Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:39])[CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][SH:30]>>[CH3:25][O:26][C:27](=[O:39])[CH:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:29][S:30][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)C(CS)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: COC(=O)C(CSc1cnc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)s1)NC(=O)OC(C)(C)C
Yield: 34.8 %

Procedure:
2-tert-Butoxycarbonylamino-3-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]thiazol-5-ylsulfanyl}-propionic acid methyl ester (196 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2-tert-butoxycarbonylamino-3-mercapto-propionic acid methyl ester (470 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][NH2:40].N1C=CC=CC=1>CO>[CH2:33]([O:32][CH:27]([CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:35]=[CH:36][C:9]([C:1](=[N:40][O:39][CH3:38])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:21][CH:22]=1)[C:28]([O:30][CH3:31])=[O:29])[CH3:34]
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
To 30 ml of methanol add the compound obtained in Step C (0.00198 mol), O-methyl-hydroxylamine hydrochloride (0.00594 mol) and pyridine (0.00594 mol). Heat at reflux for 3 hours. Evaporate to dryness. Add 100 ml of hydrochloric acid (1N) and then extract with 50 ml of dichloromethane twice. The organic phase is dried over MgSO4 and then evaporated to yield the title compound.
Reaction SMILES: [CH3:1]C(C[AlH]CC(C)C)C.[CH3:10][C:11]1([CH3:24])[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CCOCC.CO>[CH3:1][O:16][CH:13]1[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([CH3:24])([CH3:10])[CH2:15][CH2:14]1
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1(C)C
Solvent: CO
Solvent: CCOCC
Product: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
DIBAL-H (73.65 mL, 110.5 mmol, 1.5M in toluene) was added portionwise to a solution of tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (23.10 g, 108.3 mmol) in dry Et2O (200 mL) cooled to −78° C. The reaction was stirred for 1 hour at −78° C. and then allowed to warm to room temperature and stirred overnight. The reaction was quenched with NH4OH (50 mL) and stirred for 20 minutes. The reaction was then diluted with EtOAc (200 mL), 0.5M Rochelle's Salt (100 mL) was added, and the layers were separated. The organic fraction was washed with 0.5M Rochelle's Salt (2×100 mL), brine (100 mL), dried (MgSO4) and concentrated to an oil. The oil was taken up in a solution of p-TsOH monohydrate (2.06 g, 10.8 mmol) in MeOH (200 mL) and stirred overnight at room temperature. The reaction was then concentrated, taken up in EtOAc (200 mL), washed with saturated Na2CO3 (2×100 mL), brine (50 mL), dried (MgSO4) and concentrated to give tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (24.07 g, 96.9% yield) as an oil.
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[CH2:45]([O:52][C:53]1[CH:58]=[CH:57][C:56]([N:59]2[CH2:64][CH2:63][N:62]([C:65](=O)[CH2:66][CH:67]3[C:76]4[C:71](=[CH:72][C:73]([Br:77])=[CH:74][CH:75]=4)[CH2:70][CH2:69][O:68]3)[CH2:61][CH2:60]2)=[CH:55][CH:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:52][C:53]1[CH:54]=[CH:55][C:56]([N:59]2[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH:67]3[C:76]4[C:71](=[CH:72][C:73]([Br:77])=[CH:74][CH:75]=4)[CH2:70][CH2:69][O:68]3)[CH2:61][CH2:60]2)=[CH:57][CH:58]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(CC1OCCc2cc(Br)ccc21)N1CCN(c2ccc(OCc3ccccc3)cc2)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: Brc1ccc2c(c1)CCOC2CCN1CCN(c2ccc(OCc3ccccc3)cc2)CC1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 4-benzyloxyphenylpiperazine (XI) and the resulting amide, 1-(4-benzyloxyphenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 7.23 mmol) is reduced according to the general procedure of EXAMPLE 50 making non-critical variations to give the title compound, mp 87°-90°.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[S:46]([NH:50][CH2:51][CH2:52][NH2:53])(=[O:49])(=[O:48])[NH2:47].[Cl-].[NH4+]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](=[O:40])[NH:53][CH2:52][CH2:51][NH:50][S:46](=[O:49])(=[O:48])[NH2:47])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCNS(N)(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NCCNS(N)(=O)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and N-sulfamoylethylenediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1cccc(C(=O)Cl)c1
Product: CCCCc1oc2ccccc2c1C(=O)c1cccc(OC)c1

