Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[CH2:17][N:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([F:26])=[C:21](Cl)[N:20]=2)=[O:15])C>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[N:18]1[C:19]2[C:24](=[CH:23][C:22]([F:26])=[C:21]([N:8]3[CH2:9][CH2:10][C:6]4([O:5][CH2:4][CH2:3][CH2:2][O:1]4)[CH2:7]3)[N:20]=2)[CH:25]=[C:16]([C:14]([OH:15])=[O:13])[CH2:17]1
Reactant: C1COC2(CCNC2)OC1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Product: O=C(O)C1=Cc2cc(F)c(N3CCC4(C3)OCCCO4)nc2N(c2ccc(F)cc2F)C1
Temperature: 45 °C

Procedure:
Following the procedure of Step 2 Example 331 a 0.168 g (1.17 mmol) of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2 Example 14, was reacted with 0.300 g (0.78 mmol) of 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-1,8-naphthyridine-3-carboxylic acid ethyl ester by heating at 40° C. instead of 45° C. for 10 instead of 24 hours. The solvent was removed by evaporation to afford the title product which was purified by column chromatography over silica gel (0% increasing to 4% methanol/methylene chloride) to afford 0.252 g of the title compound. The ester was not further purified, but was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: COc1ccc(C)cc1N=C=O
Product: COc1ccc(C)cc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3ncccc23)cc1

Procedure:
44.9 mg of solid beige-coloured 3-{4-[3-(2-methoxy-5-methylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-methoxy-5-methylphenyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[O:23]=[CH:24][C@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])O)[OH:26]>>[Br:15][C:11]1[C:12](=[O:14])[NH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:1][CH:33]3[CH:31]([OH:32])[CH:29]([OH:30])[CH:27]([CH:25]([OH:26])[CH2:24][OH:23])[O:34]3)[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])=[N:9][C:10]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CCCOc1ccc(NC2OC(C(O)CO)C(O)C2O)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 34 with mannose in the same manner as that of example 77. 1H NMR (DMSO-d6) δ: 7.47 (1H, d), 7.21 (1H, dd), 7.09 (1H, d), 4.75 (1H, d), 4.01 (2H, t), 3.78-3.37 (7H, m), 2.57 (2H, q), 2.46 (2H, q), 1.72 (2H, m), 1.18 (6H, d), 0.95 (3H, t).
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[NH:19][N:18]=1)(=O)C1C=CC=CC=1>[OH-].[Na+].C(O)C>[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[NH:19][N:18]=1
Reactant: COc1cccc(-c2nc(-c3ccccc3COC(=O)c3ccccc3)n[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2nc(-c3ccccc3CO)n[nH]2)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 3-(2-benzoyloxymethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (37.1 g, 0.1 mole) in 10% NaOH (160 ml) and 95% ethanol (240 ml) is heated to 70° C. for one hour, then ethanol is distilled under vacuum and the reaction mixture is diluted with water (240 ml) and decolorized with activated carbon. The filtrate is brought to pH 8 by the addition of 10% HCl and stirred at room temperature for a few hours. The solid which separates is recovered by filtration and dried under vacuum yielding 24.2 g of 3-(2-hydroxymethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole. M.p. 155°-56° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]([N:24]4[CH2:29][CH:28]=[C:27]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)=O)=[CH:21][C:15]=3[O:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:37]1([C:13]2([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:17][C:16]3[CH:18]=[CH:19][C:20]([CH2:22][N:24]4[CH2:25][CH:26]=[C:27]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[CH2:28][CH2:29]4)=[CH:21][C:15]=3[O:14]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CC=C(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(C2=CCN(Cc3ccc4c(c3)OC(c3ccccc3)(c3ccccc3)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
