Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH3:30]
Reactant: CCOCCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 80.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl)-amide (97 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 3-ethoxy-propylamine (28 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 494.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.36 (bs, 1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.78-7.64 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.45-3.37 (m, 4H), 3.36-3.31 (m, 2H), 1.83-1.70 (m, 2H), 1.10 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.CCOCC.CO>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)([O-:3])=[O:2]
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a cooled solution (−5° C.) of (3,4-dinitrophenyl)-(4-methylpiperazin-1-yl)methanone (5.88 g, 20 mmol) in THF, was added powdered NaBH4 (1.89 g, 50 mmol), followed by the dropwise addition of BF3.OEt2 (6.4 mL, 50 mmol), while keeping the temperature below 5° C. The mixture was allowed to come to room temperature over 2 hrs, and then stirred for a further 3 hrs at room temperature. MeOH was then added cautiously to the mixture, the stirring was continued for 10 minutes and then the mixture was concentrated. The residue was partitioned between EtOAc (150 mL) and saturated aqueous NaHCO3 (150 mL). The organic layer was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluent: 2% MeOH in CH2Cl2) to give a yellow solid (4.5 g, 80.3%). 1H NMR (300 MHz, CDCl3) δ: 7.90-7.92 (1H, d, J=6.0 Hz), 7.90 (1H, s), 7.69-7.71 (1H, d, J=6.0 Hz), 3.73 (2H, s), 3.07-3.10 (2H, m), 2.94-2.99 (2H, m), 2.76-2.81 (2H, m), 2.67 (3H, s), 2.53-2.56 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:31]([O:33]CC)=O)=[N:4][C:5]([NH:17][CH2:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2C(OC(C)(C)C)=O)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C(OC([N:43]1CCC[C@H]1CNC1N=C(C(OCC)=O)C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=1)=O)(C)(C)C.[CH2:73]([OH:75])C>[Pd]>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:73](=[O:75])[NH:1][C:2]2[C:7]1=[N:6][C:5]([NH:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)=[N:4][C:3]=2[C:31]([NH2:43])=[O:33]
Reactant: CCO
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@@H]3CCCN3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(S)-Ethyl 5-amino-2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. (S)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (0.416 g, 0.802 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.083 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.340 g, 84%). MS (ESI) m/z 487.6 [M+1]+.
Reaction SMILES: C([C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(O)=O.C1(P([N:43]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:43][C:4]1[C:13]2[C:8](=[C:9]([NH:14][C:15]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(C(=O)O)nccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: Nc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12
Temperature: 100 °C
Yield: 26.9 %

Procedure:
A mixture of N-(1-carboxyisoquinolin-5-yl)-N′-[4-(trifluoromethyl)benzyl]urea (Example 117, 309 mg, 0.794 mmol), diphenylphosphoryl azide (210 μl, 0.975 mmol) and triethylamine (210 μl, 1.50 mmol) in 1,4-dioxane (25 ml) was heated at 100° C., under a nitrogen atnosphere for 1.5 h. Water (0.25 ml) was then added and the reaction mixture heated for a further 1 hour. The reaction mixture was then cooled to room temperature, filtered and the filtrate evaporated. The residue was purified using a Bond-Elut SCX ion-exchange cartridge, first eluting non-basic materials with methanol, then eluting the product with 2M methanolic ammonia. The basic fractions were evaporated and further purified by flash column chromatography (eluant 5% MeOH-95% dichloromethane increasing to 10% MeOH-90% dichloromethane). The product was then passed through a second SCX purification to give the title compound (77 mg, 27%). m/z (ES+) 361 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[C:28]3[F:50])[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:54])=[O:53])[NH:1][C:58](=[O:59])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[CH:34][CH:33]=2)[C:28]([F:50])=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:42])([CH3:40])([CH3:39])[CH3:41]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
To a solution of 19A (135 mg, 0.168 mmol) in acetonitrile (6 mL) and dichloromethane (3 mL) at 0° C., was added phosgene solution (20% in toluene, 0.106 mL, 0.201 mmol) dropwise. The mixture was stirred at 0° C. for 40 min, then at rt for 10 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was redissolved in acetonitrile (1.0 mL) and dichloromethane (1.0 mL), and was added dropwise via syringe pump into a solution of TEA (0.187 mL, 1.340 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. The solvent was removed and the crude residue was purified using a prep HPLC equipped with a C18 PHENOMENEX® Luna Axia column (30 mm×75 cm, 5μ). The desired fractions were collected and concentrated to give a mixture of diastereoisomers (114 mg). The diastereoisomers were separated by a prep chiral HPLC [(R,R)-Whelk-01 250×21.1 mm column] to give 19B (48 mg, 0.058 mmol, 34.4% yield). MS (ESI) m/z: 832.