Procedure:
Acylation of 9.4 g. (0.054 mol.) of 2-n-butylbenzofuran with 9.9 g. (0.058 mol.) of m-anisoyl chloride according to the procedure described in Example 10 gave 2-n-butyl-3-(3'-methoxybenzoyl)benzofuran.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)C=C.[OH-].[K+].C[N+]1([O-])CC[O:21][CH2:20][CH2:19]1>O=[Os](=O)(=O)=O.O.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]#[C:10][CH2:19][CH:20]=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C#CCCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: O
Solvent: ClCCl
Product: O=CCC#CCCc1ccccc1

Procedure:
Reaction of 4-phenyl-1-butyne (5; commercially available from Lancaster Synthesis, Windham, N.H.) with allyl bromide under phase-transfer conditions (CH2Cl2, n-BU4NCl, water, KOH), selective oxidation of the alkene moiety using catalytic OsO4/pyr and stoichiometric N-methylmorpholine-N-oxide, and oxidative cleavage of the resultant diol using NalO4 affords 6-phenyl-hex-3-ynal (6). Lithiation of phosphine oxide 7 [Katritzky, Alan R., Feng, Daming, Lang, Hengyuan J. Org. Chem., volume 62(12) page 4131 (1997)], Wittig condensation with 6, and heating of the intermediate dienyne (not shown) with p-toluenesulfonic acid in ethanol affords enyne 8. Asymmetric dihydroxylation of 8 with AD mix α (Aldrich Chemical Co., Milwaukee) and methanesulfonamide [Sharpless, K. B., Amberg, W., Bennani, Y. Crispino, G. A.; Hartung, J; Jeong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D. Zhang, X.-L. J. Org. Chem., volume 57, page 2768 (1992)], followed by selective reduction with H2 over Pd/BaSO4, affords β-hydroxy lactone 9. Sequential treatment of 9 with CH3SO2Cl/NEt3 and diisobutylaluminum hydride (DIBAL-H) provides lactol 10. Sodium borohydride reduction, K2CO3 treatment, and oxidation of the resulting β-hydroxyepoxide with the Dess-Martin reagent produces the epoxyaldehyde 11. Wittig olefination of 11 and known ylide 12 [Zamboni, R.; Milettee, S.; Rokach, J. Tetrahedron Lett., volume 24, page 4899 (1983)] followed by saponification of the resulting methyl ester with LiOH in dimethoxyethane (DME)/water yields 2.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37](O)=[O:38])[C:32]2=[O:40])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:33]5[C:32](=[O:40])[N:31]([C:28]6[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=6)[CH:36]=[CH:35][CH:34]=5)=[O:38])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 71.1 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.486 mmol), N,N-dimethylacetamide (3.0 mL), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (170 mg, 0.729 mmol), HATU (277 mg, 0.729 mmol) and N,N-diisopropylethylamine (127 μL, 0.729 mmol) and in the same manner as in Example 10, the title compound (181 mg, 71%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C1COCC1>[F:21][C:22]([F:24])([F:23])[C:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Yield: 99.3 %

Procedure:
A mixture of 1,3-dibenzyloxy-2-propanone (2 g) and (trifluoromethyl)trimethylsilane (2.56 ml, 2.3 equivalents) in dichloromethane (20 ml) was stirred and cooled to 0° C. A solution of 1M tetrabutylammonium fluoride in THF (4 ml) was added dropwise over 3 minutes. Initial addition of a few drops gave an exotherm of 10° C. Throughout the addition the batch temperature was maintained below 10° C. After completing the addition the dark brown mixture was stirred at +5° C. for 5 minutes when HPLC analysis indicated the reaction to be complete. The reaction mixture was stirred for an additional 5 minutes and then washed with 1M aqueous hydrochloric acid (15 ml), saturated sodium bicarbonate (15 ml) and 1% w/v aqueous sodium chloride solution (2×15 ml). The organic extract was concentrated in vacuo to give 2.5 g of the desired product as dark oil in 99.3% yield. The NMR spectrum of the product was concordant with a reference sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](S)=[N:8][C:7]=2[CH:12]=1.S(Cl)([Cl:15])=O>CN(C=O)C.ClCCl>[Cl:15][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=2[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2oc(S)nc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2oc(Cl)nc2c1
Temperature: 68 °C

