (70%), mp 215°-7°.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3

Procedure:
An 8.17 gm (0.030 mole) quantity of the compound of Example 9 was added to 3.54 gm (0.035 mole) of triethylamine, 300 mg of 4-dimethylaminopyridine, 3.24 gm (0.035 mole) of propionyl chloride and 50 ml of methylene chloride. This mixture was refluxed for 61/2 hours. The solvent was evaporated. The residue was patitioned between CH2Cl2 and water. The organic layer was washed with water, dried, and evaporated, resulting in a gummy residue. This residue was triturated with ether and hexane, producing a white solid. The solid was filtered and washed with ethane, then treated with benzene and hexane producing crystalline N-(7,8,9,10-tetrahydro-6-(1-piperidinyl)-1,2,4-triazolo [3,4-a]phthalazin-3yl)propanamide; mp 173-174° C. (benzene-hexane).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[NH2:12].NC1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C)cc(C)c1
Temperature: 25 °C
Yield: 99 %

Procedure:
Acetic anhydride (2.84 mL, 30 mmol) was dissolved in dry THF (10 mL), purged with N2 and brought to 0° C. 3,5-Dimethylaniline (1.25 mL, 10 mmol) was then added dropwise. After the addition of the aniline, the reaction was allowed to warm to room temperature and stirred for an additional hour. The solution was then poured over ice and 1 M NaOH (aq) was added until the pH was between 12 and 14. The precipitate was filtered, dissolved in DCM and dried over Na2SO4. The drying agent was filtered and solvent was removed under reduced pressure to afford pure product in 99% yield as a white solid.