Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH3:14][CH:15]([CH3:22])[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:15]([CH3:22])[CH3:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: CCCC(N)CC(C)C
Product: CCCC(CC(C)C)NC(=O)C=Cc1ccc(OC)cc1
Yield: 65 %

Procedure:
Prepared in a similar manner to example 4 using 3-(4-methoxy-phenyl)-acrylic acid and 3-methyl-1-propyl-butylamine (example 2a). Yield: 65%. 1H NMR (500 MHz, CDCl3): δ 0.90-0.95 (m, 9H), 1.30-1.39 (m, 5H), 1.49-1.50 (m, 1H), 1.64-1.67 (m, 1H), 3.82 (s, 3H), 4.17-4.18 (m, 1H), 5.18-5.20 (d, 1H), 6.22-6.26 (d, 1H), 6.86-6.89 (d, 2H), 7.42-7.45 (d, 2H), 7.56-7.59 (d, 1H). MS (M+H, 290.1).
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][N:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20](=[O:33])[NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[C:25]([O:29][CH3:30])=[CH:24][C:23]=2[O:31][CH3:32])[C:9]1=[O:34])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:28][C:26]1[C:25]([O:29][CH3:30])=[CH:24][C:23]([O:31][CH3:32])=[C:22]([NH:21][C:20]([CH2:19][N:10]2[C:11]3[CH:18]=[N:17][CH:16]=[CH:15][C:12]=3[C:13](=[O:14])[N:8]([CH2:7][C:6]([OH:35])=[O:5])[C:9]2=[O:34])=[O:33])[CH:27]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)OC(C)(C)C)c(=O)c3ccncc32)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccncc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vial containing a solution of {1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl}-acetic acid tert-butyl ester (Intermediate V) (15 mg, 0.029 mmol) in DCM (1 ml), TFA (1 ml) is added. The mixture is stirred at RT overnight. The reaction mixture is then transferred to a 10 ml round bottomed flask, diluted with a minimal amount of DCM and concentrated in vacuo. This process is repeated once with DCM, twice with EtOAc, and once with MeOH, the solvent being concentrated in vacuo each time, finally giving the title, [M+H]+ 448.93.
Reaction SMILES: Cl[CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:14]([NH:18][C:19]([NH2:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:15][C:14]([NH:18][C:19]1[O:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:21]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(C)(C)NC(N)=O
Solvent: ClCCl
Product: CCOC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Yield: 62.8 %

Procedure:
A reaction vessel was charged with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate and 7.0 g (60 mmol) of tert-butylurea. The reaction mixture was stirred and heated at 140°-150° C. for 19 hours under a calcium sulfate drying tube. With the mixture at room temperature, the mixture was slurried in methylene chloride and washed three times with water. The methylene chloride extract was dried over magnesium sulfate and then concentrated under reduced pressure to yield 8.8 g of a mustard-colored solid material. This solid material was dissolved in hot hexane and then filtered hot. The filtrate was cooled in a dry ice bath. The filtrate yielded 7.3 g of a beige solid product (m.p.=56°-59° C.) identified in Table I.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[CH3:16]I>CS(C)=O.O>[CH3:16][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[O:11][C:10]1=[O:13]
Reactant: CI
Reactant: O=c1[nH]c2cccc([N+](=O)[O-])c2o1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(=O)oc2c([N+](=O)[O-])cccc21
Reaction time: 16 h
Yield: 84.7 %

Procedure:
3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolinone (for preparation of the latter compound, and European patent EPO189612 and references cited therein) were dissolved in 40 ml of DMSO after which 1.72 g of 85% powdered KOH (26.2 mmol) were added. While stirring and cooling (water) 3.72 g (26.2 mmol) of MeI dissolved in 6 ml of DMSO, were added dropwise over a period of 10 minutes. Stirring was continued at room temperature for 16 hrs, during the latter period an extra amount of MeI (0.5 g) was added. After the reaction was completed, the reaction mixture was diluted with water after which extraction took place with CH2Cl2. The combined organic fractions were washed with respectively water and brine after which the organic fraction was dried on MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo, 4.1 g of a solid residue was left. Flash column chromatography (SiO2, eluent: CH2Cl2) of the latter yielded 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(Cl)cn1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-chloropyridin-2-yl)oxy]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.04 (1H, d, J=2.6 Hz), 7.94 (1H, d, J=2.6 Hz), 7.91 (2H, d, J=8.3 Hz), 7.63 (1H, dd, J=8.8, 2.6 Hz), 7.43 (1H, dd, J=8.8, 2.6 Hz), 7.22 (2H, d, J=8.3 Hz), 7.18 (1H, d, J=8.0 Hz), 7.00 (1H, d, J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), 5.28–5.16 (1H, m), 3.91 (3H, s), 1.42 (3H, d, J=7.0 Hz).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:5]=[C:4]2[N:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:3]=12.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.O>CN1C(=O)CCC1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:2]([N:30]2[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]2)=[C:3]2[CH:17]=[CH:16][N:15]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C:4]2=[N:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(F)c(-c3ccccc3F)cnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 160 °C
Yield: 35.2 %

