Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCCOS(C)(=O)=O
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCCCCCC

Procedure:
Compound VI-12 (319 mg, 88.3%) was obtained in the same manner as that in Reference Example 5, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 100 mg, 0.517 mmol) and octadecyl methanesulfonate (Nu-Chek Prep, Inc; 451 mg, 1.29 mmol).
Reaction SMILES: C(S[C:9]1[N:14]=[N:13][C:12]2[CH2:15][CH2:16][N:17]([C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][C:11]=2[CH:10]=1)C1C=CC=CC=1.O.[NH2:28][NH2:29]>C(O)C>[C:19]([N:17]1[CH2:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([NH:28][NH2:29])=[CH:10][C:11]=2[CH2:18]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: O=C(c1ccccc1)N1CCc2nnc(SCc3ccccc3)cc2C1
Solvent: CCO
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2

Procedure:
A solution of 4.0 g of 3-benzylmercapto-6-benzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 1.5 g of hydrazine hydrate in 10 cc of 95% ethanol is heated in an autoclave at a bath temperature of 150° for 16 hours. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and a small amount of water, and the organic phase is concentrated to a red oil. The title compound is obtained by crystallization from dimethyl formamide. M.P. 220°-223° (decomp.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:42]=[CH:43][N:44]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCn1ccnc1CSc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCn1ccnc1CS(=O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-pentylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (680 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (362 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-pentylimidazole-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (411 mg) (Compound 354) as yellow amorphous.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])=[CH:22][CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1ccc(N(C)C(=O)CN(C(=O)CN)c2ccccc2)cc1
Product: COc1ccc(N(C)C(=O)CN(C(=O)CNC(=O)Nc2cccc(C)c2)c2ccccc2)cc1
Yield: 37.5 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.9 g of 2-(2-amino-N-phenylacetamido)-N-(4-methoxyphenyl)-N-methylacetamide and 0.77 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate/cyclohexane (80-20 by volume)], collecting 20 cm3 fractions. Fractions 14 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from acetonitrile, 1.0 g of N-(4-methoxyphenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 202° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([Cl:12])[CH:3]=1.Cl.Cl[C:15]1[N:20]=[C:19]([NH:21][C@@H:22]2[CH2:30][C@H:29]3[N:25]([CH2:26][CH2:27][CH2:28]3)[C:24]([CH3:32])([CH3:31])[CH2:23]2)[C:18]([F:33])=[CH:17][N:16]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][C:15]2[N:20]=[C:19]([NH:21][C@@H:22]3[CH2:30][C@H:29]4[N:25]([CH2:26][CH2:27][CH2:28]4)[C:24]([CH3:31])([CH3:32])[CH2:23]3)[C:18]([F:33])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:5]=1[O:6][CH2:7][CH2:8][OH:9]
Reactant: Nc1ccc(OCCO)c(Cl)c1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OCCO)c(Cl)c3)ncc2F)C[C@@H]2CCCN21
Yield: 71.1 %

Procedure:
The general displacement procedure described herein was used with 2-(4-amino-2-chlorophenoxy)ethan-1-ol (9 mg, 0.05 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (16 mg, 0.05 mmol) and pTsOH.H2O (18 mg, 0.1 mmol) in IPA (5 mL) at reflux to give the product (16 mg, 74% yield) as a solid after workup and purification by preparative thin-layer chromatography using DCM/2M NH3 in MeOH as eluent (9:1; 5 preparative TLC plates).
Reaction SMILES: [H][H].CC(O)=O.[OH:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]3[CH2:11][C:10]=2[CH:9]=1>C1COCC1.CCO.[OH-].[OH-].[Pd+2]>[OH:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC1CCN2c3ccc(O)cc3CC12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Temperature: 50 °C