Lithium aluminium hydride (13 mg, 0.36 mmol) was suspended in THF (10 ml). At room temperature (2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone (104 mg, 0.22 mmol) dissolved in THF (1.5 ml) was added dropwise under argon. The reaction was heated to reflux for 2 hours. Lithium aluminium hydride (50 mg) was added and the reaction was heated to reflux overnight under argon. Lithium aluminium hydride solution (0.3 ml, 1M solution in THF) was added and the reaction heated to reflux for 4 hours. The reaction was cooled (ice bath) and under argon a mixture of water (0.4 ml) and THF (1.5 ml) was added slowly. The reaction was stirred for 10 minutes and solid potassium carbonate (2 g) was added. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic solution was dried over sodium sulfate, filtered and the solvent was evaporated to yield the product as a white colorless viscous oil (85 mg, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:59](O)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66].CN1CCNCC1NC(N=NC(NC1CNCCN1C)=O)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH:14]=2)[C@H:9]([N:19]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([C:35]([F:36])([F:38])[F:37])[CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2]
Reactant: CCCCCCCCO
Reactant: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: CN1CCNCC1NC(=O)N=NC(=O)NC1CNCCN1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1cc2c(cc1OC)[C@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC)C[C@H](C)N2C(=O)OCC
Yield: 50.2 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-hydroxy-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (30 mg, 0.053 mmol), triphenylphosphine (28 mg, 0.11 mmol), 1-octanol (33 μL, 0.21 mmol), and bis-(N-methylpiperazinyl)-azodicarboxamide (30 mg, 0.11 mmol) in benzene (1 mL) was stirred at room temperature for 2 days. Purification of the solution directly by silica gel chromatography using 0-20% ethyl acetate/hexanes as eluent afforded the title compound (18 mg, 50%). MS m/z 695 (M+ +19), 376 (M+ -300); 1H NMR (CDCl3) δ 7.08 (C8, s, 1H), 6.40 (C5, s, 1H), 1.17 (C2-Me, d, 3H, J=6.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(F)c(Cl)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc(F)c1Cl
Temperature: -74 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
2-Chloro-3-fluoro-6-methoxybenzaldehyde (46.0 g, 245 mmol) was added in a three neck flask equipped with a nitrogen inlet, a thermometer and an addition funnel. DCM (800 mL) was added and cooled to −70 to −78° C. using an acetone/dry ice bath. Boron tribromide (25.4 mL, 269 mmol) was diluted in 200 mL of dichloromethane and added to the reaction mixture slowly over a period of 1 h. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Then the reaction mixture was cooled to 0° C. in an ice bath and quenched by adding methanol (150 mL) over a period of 30 minutes and stirred at room temperature for 20 min. The solvents were removed, and the residue was diluted with dichloromethane and washed with aq. sodium bicarbonate solution followed by water. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude product. It was purified by column chromatography on silica gel eluting with 2→3% methanol in dichloromethane, giving 34 g (80% yield) of the title compound. 1HNMR (300 MHz, CDCl3): δ=11.68 (s, 1H), 10.39 (s, 1H), 7.26-7.35 (m, 1H), 6.86-6.90 (m, 1H).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[CH:12][CH:13]1[NH:19][C:18](=[NH:20])[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-])=O>CO.[Pd]>[ClH:1].[ClH:1].[NH:20]=[C:18]1[NH:19][CH:13]([CH2:12][CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH2:2])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: N=C1CCCCC(C=Cc2ccccc2[N+](=O)[O-])N1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C1CCCCC(CCc2ccccc2N)N1

Procedure:
The title material of Example 157 in MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 reducing both the nitro and double bond functions to generate the title product.
