Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CN.C(N(CC)CC)C.FC(F)(F)C1C=C(C=CC=1)C(Cl)=[O:26]>C1COCC1>[C:3]([NH2:2])(=[O:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C(CN)c1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
As shown in reaction scheme 83, N,N-dimethyl-1-phenylethane-1,2-diamine represented by Formula 101 (439.1 mg, 2.67 mmol, purchased from Alfa Aesar Co.) and triethylamine (0.75 mL, 5.35 mmol) in THF (10 mL) solution were cooled to 0° C. under a nitrogen atmosphere, then, 3-(trifluoromethyl)benzoic acid chloride represented by Formula 153 (613.17 mg, 2.94 mmol, purchased from TCI Co.) in THF (15 mL) solution was slowly added thereto. After agitating the mixture at the same time for 30 minutes, the mixture was left at room temperature for 18 hours. A precipitate generated during the reaction was removed through filtration. The remaining solution was diluted with chloroform and this diluted solution was washed with a potassium carbonate (K2CO3) solution, followed by separation and drying the same with sodium sulfate (Na2SO4). The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 83 as a desired product (VVZ-078; 632.5 mg, 70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+].ClCCl.CO>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCN(C)CC3)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(CCN3CCN(C)CC3)c2cc1OC
Yield: 33.5 %

Procedure:
But using 0.2 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.65 g of potassium hydroxide in 7 ml of methanol. After flash chromatography on a silica column [eluent: dichloromethane/methanol (80/20 by volume)], 0.05 g of 4-chloro-2-{5,6-dimethoxy-1-[2-(4-methylpiperazin-1-yl)ethyl]-1H-indol-3-yl}-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:16]([O:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 99.7 %

Procedure:
m-Phenoxybenzyl chloride (218.5 g; 1 mole), sodium acetate (205 g; 2.5 mole), tetrabutylammonium bromide (10.9 g; 0.034 mole) and water (327 ml) were heated and stirred under reflux for 2 hours. On cooling m-Phenoxybenzyl acetate (241.5 g; 99.8% yield) separated as the upper layer. Its purity was 99%. m-Phenoxybenzyl acetate (242 g; 1 mole), sodium hydroxide (80 g; 2 mole), tetrabutylammonium bromide (12 g; 0.037 mole) and water (240 ml) were stirred at ambient temperature for 4 hours. The upper organic layer was dissolved in toluene (400 ml). The resulting solution was washed with water (2×200 ml) and treated with ion-exchange resin (Zerolit 236) and charcoal. Evaporation of the toluene gave the alcohol with a purity of 98.9% by gas chromatography (198 g, 99% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Br:27])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([Br:27])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 68 °C
Reaction time: 8 h

Procedure:
6.4 kg of methyl 2,4-bisbenzyloxy-5-bromobenzoate in 18 l of THF are added to a solution of 3 kg of sodium hydroxide in 30 l of water. After stirring overnight at 68° C., the mixture is cooled to 10° C., and 7.5 l of HCl (w: 37%) are added via a dropping funnel (pH 1). The mixture is stirred for a further 1 h and subsequently filtered. The residue is dried to constant weight in vacuo at 60° C.; 5.687 kg (91%) of 2,4-bisbenzyloxy-5-bromo-benzoic acid (m.p. 150-152° C.; MW 413.3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2C=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2].OC1C(C(=S)N)=[N:22]C=CC=1.ClCC(=O)CC(OCC)=O.[Li+].[Br-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[C:12]([OH:17])=[CH:13][CH:14]=[CH:15][N:22]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: NC(=S)c1ncccc1O
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Agent: CCOC(=O)CC(=O)CCl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2ncccc2O)n1
Yield: 90 %