Procedure:
tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium on carbon (50% in water, 217 mg) was added. The reaction mixture was placed under 225 psi of hydrogen in a hydrogenation reactor for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The above material was taken up in a mixture of THF (20 mL) and EtOH (20 mL) and Pd(OH)2/C (250 mg) was added. The reaction mixture was placed under 200 psi of hydrogen in a hydrogenation reactor for 2 days. Additional Pd(OH)2/C (250 mg) was added and the reaction mixture was placed under 300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)2/C (250 mg) was again added and the vessel placed under 500 psi of hydrogen in a hydrogenation reactor for 24 h. The hydrogenation reactor was warmed to 50° C. for 8 h. The reaction mixture was cooled to room temperature and AcOH (5 mL) was added. The reaction mixture was placed under 500 psi of hydrogen for 16 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to provide a mixture of the title compound and tert-butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The title compound (150 mg) was isolated by silica gel column chromatography. tert-Butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added. The reaction mixture was warmed to 80° C. and stirred for 2 days. The reaction mixture was filtered through Celite® and the title compound (250 mg) was isolated as a white solid resulting from precipitation during concentration of the filtrate. LCMS m/z=288.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[SH:15])[NH:11][C:10](=[O:16])[C:9](=[O:17])[NH:8]2)([CH3:4])([CH3:3])[CH3:2].[S:18](Br)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12]([NH:11][C:10](=[O:16])[C:9](=[O:17])[NH:8]2)=[CH:13][C:14]=1[S:15][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1S
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc3[nH]c(=O)c(=O)[nH]c3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using 6-tert-butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione (prepared in Example DDD, 9.1 mmol), tosyl bromide (2.1 g, 9.1 mmol), pyridine (2 mL), EtOAc (50 mL). The crude product was purified by flash silica gel chromatography (5%-10% MeOH in CH2Cl2) as eluents. MS(APCI): 405 (M+H).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:9]=1[CH3:10].[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)/[CH:25]=[CH:10]/[C:9]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)([O-:21])=[O:20]
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To 3.1 g of acetic anhydride, 7.2 g of quinaldine and 7.6 g of m-nitrobenzaldehyde were added and the resulting mixture was stirred under nitrogen atmosphere at 160° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture and the resulting solid was collected by filtration and dried. Recrystallization from toluene gave 12.1 g (yield: 88%) of the captioned compound as an yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:15]1[O:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COC(=O)c1ccco1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)c2ccccc2C)o1
Yield: 90.4 %

Procedure:
A mixture of 2-methylbenzoyl chloride (prepared as described by Frankland and Ashton, Trans. Chem. Soc. 1899, 75, 494; 77 g.), methyl 2-furoate (83 g.), anhydrous ferric chloride (1.5 g.) and carbon tetrachloride (125 ml.) was heated under reflux on a steam bath for 7.5 hours and then distilled to give methyl 5-(2-methylbenzoyl)-2-furoate (110 g.) in the form of a colourless oil, b.p. 170° C./0.2 mm.Hg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH:9][C:10]([NH:12][CH3:13])=[O:11])=O.ClC1C=CC(C(NNC(NCC)=O)=O)=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:12]([CH3:13])[C:10](=[O:11])[NH:9][N:8]=1
Reactant: CNC(=O)NNC(=O)c1cccs1
Agent: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Product: Cn1c(-c2cccs2)n[nH]c1=O