Reaction SMILES: [C:1]1([N:7]2[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][N:25]1[C:29](=[O:30])[C:28]2[C:31]([CH:36]([CH3:38])[CH3:37])=[CH:32][C:33]([OH:35])=[CH:34][C:27]=2[S:26]1(=[O:40])=[O:39].CCOCC.[Cl-].[Na+].O>CO.CN(C=O)C>[CH:36]([C:31]1[C:28]2[C:29](=[O:30])[N:25]([CH2:24][O:12][C:11]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=3)[S:26](=[O:40])(=[O:39])[C:27]=2[CH:34]=[C:33]([OH:35])[CH:32]=1)([CH3:38])[CH3:37]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CBr)S2(=O)=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)S2(=O)=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole (20.5 g; 89.92 mmol) and Cs2CO3 (17.6 g; 53.8 mmol) in methanol (50 ml) was stirred at 20° C. for 5 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo at 50° C. for 4 hours. To a solution of the above residue in 50 ml of DMF was added 2-bromomethyl-4-isopropyl-6-hydroxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (25 g, 74.9 mmol) and the resulting mixture was stirred at room temperature (20° C.) overnight and poured into ether/brine. The above mixture was extracted with ether and the combined organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue (46 g) was purified by column chromatography (silica gel; chloroform, 2% ethyl acetate in chloroform) and recrystallized from hexane to afford 25.7 g (71%) of 4-isopropyl-6-hydroxy-2-(1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OH) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[H-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(Cl)c21
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OS(C)(=O)=O)cc(Cl)c21
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(4-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (60 mg, 0.22 mmol) in DMF (3 mL) was slowly added NaH (27 mg, 0.66 mmol) at 0° C. The reaction mixture was stirred for 20 min and MsCl (29 mg, 0.27 mmol) was added. The reaction mixture was stirred overnight at room temperature and quenched with ice water. The resulting mixture was extracted with EtOAc (2×15 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in the next step reaction without further purification. MS (ESI) m/z=349 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2Cl)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.166 g, 0.00053 mole), in DMF (10 mL) was added, NaH (60% w/w dispersion in oil) (0.0512 g, 0.0021 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (0.303 g, 0.0021 mole) was then added, and the stirring was continued for 30 minutes at ambient temperature. The reaction mixture was heated to 45° C. for 30 minutes. The reaction mixture was then quenched with aqueous 10% NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous NaHCO3 solution followed by brine solution. The organic layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 0.08 g (46%) of 4-[(2-chloro-phenyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.6-7.54 (m, 1H), 7.28-7.2 (m, 1H), 7.14-7.08 (m, 1H), 6.96-6.88 (m, 1H), 4.2-4.0 (m, 2H), 3.3-3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.7 (s, 3H), 1.7-1.6 (m, 2H), 1.6 (m, 1H), 1.45 (s, 9H). A solution of 4-(2-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.078 g, 0.00024 mole) in dioxane.HCl (1 mL) was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to afford 0.072 g (99%) of (2-chloro-phenyl)-methyl-piperidin-4-yl-amine hydrochloride which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccc(F)cc2)CC1

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-fluoro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (7.6 mg, II %) as light yellow oil. MS m/e=509.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1CCCCC1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[C:28]2[S:24][C:25](=[O:30])[NH:26][C:27]2=[O:29])=[CH:18][CH:17]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 77.1 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (5.0 g), 2,4-thiazolidinedione (3.8 g), piperidine (0.32 ml) and ethanol (100 ml) was stirred under reflux for 5 hours. After cooling, the crystals which separated out were collected by filtration to give 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidene}-2,4-thiazolidinedione (5.1 g, 76.8%). Recrystallization from chloroform-ethanol afforded colorless needles, m.p. 213°-214° C. Elemental analysis for C22H18N2O4S, Calcd.: C, 65.01; H, 4.46; N, 6.89. Found: C, 64.81; H, 4.55; N, 6.78.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10](N2C(C)=CC=C2C)[CH3:11])[C:5]=1[F:19])[CH3:2].Cl.[NH2:21]O.[OH-].[K+].C(O)C>O>[NH2:21][CH2:11][CH2:10][C:6]1[C:5]([F:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: NO
Reactant: CCOc1ccnc(C(C)n2c(C)ccc2C)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccnc(CCN)c1F
Temperature: 25 °C

Procedure:
A mixture of 825 mg (3.15 mmole) of N-[(4-Ethoxy-3-fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole, 1.4 g (20.1 mmole) of hydroxylamine hydrochloride, 700 mg (12.5 mmole) of potassium hydroxide, 20 ml of ethanol, and 8 ml of water was refluxed for 3 days under nitrogen. The solution was cooled to room temperature, concentrated, and partitioned between 50 ml of 2N hydrochloric acid and ethyl acetate (3×). The aqueous layer was basified with 5N sodium hydroxide, extracted with ethyl acetate (3×), dried over sodium sulfate, and concentrated. The resulting red oil was found to be the titled compound with a small amount of 2,5-hexanedione dioxime also present. The oil was used as such for reaction without further purification: IR (KBr, cm−1) 2989, 1609, 1495, 1306, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, 11H), 7.05 (t, 1H), 4.20 (q, 2H), 2.60-3.00 (m, 6H), 1.38 (t, 3H); MS (FD) m/e 185 (Mt).