Procedure:
The procedure used for the preparation of 4a was repeated with 3-hydroxy-2-pyridinecarbothioamide 3c (358 mg, 2.32 mmol), ethyl 4-chloroacetoacetate (0.628 mL, 4.65 mmol), and LiBr (202 mg, 2.32 mmol) in dry THF (6 mL) to give 4c (552 mg, 90%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-12% ) and recrystallization from CH2Cl2 /hexane. mp 85.5°-86.5° C.; IR (KBr) 3400, 1723, 1436, 1202, 1178 cm-1 ; 1H NMR (DMSO-d6) δ 1.16 (3H, t, J=7.1 Hz, CH3), 3.93 (2H, s, CH2), 4.08 (2H, q, J=7.1 Hz, CH2), 7.37 (1H, dd, J=8.3 and 4.2 Hz, Ar), 7.45 (1H, d, J=8.3 Hz, Ar), 7.66 (1H, s), 8.15 (1H, d, J=4.2 Hz, Ar), 11.64 (1H, s, OH); FDMS m/z 264 (M+); Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found: C, 54.83; H, 4.66; N, 10.30.
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:17](S(C3C=CC=CC=3)(=O)=O)[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC=CC=1.[NH4+].[Cl-]>ClCCCl>[ClH:27].[CH2:28]([O:35][N:36]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[NH:17][C:12]2=[CH:13][N:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2n1S(=O)(=O)c1ccccc1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: c1ccc(CON=C(c2ccccc2)c2cc3ccncc3[nH]2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 42 %

Procedure:
A mixture of phenyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanone (Reference Example 13) (200 mg, 0.55 mmol), O-benzylhydroxylamine hydrochloride (97 mg, 0.92 mmol) and pyridine (74 μL, 0.92 mmol) in 1,2-dichloroethane (8 mL) was heated at 60° C. After 24 h, saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (2×25 mL). The combined extracts were washed with saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-benzyloxime hydrochloride (84 mg, 47%) as a mixture of isomers: mp 153-155° C.; 1H NMR (500 MHz, DMSO-d6) δ 5.35-5.40 (2H, m), 6.66 (0.5H, s), 7.12 (0.5H, s), 7.34-7.56 (10H, m), 8.07 (0.5H, d, J=6.3 Hz), 8.19 (0.5H, d, J=6.3 Hz), 8.29 (0.5H, d, J=6.3 Hz), 8.34 (0.5H, d, J=6.3 Hz), 8.99 (0.5H, s), 9.17 (0.5H, s), 13.04 (0.5H, s), 13.14 (0.5H, s), 15.14 (1H, br s); ESI MS m/z 328 [C21H17N3O+H]+; HPLC (Method A) 98.3% (AUC), tR=19.1 and 19.3 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2([CH3:23])[CH3:22])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:22][C:16]1([CH3:23])[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][N:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Yield: 75 %

Procedure:
A mixture of [5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 110.2) (1.94 g, 5.8 mmol), a 4 N solution of HCl in dioxane (20 mL) and MeOH (5 mL) was stirred for 12 h at it and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 95:4:1) to afford 1.02 g of the title compound as a white solid. Title compound: ESI-MS: 235.2 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].F[B-](F)(F)F.[CH3:17][O+](C)C.[OH-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:11])[N:6]([CH3:17])[N:7]=2)[CH:3]=1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c2cc(Br)ccc2nn1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole (4.25 g) in ethyl acetate (100 ml) was added trimethyloxonium tetrafluoroborate (4.47 g) at room temperature, and the mixture was stirred at the same temperature for 5 hr. To the obtained reaction mixture was added 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][CH:9]2[C:13](=[O:14])[N:12]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=O)[C:11](=[O:22])[NH:10]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl>CN(C=O)C>[CH2:53]([O:60][NH:61][C:16](=[O:18])[CH:15]([N:12]1[C:13](=[O:14])[CH:9]([CH2:8][O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[NH:10][C:11]1=[O:22])[CH:19]([CH3:21])[CH3:20])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COCc2ccc(Br)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of the compound obtained in step f above (409 mg, 1.020 mmol), NMM (0.4 mL, 3.58 mmol) and HOBt (234 mg, 1.734 mmol) in DMF (10 mL) at −15° C. was added EDCI (214 mg, 1.123 mmol). After the reaction was stirred for 30 minutes, it was allowed to warm to room temperature, BnONH2HCl (179 mg, 1.123 mmol) was then added and the reaction was stirred overnight. The solvent was removed under vacuum; the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as an oil (426 mg, 83% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.CS(O[CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])[CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=O)=O>>[CH:15]1([CH2:14][CH2:13][CH:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:11][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)OCC(CCC1CCCC1)c1ccc(Cl)cc1Cl
Product: Clc1ccc(C(CCC2CCCC2)Cn2cncn2)c(Cl)c1