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][N:68]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)=[CH:21][N:20]=2)=[O:24])[CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)nc3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 (0.12 mmol) in DMF (0.5 mL) is added HATU (0.13 mmol) and DIEA (0.36 mmol) at rt. The resulting mixture is stirred for 2 min and then a solution of piperazine-1-carboxylic acid tert-butyl ester (0.12 mmol) in DMF (1 mL) is added. The reaction mixture is stirred at rt for 4 h and directly purified by preparative LCMS to give 4-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 6 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.89 (s, 2H), 8.39-8.37 (m., 2H), 7.86 (dd, J=4.0 and 8.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.08-7.06 (m, 2H), 3.81 (s, 3H), 3.55-3.51 (bm, 4H), 3.96-3.94 (bs, 4H), 1.42 (s, 9H). MS (m/z) (M+1)+: 491.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:25])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:9]#N.[OH2:26].[OH-:27].[Na+].Cl>C(O)C.CC(OC)(C)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:25])[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:9]([OH:27])=[O:26]
Reactant: [OH-]
Reactant: COC[C@H](C)Oc1cc(C#N)cc(Oc2ccc(S(C)(=O)=O)cc2)c1
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzonitrile (0.1 g, 0.27 mmol) was dissolved in ethanol (1.0 ml) and charged to a 5 ml round bottomed flask equipped with condenser and magnetic stirrer. Water (0.2 ml, 11.1 mmol) was added, followed by sodium hydroxide (18.9M in water, 0.2 ml, 3.78 mmol). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to ambient temperature, and the solvent was evaporated in vacuo. The residue was partitioned between water (10 ml) and MTBE (10 ml) and the layers were separated. The aqueous phase was acidified to pH1 with 2M HCl (2.5 ml, 5 mmol) and MTBE (10 ml) was added to extract the product. The MTBE extract was dried over MgSO4, and then evaporated in vacuo to afford a pale yellow oil (0.1 g, 100% yield).
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([O:11][C:12]([NH:14][C:15]([CH3:19])([CH3:18])[CH:16]=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:22]([O:21][C:25](=[O:4])/[CH:24]=[CH:16]/[C:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])([CH3:19])[CH3:18])[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Product: CCOC(=O)/C=C/C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethyl phosphonoacetate (9.6 ml, 48 mmol) was added slowly to a suspension of potassium tert-butoxide (5.39 g, 48 mmol) in tetrahydrofuran (140 ml). After 30 min at 20° C. 2-tert-butoxycarbonylamino-2-methylpropanal (5.0 g, 26 mmol) was added. After 2.5 h at 20° C. 1N hydrochloric acid (80 ml) was added slowly. The mixture was extracted with ethyl acetate (120 ml, 2×50 ml) and the combined organic layers were washed with a saturated solution of sodium hydrogencarbonate (100 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the crude product was chromatographed on silica gel (100 g) with ethyl acetate/heptane 1:4 as eluent to give 5.7 g of (2E)-4-tert-butoxycarbonylamino-4-methylpent-2-enoic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:23]5C=CC(C(=O)C)=C[CH:24]=5)[CH:19]=4)[CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[OH2:35]>CCO>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:32])[CH2:12][N:13]3[CH2:22][CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]([OH:35])[CH3:24])[CH:19]=4)[CH2:14]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)c1ccc(-c2ccc3c(c2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)cc1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(4-{2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}phenyl)ethanone (153 mg) in EtOH (10 mL) is added sodium borohydride (20 mg). The resulting mixture is stirred at rt for 2 hr. Water (10.0 ml) is added to quench the reaction, and then the EtOH is evaporated. The residue is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and the solvent is removed under reduced pressure to give a residue that is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.08˜7.14 (2H, m), 6.92-6.98 (1H, m), 4.82 (1H, q), 3.58-3.64 (6H, m), 3.28 (2H, s), 2.60-2.84 (6H, m), 2.20-2.28 (4H, m), 1.60-2.20 (6H, m), 1.42 (3H, d); MS (+VE) m/z 358.2 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:11])[CH2:9][SH:10])([CH3:6])([CH3:5])[CH3:4].[CH3:12][O:13][C:14](=[O:25])[CH:15](Br)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCC[CH2:27]1>C(OCC)(=O)C>[CH2:12]([O:13][C:14](=[O:25])[CH:15]([S:10][CH2:9][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:11])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)CS
Reactant: COC(=O)C(Br)CCc1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCc1ccccc1)SCC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
2.3 g (53.2 mmol) of sodium hydride in the form of a suspension in mineral oil are placed at 0° in 30 ml of tetrahydrofuran. Then at 0° to 10°, 6.6 g (44.:3 mmol) of thioglycolic acid tert-butyl ester are added dropwise thereto. A viscous suspension is formed which is diluted with 50 ml of tetrahydrofuran. The mixture is then stirred for 20 minutes at 0° and then 12 g (44.3 mmol) of 2-bromo-4-phenyl-butyric acid methyl ester are added dropwise thereto. The mixture is stirred for 2 hours at room temperature, then taken up in 100 ml of ethyl acetate and extracted by shaking in succession with 50 ml of water and 50 ml of saturated sodium chloride solution. The aqueous phases are combined and extracted by shaking with 25 ml of ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica g al with hexane/ethyl acetate (20:1) as eluant yields 5.7 g (38% of theory) of 2-tert-butyloxycabonylmethylthio-4-phenyl-butyric acid ethyl ester in the form of an oil.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:25][C:26](=[O:36])[NH:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C(OO)=[O:45])C=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:25][C:26](=[O:36])[NH:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:45])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1)NOCc1ccccc1