Procedure:
4-Fluoro-5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.200 g, 0.540 mmol) and tert-butyl piperazine-1-carboxylate (0.121 g, 0.648 mmol) were placed in NMP (2 mL). The reaction was then placed in the microwave and heated to 160° C. for 1 hour. The reaction was then cooled, poured into water and extracted with ether. The combined organic fractions were dried, filtered, and concentrated to give a crude oil that was purified by column chromatography (3:1 hexane:EtOAc) to give tert-butyl 4-(5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.102 g, 35.2% yield).
Reaction SMILES: [Br:1]Br.ClCCl.[C:6]1([C:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][O:14][C:13]=2[C:23]([O:25][CH3:26])=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[O:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1oc(Br)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 4 h

Procedure:
Bromine (0.18 ml) was added to a dichloromethane (10 ml) solution of methyl 3,4-diphenyl-2-furancarboxylate (1.00 g) at 0° C., and stirred at this temperature for 4 hours. The reaction solution was diluted with chloroform, and successively washed with water, saturated aqueous sodium hydrogencarbonate solution, and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 1.28 g of methyl 5-bromo-3,4-diphenyl-2-furancarboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.C(O)C>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Reactant: COCCC(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCn1c(CCOC)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxypropionyl chloride (4.85 g, 39.8 mmol) was added dropwise over a period of ten minutes to a solution of ethyl 6-(3-aminoquinolin-4-ylamino)hexanoate (10.0 g, 33.2 mmol, prepared as described in Part A of Example 8) in dichloromethane (200 mL). The reaction was stirred for one hour at ambient temperature and then concentrated under reduced pressure. Triethylamine (18.49 g, 132.7 mmol) and ethanol (200 mL) were added, and the resulting solution was heated at reflux for three hours. The solvent was removed under reduced pressure. Dichloromethane (75 mL) was added, and the resulting solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 12.05 g of ethyl 6-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoate as a dark oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[Br:24][CH2:25][C:26](=O)[CH2:27][OH:28]>O1CCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([CH2:27][OH:28])[CH2:25][Br:24])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: O=C(CO)CBr
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: OCC(CBr)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl)-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-bromo-3-hydroxypropanone under nitrogen to give 7-(trifluoromethyl)-2-[[2-bromo-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: Cl.[CH2:2]([O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)[CH2:3][CH2:4][CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:32]([N:35]([CH:38]([CH3:40])C)[CH2:36][CH3:37])(C)C.Cl.[O:42]=[C:43]1[NH:52][C:51]2[N:50]=[CH:49][C:48](/[CH:53]=[CH:54]/[C:55](O)=[O:56])=[CH:47][C:46]=2[CH2:45][CH2:44]1>CN(C)C=O.O.C(OCC)(=O)C>[CH2:2]([O:6][CH:7]1[CH2:10][N:9]([C:55](=[O:56])/[CH:54]=[CH:53]/[C:48]2[CH:47]=[C:46]3[C:51](=[N:50][CH:49]=2)[NH:52][C:43](=[O:42])[C:44]2([CH2:37][CH2:36][N:35]([CH3:32])[CH2:38][CH2:40]2)[CH2:45]3)[CH2:8]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC1CN(C(=O)/C=C/c2cnc3c(c2)CC2(CCN(C)CC2)C(=O)N3)C1
Reaction time: 8 h

