Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].O.C([O:10][C:11]1[CH2:15][CH2:14][CH2:13][C:12]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])(=O)C.BrBr>CN(C)C(=O)C.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:12]1[C:11](=[O:10])[CH2:15][CH2:14][CH:13]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCCCC1=CCCC1=O

Procedure:
To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5 l. of chloroform cooled to 5° C. is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below 10° C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO4), and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l of N,N-dimethylacetamide under nitrogen and the mixture is then refluxed for thirty minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield 757 g. of an oil, b.p. 116°-118° C. (0.25 mm.).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH2:14]2)=[O:10]>C1COCC1>[O:20]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([C:9]([C:8]3[CH:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][CH:21]=3)=[O:10])[CH:12]=2)[NH:16]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A dry 25 mL flask was charged with acetyl chloride (0.273 g, 3.48 mmol) and THF (5 mL). 5-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 1, 0.675 g, 2.67 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The tan precipitate was filtered to afford N-[3-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.478 g, 1.48 mmol, 61%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:14][CH3:15])[C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1.CCN(C(C)C)C(C)C.[H][H].O>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[C:6]([CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: [H][H]
Reactant: COc1c(C)ccc2c(Cl)nc(Cl)nc12
Agent: [Pd]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1c(C)ccc2cnc(Cl)nc12
Yield: 67.4 %

Procedure:
To a solution of 2,4-dichloro-8-methoxy-7-methylquinazoline (43 g, 0.177 mol) in EtOAc (2580 mL) were added DIPEA (22.9 g, 0.177 mol) and Pd/C (8.6 g) in one portion. The reaction mixture was stirred at room temperature for 6 h under 20 psi of hydrogen. Water (800 mL) was added and the mixture was filtered. The filtrate was separated, the organic layer was washed with water (500 mL). The combined aqueous layers were re-extracted with EtOAc (700 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product. The crude product was re-crystallized from EtOAc (64 mL)/petroleum ether (192 mL) to give the title compound (24.9 g, 67.5%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C2CCCN2)cc1Cl
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(F)c(Cl)c1

Procedure:
The title compound, white solid, m.p. 116° C. and MS: m/e=358.1 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-chloro-4-fluoro-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([N+:13]([O-])=O)[C:6]=2[O:5]1>C1COCC1.[Pd]>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([CH3:16])[CH:11]=[C:12]([NH2:13])[C:6]=2[O:5]1
Reactant: COCC1Cc2cc(C)cc([N+](=O)[O-])c2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: COCC1Cc2cc(C)cc(N)c2O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-(methoxymethyl)-5-methyl-7-nitro-2,3-dihydrobenzofuran (8a) (0.85 g, 3.8 mmol) and Pd/C (90 mg, 10%) in THF (10 mL) was introduced H2 and stirred at ambient temperature for 12 h. The mixture was filtered through celite and concentrated to give the title compound (8b) as oil. MS-ESI (m/z): 194 (M+1)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 63.5 %

Procedure:
tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (3.00 g, 16.02 mmol) was dissolved in dry DCM (50 mL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38 g, 20.83 mmol) was added followed by TEA (2.43 g, 24.03 mmol) and the reaction mixture was stirred at 0° C. for 3.5 h. The reaction mixture was washed with water (250 mL) and dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compound (2.70 g, 63.5%). 1H NMR (500 MHz, CDCl3): δ 1.38 (s, 9H), 2.07 (bs, 1H), 2.18 (bs, 1H), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.
Reaction SMILES: CO[C:3]1[C:7]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:6][S:5](=[O:16])[N:4]=1.CN(CC1OC(CSCCN)=CC=1)C>CO>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:7]2[CH:3]=[N:4][S:5](=[O:16])[N:6]=2)[CH:11]=1
Reactant: COC1=NS(=O)N=C1NCc1cccnc1
Agent: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: O=S1N=CC(NCc2cccnc2)=N1
Reaction time: 18 h