Procedure:
When, in the procedure of Example 4, 1-(2-thienoyl)-4-methylsemicarbazide is substituted for 1-(4-chlorobenzoyl)-4-ethylsemicarbazide, the title compound is obtained. Mp 183°-185° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16](O)=[O:17])[S:14][CH2:13][C:12](=[O:19])[C:11]=3[CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(C#N)(=O)(OCC)OCC.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C.O>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]([C:16]([NH:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[O:17])[S:14][CH2:13][C:12](=[O:19])[C:11]=3[CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccnc1
Reactant: O=C1CSC(C(=O)O)c2ccc(C3CCCCC3)cc21
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CSC(C(=O)Nc2cccnc2)c2ccc(C3CCCCC3)cc21
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
In DMF (10 ml) was dissolved 6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (500 mg) followed by addition of diethyl phosphorocyanidate (85%, 365 mg). The mixture was stirred for 30 minutes under ice-cooling and, then, 3-aminopyridine (160 mg) and triethylamine (202 mg) were added thereto. The reaction mixture was further stirred for one hour under ice-cooling and poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 6-cyclohexyl-N-(3-pyridyl)-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (490 mg, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless plates.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[NH:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19].C(OCC)(=O)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:15][CH:14]([C:12]1[CH:13]=[CH:8][C:9]2[NH:17][C:18](=[O:19])[N:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[C:10]=2[CH:11]=1)[CH3:16]
Reactant: CC(C)c1ccc(NC(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)c1ccc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium (0) (0.14 g), 1,1′-bis(diphenylphosphino)ferrocene (0.07 g), sodium tert-butoxide (0.4 g) in 1,4-dioxane (10 mL) was stirred under an atmosphere of argon for 10 minutes. 1,1-dimethylethyl 4-[({[2-bromo-4-(1-methylethyl)phenyl]amino}carbonyl)amino]-1-piperidinecarboxylate D33 (2.7 g) was added and the mixture was heated to 90° C. The mixture was stirred at this temperature overnight. The mixture was poured into ethyl acetate which was washed with dilute sodium bicarbonate, brine and dried over sodium sulphate. The solvent was removed and the residue was chromatographed on silica gel eluted with ethyl acetate/hexane 0-50% to give the title compound as a solid. (0.723 g)
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12](I)[C:6]=2[N:5]=1)[CH3:2].[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[N:23]1.COCCOC>O>[CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][C:25]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(I)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Cn1ncc(-c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Solvent: O
Solvent: COCCOC
Product: CCOc1nc2c(-c3c(-c4ccccc4)cnn3C)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 130 °C
Yield: 14.9 %

Procedure:
4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (100 mg, 0.26 mmol) and 1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (18 mg, 0.026 mmol) and CsCO3 (127 mg, 0.39 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 8 mg product 4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole.
Reaction SMILES: [N:1]([C@H:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][O:6][C:5]1=[O:11])=[N+]=[N-].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>CO.C(Cl)Cl.CCOC(C)=O.[Pd]>[CH3:9][C:8]1([CH3:10])[CH2:7][O:6][C:5](=[O:11])[C@H:4]1[NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)OCC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-3-azido-4,4-dimethyldihydrofuran-2(3H)-one (5.52 g) in MeOH 910 mL) was added 10% Pd/C (0.379 g, 0.356 mmol) under N2. The reaction mixture was stirred under H2 at rt for 16 hrs. The reaction was filtered through diatomaceous earth (Celite®), washed with EtOAc and the filtrate was concentrated to yield a clear oil. To the above oil in DCM (10 mL) was added BOC2O (9.09 mL) and TEA (13.88 mL). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3, citric acid, water, sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield an oil. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (S)-tert-butyl 4,4-dimethyl-2-oxotetrahydrofuran-3-ylcarbamate (3.8 g) as a white solid. LC/MS (Cond. N-1): [M+Na]+ 252.06, RT=2.75 min. 1H NMR (400 MHz, CHLOROFORM-d) ppm 4.81-4.95 (1H, m), 4.38 (1H, d, J=7.78 Hz), 3.97-4.07 (2H, m), 1.47 (9H, s), 1.25 (3H, s), 1.01 (3H, s).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:5]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:6][C:7]([F:10])([F:9])[F:8].[Li+].[BH4-]>C1COCC1.CCOC(C)=O.CCCCCCC>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C@H:4]([CH2:3][OH:2])[CH:5]([CH2:6][C:7]([F:8])([F:9])[F:10])[CH2:11][C:12]([F:14])([F:13])[F:15])(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(N[C@H](CO)C(CC(F)(F)F)CC(F)(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.8 %