Procedure:
3-Butoxyazetidine hydrochloride (33 mg, 0.20 mmol), EDCI (72 mg, 0.4 mmol), HOBt (54 mg, 0.4 mmol) and diisopropylethylamine (116 μL, 0.66 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (45 mg, 0.13 mmol) in dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (7:3 to 5:5) as eluent. After precipitation in DCM/Et2O and triturations in acetone, the title product was obtained as a white solid (10 mg, 17%).
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH:29](C)C)[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O.COC(=O)[C@H](C)NC(OC1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:12][O:13][C:14](=[O:32])[C@H:15]([CH3:29])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=1)=[O:19]
Reactant: CNCc1coc(C(C)C)n1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Agent: COC(=O)[C@H](C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Product: COC(=O)[C@H](C)NC(=O)N(C)Cc1coc(C(C)C)n1
Yield: 66 %

Procedure:
Using the procedure of Example 1S, but replacing 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with 2-isopropyl-4-(((N-methyl)amino)methyl)-oxazole and relacing N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester with N-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester provided the desired compound in 66% yield. 1H NMR (CDCl3) δ1.32 (d, 6H), 1.42 (d, 3H), 2.96 (s, 3H), 3.05 (m, 1H), 3.75 (s, 3H), 4.30 (s, 2H), 4.47 (m, 1H), 5.80 (br d, 1H), 7.46 (s, 1H). Mass spectrum: (M+H)+ =284.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:31][NH2:32]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:31][NH2:32])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NN
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)NN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (559 mg, 3.45 mmol). After stirring at room temperature for 2 h, the solution was added to a stirred mixture of hydrazine hydrate (0.729 mL, 5.75 mmol) in THF (2 mL) and stirred a further 2 h. The reaction mixture was poured onto water (20 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, washed with water (2×10 mL) then acetonitrile (3 mL) to afford 0.54 g (71%) of 4-(heptyloxy)benzohydrazide as a white solid. LCMS-ESI (m/z) calculated for C14H22N2O2: 250.3 found 251.0 [M+H]+, tR=2.05 min. (Method 4).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15](Cl)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.O>O1CCCC1>[CH:8]1([N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:15]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CNC(N)=O
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)NC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 0.9 %

Procedure:
Prepared as described in General Procedure 1. To methyl urea (0.24 g) in tetrahydrofuran was added sodium hydride (22 mg of 60% in oil) and the reaction mixture stirred for 50 min at room temp. Dicyclohexyl carbamoyl chloride (0.8 g) was then added (ice bath cooling used during addition) and the mixture was stirred overnight. The reaction mixture was then added to 0.5 ml water, partially concentrated in vacuo and water (2 mL) and ethyl acetate (10 mL) was added. The non soluble material was removed by filtration and the organic layer collected and concentrated in vacuo. An aliquot of the crude was then dissolved in THF and purified by preparative LCMS to give the desired product (8 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[OH2:18].C(O)(=[O:21])C>>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)(=[O:21])=[O:18]
Reactant: O
Reactant: CSc1ccccc1-c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)O
Product: CS(=O)(=O)c1ccccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A solution of 20.0 g (81.5 mmol) of 2-methylsulfanyl-4′-nitrobiphenyl in 150 ml of glacial acetic acid is treated with 66 g of sodium perborate trihydrate and heated at 60° C. with stirring for 3 days. The reaction mixture is added to water, and the precipitate is filtered off and recrystallized from petroleum ether/ethyl acetate. A yellowish solid is obtained; FAB 278
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([N:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)(OCC1C=CC=CC=1)=O.S([O-])([O-])(=O)=[O:47].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:47])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:42]2[CH2:43][CH2:44][NH:39][CH2:40][CH2:41]2)[CH2:6]1
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(C2CCNCC2)C[C@@H]1CCCB(O)O
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 97.6 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-CBZ-piperidine-4-one (0.233 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 2.5 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (265 mg, 1.25 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-4-yl)pyrrolidine-3-carboxylic acid (146 mg, 71%) as a pale amber solid. NMR (D2O) δ 4.02 (d, J=13 Hz, 1 H), 3.90 (m, 1 H), 3.77 (m, 1 H), 3.45-3.65 (m, 3 H), 3.36 (m, 1 H), 3.00 (m, 2 H), 2.50-2.60 (m, 1 H), 2.30-2.40 (m, 2 H), 1.75-1.95 (m, 2 H), 1.55-1.65 (m, 1 H), 1.15-1.40 (m, 3 H), 0.62-0.70 (m, 2 H). MS (m+1): 300.0; MS (m−H2O+1): 282.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-:13][Mn](=O)(=O)=O.[K+].C1OCCOCCOCCOCCOCCOC1.CC(O)(C)C.[OH2:42]>>[Br:1][C:2]1[CH:11]=[C:10]([CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:13])=[O:42]
Reactant: O
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: O=[Mn](=O)(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(C(=O)O)cc1Br
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
A mixture of methyl 2-bromo-4-methylbenzoate (4.58 g, 20 mmol), KMnO4 (12.64 g, 80 mmol) and 18-crown-6 (1.06 g, 4.0 mmol) in t-BuOH:H2O (1:1, 60 mL) was stirred for 20 min at 75° C. Then the mixture was cooled to rt and KMnO4 (3.16 g, 20 mmol) was added. The reaction mixture was stirred for additional 1 h at 75° C. After that, the mixture was cooled to rt and KMnO4 (1.58 g, 10 mmol) was added again. The mixture was stirred for 1 h more at 75° C., cooled to rt and filtered. The filtrate was acidified by citric acid and the white solid was precipitated. It was filtered and washed with water to give the product (2.5 g, yield 48.5%) as a white solid. MS: m/z==258.9 (M+1, ESI+).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29][CH3:30])=[O:21])[CH2:15][CH2:14]1.B1([O-])O[O:35]1.O.O.O.O.[Na+]>C(O)(=O)C>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH:22][C:23]2[C:24]([S:32][CH3:33])=[N:25][C:26]([CH3:31])=[CH:27][C:28]=2[S:29]([CH3:30])=[O:35])=[O:21])[CH2:17][CH2:18]1
Reactant: [O-]B1OO1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(C)cc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 3 h
Yield: 7.1 %