Procedure:
To the methanol solution of 3-methoxy-4-(3-pyridyl)methylamino-1,2,5-thiadiazole 1-oxide produced in Step A was added a solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (4.0 g; 18.7 mmoles) in 30 ml of methanol. The reaction mixture was stirred at ambient temperatures for 18 hours and the solvent was removed in vacuo. The residue was placed on 500 g of silica gel (230-400 mesh) and purified by flash chromatography using a gradient elution of acetonitrile-methanol After combining the appropriate fractions, the title compound was obtained as an amber oil (4.25 g) containing one mole of methanol.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([F:1])[C:3]=2[F:12])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cc2ccoc2c(Br)c1F
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)c(F)cc2ccoc12
Yield: 38.7 %

Procedure:
Beginning with 0.22 gm (0.94 mMol) 5,6-difluoro-7-bromobenzofuran and 0.21 gm (1.04 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 0.13 gm (38%) of the desired compound were prepared essentially as described in EXAMPLE 19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:25][C:22]1[CH:23]=[CH:24][C:19]([S:17]([NH2:27])(=[O:18])=[O:26])=[CH:20][CH:21]=1)[N:8]=[CH:7]2
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)ncc2c1
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(C(F)(F)F)cc(Br)c3n2)cc1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a 0.30 M solution of 8-bromo-2-chloro-6-(trifluoromethyl)quinazoline in 2-propanol was added sulfanilamide (1.0 eq). The reaction was stirred at 110° C. for 14 h. The hydrochloride was collected by vacuum filtration and then stirred in aqueous sodium bicarbonate. The solid was collected by vacuum filtration and rinsed with water. The light yellow solid was dried in a desiccator to give 343 mg of the desired product. ES/MS m/z 447, 449 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([C:50]1[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=1[NH2:52])[CH2:48][CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][C:51]4[CH:53]=[CH:54][CH:55]=[CH:56][C:50]=4[CH2:47][CH2:48][CH3:49])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCc1ccccc1N
Product: CCCc1ccccc1NC(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-n-propylaniline (Aldrich) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [CH2:1]([PH:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:29]=1[C:30](Cl)=[O:31]>O1CCCC1>[CH2:1]([P:8](=[O:13])([CH2:9][CH2:10][CH2:11][CH3:12])[C:30](=[O:31])[C:29]1[C:28]([O:27][CH3:26])=[CH:36][CH:35]=[CH:34][C:33]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CCCC[PH](=O)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCP(=O)(Cc1ccccc1)C(=O)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 13.2 g (0.067 mol) of benzyl-butylphosphin oxide and 12.7 ml (0.101 mol) of trimethylchlorosilane in 100 ml of tetrahydrofuran are added 18.7 ml (0.134 mol) of triethylamine under a nitrogen atmosphere at 0°-5° C. in the course of 15 minutes. After 2 hours of stirring at 0°-5° C., 13.5 g (0.067 mol) of 2,6-dimethoxybenzoyl chloride, diluted in 50 ml of tetrahydrofuran, are added during the course of 20 min. the stirring at 0°-5° C. is continued for 2 h, then the solution is allowed to warm to room temperature and filtered over silicea gel. The solution is concentrated in vacuo and the residue recrystallized from a hexan/acetic acid ester mixture. 3.8 g (15.8% of theory) of the title compound with a melting point of 56°-57° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15]>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:15]=[N:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]12
Reactant: Cn1c(=O)[nH]c2ccccc2c1=O
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c3ccccc3c(=O)n(C)c12

Procedure:
M.p. 211.4°-211.8° C. by reaction between 3-methyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and ethyl isocyanoacetate.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[C:12]([CH3:19])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[S:18])[N:3]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:1][CH3:2])=[C:12]([CH3:19])[CH:11]=1
Reactant: CCNCCC(=O)O
Reactant: Cc1cc(Cl)ccc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCC(=O)O)C(=S)Nc1ccc(Cl)cc1C
Yield: 36.6 %