Procedure:
To a solution of (2S)-2-(4-chloro-benzenesulfonylamino)-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)pentanoic acid methyl ester (2.924 g, 6.6 mmol) in THF (30 mL) was added LiBH4 (9.9 mL of 2M THF solution, 19.8 mmol) over 10 minutes at 4-6° C. The reaction mixture was stirred at 25° C. for 4 days. Additional LiBH4 (6.6 mL of 2M THF solution, 13.2 mmol) was added, and the reaction mixture was stirred at 25° C. for an additional 24 hours. The reaction mixture was cooled to 0° C. and quenched by slow addition of 30 mL of 2N HCl (vigorous gas evolution). The mixture was partially concentrated in vacuum and extracted with EtOAc. The organic fraction was washed with brine, dried over Na2SO4, and concentrated to afford 2.66 g of crude product. The crude product was dissolved in a mixture of EtOAc (10 mL) and heptane (3 mL) at 55° C., cooled to 25° C., and the resultant suspension was aged for 48 hours. Heptane (27 mL) was added and the mixture was stirred at 25° C. for additional 48 hours. The precipitate was filtered and washed with heptane to afford 1.962 g of the title compound (72% yield), mp: 186-187° C. Chiral HPLC: 97% ee (the Chiralcel® AD column 0.46×25 cm, 10% EtOH in hexanes). HRMS calc. (for M+H): 414.0360. Found: 414.0359.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>C1COCC1>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7])=[O:21]
Reactant: O=C1CCCCN1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCCCN1C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All glassware is dried thoroughly, and the reaction is kept under an inert atmosphere (argon) at all times. With stirring, 20.0 g (0.18 mol) of 2-furoic acid (Aldrich) and 40.0 mL (0.53 mol) of thionyl chloride (Aldrich, d=1.631 g/mol) are added to 300 mL THF (Aldrich, HPLC grade) in a single-neck round bottom flask equipped with a reflux condenser and magnetic stirrer. The resulting reaction mixture is heated to reflux and stirred for 16 h. After cooling to room temperature, the solvent and excess thionyl chloride are removed by evaporation under reduced pressure to yield 2-furoyl chloride. In a subsequent reaction, 9.2 g (92 mmol) of valerolactam (Aldrich) and 14.1 mL (101 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 150 mL THF (Aldrich, HPLC grade) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and magnetic stirrer. Addition of a solution of 12.0 g (92 mmol) of the 2-furoyl chloride in 150 mL THF proceeds dropwise over a period of 30 min, and the resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the THF is removed by evaporation under reduced pressure. The solid residue is redissolved in methylene chloride, and extracted several times with 5% aqueous hydrochloric and then deionized water. The organic layer is dried over Na2SO4, filtered, concentrated by removal of solvent, and poured into hexane to precipitate the product. The precipitate is collected by suction filtration, rinsed with hexane, and dried under vacuum to yield N-(2-furoyl)valerolactam as a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][C:11]=1[Cl:20])=[O:8].[CH2:24]=O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:6][C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:12][C:11]=3[Cl:20])[CH2:24]2)[CH:21]=[CH:22][CH:23]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2cccc(Cl)c2)c(Cl)c1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3cccc(Cl)c3)CC2=O)c(Cl)c1

Procedure:
2-(3-Chloroanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (18.5 g) were dissolved in ethanol and reacted with paraformaldehyde as before (3.0g) to yield 14.0 g, m.p. 208°-216°C (ethanol).
Reaction SMILES: [Na+].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([O-])=[O:9].C=O.O1CCOCC1.[ClH:19]>C(O)C>[ClH:19].[OH:9][CH2:8][C:4]1[N:5]=[CH:6][NH:7][C:3]=1[CH3:2]
Reactant: Cc1[nH]cnc1C(=O)[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1[nH]cnc1CO
Yield: 63 %

Procedure:
A mixture of 1.48 g (0.01 mol) of 5-methylimidazole-4-carboxylic acid sodium salt, 2 ml of ~37% formaldehyde solution and 3 ml of 1,4-dioxane was heated at 75°-85° C. for 3 hours. After completion of the reaction, the solvent was stripped off, and the remaining residue was extracted with isopropanol. The isopropanol extract was concentrated to give a viscous oil. This viscous oil was dissolved in absolute ethanol and dry hydrogen chloride gas was passed through the resulting solution to afford 0.93 g of 4-hydroxymethyl-5-methylimidazole hydrochloride, m.p. 241°-244° C. Yield 63%.