Procedure:
To a solution of 2-[4-[2-(benzimidazol-2ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (1.00 g, 1.99 mmol) in acetic acid (20 ml) was dropped a solution of sodium perborate tetrahydrate (321 mg, 2.09 mmol) in acetic acid (30 ml), and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol 15:1) to provide 73 mg (yield 7%) of 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[4-methanesulfinyl-6-methyl-2-(methylthio)-3-pyridyl]acetamide as pale yellow oil. IR (KBr) cm−1: 3375, 2496, 1672, 1553, 1122. 1H-NMR (CD3OD) δ: 2.45 (3H, s), 2.51 (3H, s), 2.52-2.64 (8H,m), 2.70 (2H, t, J=6.8 Hz), 2.72 (3H, s), 3.04 (1H, d, J=16.1 Hz), 3.13 (1H, d, J=16.1 Hz), 3.30 (2H, t, J=6.8 Hz), 7.04-7.10 (2H, m), 7.32 (1H, s), 7.33-7.38 (2H, m), 7.78 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:23])=[C:12]([C:18](OCC)=[O:19])[C:13](=[O:17])[NH:14]3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:23])=[C:12]([C:18]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:19])[C:13](=[O:17])[NH:14]3)=[N:9][CH:8]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (35 mg, 0.102 mmol) and 2-methoxyethylamine (384 mg, 5.11 mmol) was heated at 120° C. in a sealed tube for 18 h. The material was triturated with hot EtOH and filtered to give the product as a white solid: 1H NMR (d6-DMSO) δ 8.37 (1H, br), 7.39 (1H, br), 7.31 (2H, br t, J˜8 Hz), 7.15 (2H, br t, J˜9 Hz), 4.07 (2H, br), 3.47 (4H, br), 3.33 (3H, s); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found: 372.1372.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][OH:12])[C:9]#[N:10].[C:13](OCC)(=[O:15])[CH3:14]>CCCCCC>[C:13]([O:12][CH2:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]#[N:10])(=[O:15])[CH3:14]
Reactant: CCOC(C)=O
Reactant: N#CC(CO)c1ccccc1Cl
Solvent: CCCCCC
Product: CC(=O)OCC(C#N)c1ccccc1Cl

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(2-chlorophenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-(2-chlorophenyl)-3-hydroxypropanenitrile is described in Example 13. The recovered ester product was a colorless oil (70% yield), Rf 0.3 (silica gel, ethyl acetate:hexane=1:4).