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[NH2:73][C:74]([N:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1)=[S:75]>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:75][C:74]([N:76]3[CH2:77][CH2:78][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:80][CH2:81]3)=[N:73][C:44]=2[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[C:47]=2[F:64])[CH:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 38 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (2.00 g, 4.53 mmol), NBS (0.85 g, 4.75 mmol) and 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (2.22 g, 9.05 mmol) the title compound of Step A was obtained (1.16 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.30 (d, J=5.49 Hz, 1H), 7.62-7.76 (m, 1H), 7.46 (td, J=7.46, 1.28 Hz, 1H), 7.38 (t, J=6.09 Hz, 1H), 7.32 (t, J=7.78 Hz, 1H), 7.25 (t, J=9.11 Hz, 2H), 6.46 (d, J=5.40 Hz, 1H), 3.56 (br. s., 4H), 3.47 (br. s., 4H), 1.42 (s, 9H). m/z (ES+): 668 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:14][N:13](C(OC(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25].[C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1)#[N:27]>CN(C=O)C>[ClH:25].[C:1]([NH:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:22]([N:29]2[CH2:30][CH2:31][CH2:32][C@H:28]2[C:26]#[N:27])=[O:24])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1CCCN1C(=O)[C@@H]1C[C@@H](NC(=O)c2ccccc2)CN1

Procedure:
(2S,4R)-4-Benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (title compound of Reference Example 8, 1.6 g) and (S)-2-cyanopyrrolidine hydrochloride (0.63 g) were dissolved in DMF (10 mL), and triethylamine (1.32 mL), HOBT (0.79 g) and EDC hydrochloride (0.99 g) were successively added. The mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-((2S,4R)-4-benzoylamino-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl)-2-cyanopyrrolidine (1.2 g) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([O:18]C)[C:7]([O:14]COC)=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([CH3:3])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl.CC(O)=O.Br>[OH:14][C:7]1[C:6]([OH:18])=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COCOc1c(OC)cc(C(C)C)cc1C(=O)OC
Agent: Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(O)c(O)c(C(=O)O)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-Isopropyl-3-methoxy-2-methoxymethoxy-benzoate in 5 mL dry CH2Cl2 cooled to −80° C., BBr3 (3.4 mL of a 1 m solution in CH2Cl2) was added dropwise via a syringe. The mixture was then stirred 30 min. at −70° C., then the cooling bath was removed and the stirring continued at r.t. for 1 h. The reaction was the quenched by addition of H2O and the resulting mixture was extracted twice with 30 mL CH2Cl2. The combined organic fractions were dried over MgSO4 and evaporated in vacuo to yield a brown solid. This material was redissolved in 1 mL AcOH to which 2.5 mL HBr (33% in AcOH) was added The mixture was stirred at 120° C. for 5 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo to yield the desired product as a brown solid.