Procedure:
3-Ethylaminopropionic acid (19.8 g) was reacted with 4-chloro-2-methylphenylisothiocyanate (20 g), triethylamine (20 g), and methylene chloride (250 mL) according to the procedure described in step 2 of Example 1 to give 12 g of 3-[3-(4-chloro-2-methylphenyl)-1-ethyl-thioureido]propionic acid. The product (12 g) was dissolved in acetone (245 mL). Conc. HCl (5 mL) was added and the mixture was heated at reflux for 18 hours. The reaction mixture was evaporated to dryness. The residue was dissolved in methylene chloride (100 mL), and washed with 1N NaOH. The organic phase was dried over anhydrous magnesium sulfate, then evaporated to dryness. The solid was recrystallized from ethanol. The title compound (8 g) was obtained as a white solid., m.p. 133°-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([S:20]([C:23]3[S:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:27]=3)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([S:20]([C:23]3[S:24][CH:25]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:27]=3)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]
Reactant: CCCC(c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1)S(=O)(=O)c1nc(-c2ccccc2)cs1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(c1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1)S(=O)(=O)c1nc(-c2ccccc2)cs1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4-{1-[(4-phenyl-1,3-thiazol-2-yl)sulfonyl]butyl}benzyl)oxy]phenyl}propanoate (0.360 g, 0.619 mmol) in a mixture of ethanol (1.5 mL) and tetrahydrofuran (3 mL) was added 1N aqueous sodium hydroxide solution (0.75 mL), and the mixture was stirred at 50° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was weak acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) and recrystallized from ethyl acetate-hexane to give the title compound (0.300 g, yield 88%) as colorless crystals.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[S:5][CH:6]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:2]2[N:3]=[C:4]([C:7]3[CH:12]=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:9]([CH3:23])[N:8]=3)[S:5][CH:6]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)cs2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-thiazol-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.80) (0.5 g, 1.253 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.354 g, 1.378 mmol) according to the general procedure VI. Obtained as a white solid (0.10 g, 15%) and additional off-white solid (0.40 g, 60%). MS (ISP) 532.1 [(M+H)+]; mp 196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=1>COCCOC>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:56])([NH:54][CH3:55])=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CNS(C)(=O)=Nc1ccc(Cl)nc1
Solvent: COCCOC
Product: CNS(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)nc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(6-chloropyridin-3-yl)-N-methyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 13 (Step 3) using 1,2-dimethoxyethane as a solvent. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=687 [M+H]+.
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].[Cl:52][C:53]1[C:54]([CH2:59]Cl)=[N:55][CH:56]=[CH:57][CH:58]=1>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:59][C:54]3[C:53]([Cl:52])=[CH:58][CH:57]=[CH:56][N:55]=3)[N:39]=2)[N:36]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: ClCc1ncccc1Cl
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 3-chloro-2-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 388.3 (MH+).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.COC(=O)C1C=CC(N2C=C(C3[C:47]([C:55]4[CH:60]=[CH:59]C=CC=4)=[N:48]OC=3C(F)(F)F)N=C2)=CC=1>>[CH:55]1([CH2:47][NH:48][C:3](=[O:31])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[CH:6][CH:5]=2)[CH2:60][CH2:59]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 69 %

Procedure:
As described for Example 10, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol), instead of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester was converted, to the title compound (75 mg, 69%) which was obtained as a white solid. MS: m/e=471.0 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([S:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([S:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.7 %

Procedure:
814 μl of a 1M aqueous solution of boron tribromide in methylene chloride were added to a solution of 300 mg of methyl 4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 9) in 1.2 ml of methylene chloride at -78° C., and the resulting mixture was allowed to react at room temperature for 5 hours, and then poured into ice-water and stirred for 30 minutes. At the end of this time, the reaction mixture was neutralized with an aqueous solution of sodium bicarbonate, and then extracted with chloroform. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography eluted with a 30:1 by volume mixture of chloroform and methanol, to give 25 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]1=[O:21].BrN1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].[CH3:35][C:36]1[NH:37][C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH2:12][C:44]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]=3[CH3:35])[S:11][C:5]=2[N:4]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:3]1=[O:21]
Reactant: COC(=O)c1c(C)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Reactant: Cc1cc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(Cc2c(C)[nH]c3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 1,2,3,4-tetrahydro-3,6-dimethyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylate [example 1 step a), 7.00 g) and N-bromosuccinimide (4.42 g) in chloroform (140 ml) was refluxed under illumination from a tungsten lamp for 2 hours. The solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (140 ml) and 2-methylindole (5.92 g) were added and the mixture stirred rapidly for 48 hours. The phases were separated and the aqueous phase extracted with dichloromethane (100 ml). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with ethyl acetate/i-hexane (1:3) to give the sub-title compound as a pale brown solid (6.68 g).