Solvent: ClCCl
Product: O=C(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-])NOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.3 %

Procedure:
To a stirring solution of (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (140 mg, 0.28 mmol) in dichloromethane (DCM) (5 mL) under nitrogen at 0° C. was added 3-chlorobenzenecarboperoxoic acid (147 mg, 0.85 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min, then warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. aq. NaHCO3 and then extracted with DCM. The organics were dried over Na2SO4, filtered, and concentrated to provide the crude product which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(5-fluoro-1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (90 mg, 0.18 mmol, 62% yield) as a white solid. MS: 512 ([M]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:9][C:8](=O)[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].P(Cl)(Cl)([Cl:15])=O>>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([Cl:15])[CH:7]=[CH:6][N:5]=1
Reactant: COCc1nccc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: COCc1nccc(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 2-methoxymethyl-4-pyrimidone (1.73 g) and phosphorus oxychloride (20 ml) were heated together under reflux for 30 minutes. The mixture was stripped, ice/water added and the pH raised to 14 (NaOH). The solution was extracted with chloroform, the extracts dried (MgSO4) and stripped to give 2-methoxymethyl-4-chloropyrimidine (1.72 g) as an oil which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][S:6][CH:7]=1.C(N(C(C)C)C(C)C)C.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30](O)=[O:31])=[N:26][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:11][O:10][C:8]([C:4]1[C:3]([NH:2][C:30](=[O:31])[CH2:29][O:28][C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)=[CH:7][S:6][CH:5]=1)=[O:9]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(O)COc1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of methyl 4-amino-3-thiophenecarboxylate hydrochloride (500 mg, 2.58 mmol) in dimethylformamide (25 mL) was added N-ethyldiisopropylamine (2.26 mL, 12.9 mmol), (5-bromo-pyridin-2-yloxy)-acetic acid ([79674-66-1], 600 mg, 2.58 mmol) and HATU (1.24 g, 3.23 mmol). The reaction mixture was allowed to stir for 2 hours at room temperature. After such time, water was added, and precipitation was eased by ultrasonication. The precipitate was isolated by filtration and washed with a mixture of water and ethanol (3:1) to yield 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (699 mg, 73%) as a light brown solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:15]=[C:14]([CH:16]2[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]2)[O:13][N:12]=1)([CH3:10])[CH3:9].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[C:24]([CH:19]1[C:18](=[O:23])[CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:15]=2)[O:21][C:20]1=[O:22])(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Cl
Reactant: CC(C)c1cc(C2CC(=O)CC(=O)O2)on1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)C1C(=O)CC(c2cc(C(C)C)no2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
12.6 g of triethylamine was added to 27.9 g of 6-(3-isopropylisoxazol-5-yl)-tetrahydropyran-2,4-dione in 200 ml of THF. At 0° C., 13.3 g of butyryl chloride was dripped in and the mixture was stirred for one hour at 0° C. The mixture was evaporated, followed by partitioning between methylene chloride and water. The organic phase was worked up, i.e., extracted with water, 10% strength sodium carbonate solution and again with water, dried with sodium sulfate and evaporated again. The residue was dissolved in anhydrous methylene chloride and stirred for 48 hours with 1.3 g of 4-(N,N-dimethylamino)-pyridine. Removal of the solvent was followed by chromatography over silica gel with methylene chloride and methanol (98.5:1.5). The isolated compound was recrystallized from a small amount of cyclohexane. There was obtained 13 g of product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 68) and propionyl chloride. m.p.: 188-190° C. (recrystallized from ethyl acetate) 1H-NMR (CDCl3) δ: 11.68 (1 H, br s), 10.88 (1 H, br s), 8.70 (1 H, d, J=5.4 Hz), 8.54 (1 H, d, J=9.1 Hz), 8.37 (1 H, d, J=2.0 Hz), 7.58 (1 H, dd, J=2.1, 5.3 Hz), 7.40 (1 H, d, J=2.0 Hz), 7.06 (1 H, dd, J=1.1, 9.1 Hz), 2.63 (2 H, q, J=7.6 Hz), 1.37 (3 H, t, J=7.6 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[C:15]=2[F:24])[CH:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3OC=CC=3C=C(F)C=2F)C(C)C1)C1C=CC=CC=1.C([SnH](CCCC)CCCC)CCC>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[CH:17]=[C:16]([F:23])[C:15]=2[F:24])[C@H:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1c(F)c(F)cc2ccoc12
Agent: CC(=O)C(=O)OC1(c2c(F)c(F)cc3ccoc23)CCN(Cc2ccccc2)CC1C
Agent: CCCC[SnH](CCCC)CCCC
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1c(F)c(F)cc2ccoc12
Yield: 32.4 %

Procedure:
Beginning with 0.75 gm (2.08 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(5,6-difluorobenzofur-7-yl)piperidine, 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(5,6-difluorobenzofur-7-yl)piperidine was prepared essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to prepare 0.23 gm (32%) of the desired compound.