Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1.2 ml) was added to a solution of tert-butyl 8-(4-methoxyphenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 0.57 mmol, 1.0 eq.) in methylene chloride (5 ml) at 0° C. and the reaction mixture was stirred at RT for 1 h. After completion of the reaction, the solvent was evaporated under reduced pressure to give the desired product as a yellow sticky solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([SH:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([S:26][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(S)c(Cl)cc3n2COCCOC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
To a solution of 1-[6-chloro-5-mercapto-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.300 g, 0.730 mmol), benzyl bromide (0.130 mL, 1.10 mmol) and DMF (20 mL) was added potassium carbonate (0.151 g, 1.10 mmol). The reaction mixture was stirred for 15 min at 23° C. and poured onto water (40 mL). The product was extracted with EtOAc (3×50 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (2-50% EtOAc/hexanes) to yield the titled compound (0.330 g, 90%). MS (ESI/CI): mass calcd. for C24H25ClN4O4S, 500.1; m/z found, 501.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:33]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH:33]4[CH2:35][CH2:34]4)[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: C1CN(C2CC2)CCN1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(C3CC3)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-cyclopropylpiperazine to afford an off-white powder. UPLC-MS (Condition 3) tR=0.84 min, m/z=489 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.22-0.45 (m, 4H) 1.56-1.66 (m, 1H) 2.56 (br. s, 4H) 3.12 (br. s, 4H) 6.67 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.79-7.91 (m, 3H) 8.32 (br. s, 1H) 8.72 (s, 1H) 10.39 (br. s, 1H) 12.98-13.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(OCC)(=[O:20])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Product: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The dione product was obtained using the same synthetic methods as shown in Example 25, step 6, using 1,2-bis(4-chlorophenyl)ethanone (2.12 g, 8.00 mmol, 1.00 equiv) and SeO2 (5.11 g, 46.0 mmol, 5.75 equiv) as reactants. The solution was allowed to react, with stifling, for 2 hr at 120° C., then diluted with ethyl acetate, washed with saturated aqueous NaCl, and concentrated under vacuum. This afforded 2.19 g (crude) of 1,2-bis(4-chlorophenyl)ethane-1,2-dione as a yellow solid.
Reaction SMILES: C[C@H]([O:10][C:11](=[O:31])[C@@H:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)C(=O)N1CCCC1.O.Cl>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[C:11]([OH:31])=[O:10])=[CH:29][CH:28]=1
Reactant: C[C@H](OC(=O)[C@H](Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1)C(=O)N1CCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To the residue prepared in STEP C above was added water (10 g) and a 36-38% HCl solution (60 g). The resulting biphasic mixture was stirred at 80° C. for between about 4 and about 8 hours (till completion of the hydrolysis as determined by HPLC) The resulting mixture was then cooled to 60° C. and toluene (125 mL) added. The aqueous phase was discarded and the organic phase washed with water (50 mL). Toluene (about 80 g) was removed by distillation to dry the organic phase. The resulting solution was then cooled to 70° C. and petrol ether 60/90 (250 mL) was added. The resulting solution was further cooled to 37° C. and seeded. The resulting mixture was stirred for 30 minutes at 37° C., the resulting suspension then cooled to 0° C. over about 2.5 hours. The precipitated crystals were filtered off and washed with a mixture of toluene (5 mL 0 and petrol ether 60/90 (9 mL) to yield wet product. The wet product was dried in a vacuum at 30° C. to yield the title compound as an off-white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][O:17]C(=O)C)[O:12][C:11](=[O:21])[C:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C(O)C.C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH2:16][OH:17])[O:12][C:11](=[O:21])[C:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(COC(C)=O)c(COC(C)=O)cc2oc1=O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cc1c(-c2ccccc2)c2cc(CO)c(CO)cc2oc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
A solution of ethyl 2-[6,7-bis(acetoxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate (240 mg) in ethanol (4 ml) was combined with DBU (0.4 ml), and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate (30 ml), and then washed with a 1 N solution of hydrochloric acid followed by a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resultant residue was recrystallized from ether to obtain the title compound (167 mg, yield: 86%). Melting point: 130-131° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[F:32])[S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH:14]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (30 ml) was dissolved 2-[6-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]hexyl]-1,4-difluorobenzene (0.70 g, 1.4 mmol). Under ice cooling, a tetrahydrofuran solution (1.0M, 4.2 ml, 4.2 mmol) of tetrabutylammonium fluoride was added and the mixture was stirred at room temperature for 1 hour. After addition of water (1.0 ml) to the reaction mixture, the mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:2) to yield a white solid. The resulting white solid was washed with hexane, whereby the title compound (0.47 g, 86%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18](C)(C)C)=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.Cl.[NH2:23][C:24]1[S:25][C:26]([F:29])=[CH:27][N:28]=1.Cl[C:31](OC)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:31](=[O:32])[NH:23][C:24]3[S:25][C:26]([F:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1ncc(F)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Agent: Cl
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(F)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that t-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that 2-amino-5-fluorothiazole hydrochloride was used instead of 2-amino-5-chlorothiazole hydrochloride, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:11]O>CC(O)=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)(C)c1ccccn1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)c1cccc[n+]1[O-]
Yield: 71.5 %