Procedure:
mp. 71° C., by the reaction of 1H-1,2,4-triazole with 4-cyclopentyl-2-(2,4-dichlorophenyl)butyl methanesulfonate; and
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C@H:23]([C:31]([OH:33])=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:34][C:35]([NH2:37])=[NH:36])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:43](OC(=O)[C@H](CC1C=CC=CC=1)NS(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)([CH3:46])([CH3:45])[CH3:44]>CS(C)=O>[C:43]([O:32][C:31](=[O:33])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:22][S:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:34][C:35]([NH2:37])=[NH:36])=[CH:17][CH:16]=1)(=[O:20])=[O:21])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](Cc3ccccc3)C(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine trifluoroacetate ##STR37## NaH (22 mg, 80% dispersion by wt in mineral oil, 0.73 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (76.7 mg, 0.80 mmol) in DMSO (5.0 mL) and the mixture was heated at 60° C. under N2 for 20 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (103 mg, 0.21 mmol) was added and the mixture heated at 95° C. for 17 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 80:20:2) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-phenylalanine t-butyl ester (34.7 mg, 0.069 mmol) as a yellow resin.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[N:12]#[C:13]Br.[NH4+].[OH-]>CO.O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:13]1[NH2:12])[CH3:2]
Reactant: N#CBr
Reactant: CCNc1ccc(F)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1c(N)nc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of N1-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0 mmol) in MeOH (20 mL) and H2O (20 mL) was added cyanogen bromide (2.1 mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirred at room temperature over night. The resulting mixture was then adjusted to pH>9 with concd NH4OH and the resulting solid was collected by filtration, washed with H2O and hexanes to yield 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[F:9][C:10]1[CH:11]=[C:12]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(F)c2)c1Br
Yield: 88 %

Procedure:
3-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-fluorobenzenesulfonyl chloride according to the procedures described in Example 40b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 125°-128° C., yield 88%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[C:4]([OH:22])[N:3]=1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>CN1CCCC1=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:48][C@H:49]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:19])=[CH:20][CH:21]=2)=[C:4]([OH:22])[N:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc(N)c(CCCCc2ccc(C(=O)O)cc2)c(O)n1
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCCCc2c(N)nc(N)nc2O)cc1)C(=O)OCC
Reaction time: 1 h