Procedure:
Preparation C3, Step 1: 2-tert-butylpyridine (2.00 g, 14.8 mmol, 1 eq.) was dissolved in HOAc (10 mL) and 30% hydrogen peroxide (1.68 mL, 14.8 mmol, 1 eq.) at room temperature then the reaction was refluxed for 20 hours. The reaction was stripped to obtain an amber oil which was dissolved in methylene chloride (10 mL) then dried over sodium sulfate and stripped to obtain 2-tert-butylpyridine-N-oxide (1.60 g) as an amber oil. Yield=71.5%. LCMS detects (M+H)+=152.09.
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][CH2:8][C:9]#[N:10].[C:11]12([CH2:22][C:21](=[O:23])[O:20][C:18](=[O:19])[CH2:17]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2>C1COCC1>[C:9]([CH2:8][CH2:7][O:6][C:21]([CH2:22][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:23])#[N:10]
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Reactant: N#CCCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCOC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
8.2 mL of 1.6M butyllithium was added to a −78° C. solution of 3-hydroxy-propionitrile (13.19 mmol) in 50 mL of THF. The reaction mixture was warmed to 30° C. and stirred for 30 minutes. Then, a solution of 1,1-cyclohexanediacetic anhydride (10.99 mmol) in 10 mL of THF was added dropwise. The reaction mixture was warmed to room temperature over a period of one hour and stirred at room temperature with monitoring by TLC. When the reaction was judged complete, the reaction mixture was quenched with saturated ammonium chloride solution and THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, washed with brine and dried over Na2SO4. After concentration in vacuo the residue was purified on silica gel (5% methanol in dichloromethane) to afford 2.64 g (95%) of the title compound. 1H NMR (CDCl3): δ 4.28 (2H, t, J=6.4 Hz); 2.71 (2H, t, J=6.4 Hz); 2.61 (4H, m); 1.52-1.42 (10H, m).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4]([O:16][CH3:17])=[CH:5][CH:6]=[N:7]2.C(O)C.[OH-].[NH4+:22]>O>[NH2:22][C:4]1([O:16][CH3:17])[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=[CH:6][CH2:5]1
Reactant: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC1(N)CC=Nc2c(C)ccc(C)c21

Procedure:
In a flask is placed 5,8-dimethyl-4-methoxy-6-nitroquinoline (1.16 g, 5.0 mmol) with stannous chloride dihydrate (5.64 g, 25 mmol) and ethanol (50 mL). The mixture is refluxed for 1 hour, diluted with water (100 mL) and concentrated ammonium hydroxide (30 mL), and extracted with chloroform (2×200 mL). The organic portion is dried over potassium carbonate, filtered and the solvents removed by rotary evaporation, yielding 4-amino-5,8-dimethyl-4-methoxyquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: N#Cc1cc(Br)c2cn[nH]c2c1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 40.7 %

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbonitrile (1.0 g, 4.50 mmol) in dichloromethane (80 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.2 g, 8.94 mmol), pyridine (0.71 mL, 8.78 mmol), copper acetate (1.2 g, 6.63 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-100% dichloromethane in hexane to yield the title compound (D5) (774 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH2:23])[CH3:19].Cl.[OH-].[Na+]>O.C(O)C>[CH2:18]([O:20][C:21]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: CCOc1ccc(OCC)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(OCC)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Yield: 17.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 2,5-diethoxyaniline (52 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (3:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered and isolated as a yellow solid (14 mg, 18%). 1H NMR (CDCl3): 9.67 (s, 1H), 8.74–8.71 (m, 2H), 7.93 (s, 1H), 7.64 (s, 1H), 7.43–7.39 (m, 1H), 6.91 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 6.65 (dd, J=2.7, 8.7 Hz, 1H), 4.13–4.04 (m, 4H), 1.47–1.42 (m, 6H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CC(C)[C@@H](CS(N1CCN(C2N=CC(C3C=CC([C:60]([F:63])([F:62])[F:61])=CC=3)=CN=2)CC1)(=O)=O)C(O)=O>>[F:61][C:60]([F:63])([F:62])[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]([N:14]3[CH2:15][CH2:16][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:21])=[O:22])[CH2:18][CH2:19]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)NO
Yield: 35 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 3-methyl-2-(R)-{4-[5-(4-Trifluoromethylphenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}butyric acid (0.086 g), to provide the title compound as a white solid (0.031 g, 35%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]=[C:13]=[S:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)CC>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]([O:8][CH2:7][CH2:6][CH3:5])=[S:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(I)ccc1N=C=S
Solvent: CCCO
Product: CCCOC(=S)Nc1ccc(I)cc1C(=O)OC

Procedure:
The process of claim 10 wherein (a) methyl 2-amino-5-iodobenzoate is treated to form methyl 5-iodo-2-isothiocyanatobenzoate; (b) the methyl 5-iodo-2-isothiocyanatobenzoate is treated with n-propanol to form methyl 5-iodo-2((propoxy-thioxomethyl)-amino)benzoate, and (c) the methyl 5-iodo-2-((propoxythioxomethyl)-amino)benzoate is treated with propylamine.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][O:17][CH3:27])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1
Reactant: CI
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 1--(3-biphenylyl)-5-hydroxymethylbenzimidazole (61a) (0.16 g, 0.5 mmol) in dry DMF (1.5 ml) under nitrogen, was added a 80% sodium hydride suspension (20 mg, 0.7 mmol) and then iodomethane (33.5 μl, 0.5 mmol). The reaction mixture was stirred overnight and then poured in water. Neutralization with 4M aqueous HCl was followed by extraction with ethyl acetate. The extract was evaporated to dryness and purified by chromatography. The product was dissolved in dry ether and precipitated as the hydrochloride. Yield: 130 mg, 0.4 mmol, 80%. mp 70°-72° C.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([S:29](O)(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH3:52][NH:53][CH3:54]>ClCCl.CN(C=O)C.O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([S:29](=[O:31])(=[O:30])[N:53]([CH3:54])[CH3:52])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:45])([F:1])[F:44])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(S(=O)(=O)N(C)C)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 0.13 g (0.19 mmol) 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-sulfonic acid in 2 ml dichloromethane were added 0.33 ml (0.39 mmol) oxalyl chloride and one drop of DMF at 0° C. After 30 min the reaction mixture was allowed to warm to room temperature during 2 h. To the yellow reaction mixture were added 1.8 ml (20 mmol) of an aqueous solution of dimethylamine (60%). After 1 h the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 92 mg (69%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.ClCCl.[C:12]([NH:19][C:20](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])SC)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(N(CC)CC)C.[Hg](Cl)Cl>[C:27]([O:26][C:24](=[O:25])[NH:23]/[C:20](/[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1)=[N:19]\[C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:30])([CH3:28])[CH3:29]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: Nc1ccnc(Cl)c1
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75 %

Procedure:
20.22 g (0.157 mol) of 4-amino-2-chloropyridine were diluted in triethylamine (67 ml) and dichloromethane (600 ml) at 0-5° C. 47 g of Mercury(II) chloride (0.173 mol) and 50.24 g (0.173 mol) of N,N′-bis(boc)-S-methyl-isothiourea were added to the reaction mixture, which was then stirred at room temperature for 4 days, filtered on a fritted funnel, concentrated in vacuo and chromatographed on silica (Heptane90/AcOEt10) to yield 43.67 g of di-tert-butyl{(Z)-[(2-chloropyridin-4-yl)amino]methylylidene}biscarbamate (yield=71%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[S:41](=[O:43])(=[O:42])[NH:40][C:39](=[O:44])[CH2:38]2)=[C:33]([F:45])[CH:32]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:11])=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C(Cl)Cl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[NH2:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[S:41](=[O:42])(=[O:43])[NH:40][C:39](=[O:44])[CH2:38]2)=[C:33]([F:45])[CH:32]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(O)cccc1OCCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methyl 2-[5-((2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-3-fluorophenyl]propanoylamino)pentyl]oxy-6-hydroxybenzoate (66.5 mg, 0.100 mmol) was dissolved in methylene chloride (5.0 mL) and treated with trifluoroacetic acid (1.0 mL). After 1 h of stirring at rt, the solution was concentrated in vacuo to afford a slightly tan oil (20.2 mg, 99%). The material was used in subsequent steps without purification. LCMS found for C25H31FN3O8S (M+H)+: m/z=652.