Procedure:
A mixture of 0.47 g (1.0 eq) of 4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoic acid, 0.62 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.79 g (5.0 eq) of N-methylmorpholine, and 50 mL of anhydrous N-methylpyrrolidone is stirred under nitrogen at ambient temperatures for one hour. There is then added 0.75 g (2.0 eq) of diethyl L-glutamate hydrochloride and stirring is continued under nitrogen for 24 hours. The solvent is removed by vacuum distillation and chloroform was added to the residue. The chloroform solution is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed with 1:9 methanol:chloroform to yield diethyl N-(4-[4-(2,4-diamino-6-hydroxypyrimidin-5-yl)butyl]benzoyl)-L-glutamate, m.p. 75°-76° C.; IR (KBr) vmax 3320, 2920, 2915, 1845, 1720, 1580, 1529, 1427, 1368, 1326, 1192, 1093, 1021, 849 and 750 cm-1 ; 1H NMR (CDCl3) delta 11.58 (bs, 1 H (3)--NH), 7.68 (d, J=7.9 Hz, 2H, Ar), 7.33 (d, J=7.9 Hz, 1H, NH), 7.17 (d, J=7.9 Hz, 2H, Ar), 5.54 (bs, 2H (2)--NH2), 4.76-4.82 (m, 1H, CH), 4.71 (bs, 2H, (6)--NH2), B 4.23 (q, J=7.11 Hz, 2H, CO2CH2), 4.12 (q, J=6.5 Hz, 2H, CO2CH2), 2.15-2.68 (m, 8H, 2° aliphatic) 1.57-1.66 (m, 2H, 2° aliphatic), 1.35-1.45 (m, 2H, 2° aliphatic), 1.30 (t, J=7.1 Hz, 3H, CH3), 1.22 (t, J=7.1 Hz, 3H, CH3); HRMS calcd for C24H33N5O6 (M+): 487.2430; found: 487.2415; other ions at m/e 348, 313, 285, 195, 167, 139, 97, and 84.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH:23]1[CH3:29])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([N:22]1[C@H:23]([CH3:29])[CH2:24][CH2:25][C@H:26]2[C@@H:27]([O:9]2)[CH2:28]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1CCC=CCN1C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
m-Chloro-perbenzoic acid (1.10 g, 57–86% pure) was added to a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.72 g, 2.94 mmol) in CH2Cl2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.660 g, 57–86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexanes) to give (1S,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield): 1H NMR: 7.42–7.22 (m, 5H), 5.13 (2H, s), 4.50–4.15 (m, 2H), 3.27 (1H, d), 3.12–2.95 (1H, m), 2.15–1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=262.0.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI>CN(C)C=O>[CH3:1][O:22][C:21]([C@H:18]1[CH2:17][CH2:16][C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20][CH2:19]1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Potassium carbonate (877 mg, 6.34 mmol, 1.05 eq) is added at room temperature to a stirred solution of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.50 g, 6.04 mmol, 1.0 eq) in N,N-dimethylformamide (30 mL), followed by methyl iodide (395 μL, 6.34 mmol, 1.05 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to afford trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester as a yellow solid (1.60 g, 98% yield).
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1.[NH2:13][C:14]1[CH:15]=[C:16]([C:21]2[C:25]([Cl:26])=[C:24]([O:27][CH:28]([F:30])[F:29])[N:23]([CH3:31])[N:22]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]>O1CCCC1>[Cl:26][C:25]1[C:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([NH:13][C:10]([CH:7]3[CH2:9][CH2:8]3)=[O:11])[CH:15]=2)=[N:22][N:23]([CH3:31])[C:24]=1[O:27][CH:28]([F:30])[F:29]
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(Cl)c(NC(=O)C3CC3)c2)c(Cl)c1OC(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.0 g (13 mmol) of pyridine and 0.7 g (6.5 mmol) of cyclopropanecarbonyl chloride were added to a solution of 2.0 g (6.5 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 30 ml of tetrahydrofuran. The solution was stirred at room temperature overnight and at 50° C. for 2 hours, an then concentrated. The residue was taken up in ethyl acetate. The ethyl acetate was washed in succession with cold 1N hydrochloric acid, water and saturated sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 2.2 g.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@@H:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8]2)=[O:6])[CH2:3][CH2:2]1.[C:17](#[N:21])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C@H:7]2[O:8][C:17]([CH:18]([CH3:20])[CH3:19])=[N:21][C@H:9]2[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)C#N
Reactant: O=C(NC1CC1)[C@H]1O[C@@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C1=N[C@@H](Cc2ccccc2)[C@@H](C(=O)NC2CC2)O1
Temperature: 5 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
(2S,3R)-3-Benzyl-2-oxiranecarboxylic cyclopropylamide (50 mg) and isobutyronitrile (2 ml) were mixed, and the mixture was cooled to 5° C. Boron trifluoride diethyl ether complex (2.5 equivalents) was gradually added, and the mixture was stirred at 5 to 20° C. for 2 hours. A mixture solution of ethyl acetate (10 ml) and saturated aqueous solution of sodium hydrogencarbonate (5 ml) was kept cooled at 5° C., and the reaction mixture was gradually added thereinto dropwise. The aqueous layer was removed, and then the solvent was evaporated away under reduced pressure to obtain the title compound as a brown solid (63 mg, yield: 96%).