Procedure:
To a mixture of 5-methoxy-benzooxazole-2-thiol (12.14 g, 0.07 mol) and thionyl chloride were added two drops of DMF. The mixture was stirred at 68° C. for forty minutes and the formation of gas had stopped. The mixture was diluted with dichloromethane, concentrated, and dried in vacuo to give the title compound as a green solid (14.31 g): 1H NMR (CDCl3, 200 MHz): δ=7.36 (m, 1H), 7.13 (m, 1H), 6.92 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH2:49][CH2:48]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:56]3[CH2:55][CH2:54][N:53]([CH:50]4[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]4)[CH2:58][CH2:57]3)=[O:22])[N:20]=2)(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(C4CCN(C)CC4)CC3)co2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.14 mmol) was dissolved in DMF (3 mL) and EDCI (32 mg, 0.17 mmol) and HOAt (23 mg, 0.17 mmol) were added. The resulting solution was stirred for 60 min at ambient temperature prior to the addition of a solution of 1-(1-methylpiperidin-4-yl)piperazine (31 mg, 0.17 mmol) in DMF (2 mL) and the reaction stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc (20 mL) and washed with water (2×5 mL), saturated brine (5 mL), dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified using FCC, eluting with 10% MeOH in DCM, to afford the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:3]1C=CC=CC=1.C1(=O)OCC[O:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][O:12][C:11]1[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=1[O:9][CH2:2][CH2:3][OH:23]
Reactant: O=C1OCCO1
Reactant: CN(C)CCOc1ccccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccccc1OCCO
Temperature: 155 °C
Yield: 76.1 %

Procedure:
To dry DMF (50 mL) was added 2-[2-(dimethylamino)ethoxy]phenol (from Step 1; 5.4 g, 28.0 mmol), ethylene carbonate (3.20 g, 36.4 mmol) and potassium carbonate (3.9 g, 28 mmol) and the mixture was heated at 155° C. for one hour 30 minutes. The solvent from the filtered solution was evaporated under reduced pressure and the resulting residue was dissolved in CHCl3 (50 mL) and filtered through a plug of silica (50 mm×50 mm) using CHCl3 (50 mL) followed by CHCl3/MeOH (95:5) as eluents. Solvents from the pure fractions were removed under reduced pressure to give 4.8 g (76%) of the title compound as a light brown oil. HRMS m/z calcd for C12H19NO3 (M)+ 225.1365. found 225.1363.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1.Cl[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH2:22][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][NH2:21])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: CC(C)(C)OC(=O)Cl
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CC(CN)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl amine trifluoroacetate (prepared in example 1) and t-butyl chloroformate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: O=C1Nc2ccccc2C1=C1CCc2cc(Cl)ccc21
Temperature: 95 °C
Yield: 20.3 %

Procedure:
A mixture of 500 mg 5-chloro-1-indanone, 1.33 g oxindole and 0.5 ml piperidine in 3 ml dimethylforamide was heated in a sealed tube at 95° C. overnight. Water was added to the reaction mixture to yield an oily solid. The mixture was sonicated for a few minutes then decanted. This washing procedure was repeated several times. The solid was then filtered and washed with ethyl acetate/hexanes (1:3) to yield 172 mg of 3-(5-chloroindan-1-ylidene)-1,3-dihydroindol-2-one as a mustard colored solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CNCC1O
Reaction time: 8 h
Yield: 100 %

Procedure:
A racemic mixture of trans-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (3.36 g, 9.99 mmol) (Method 190) in MeOH (40 mL) was degassed, then 10 wt % Pd/C (3.19 g, 3.00 mmol) was added. The mixture was degassed, charged with H2, and stirred overnight. The mixture was filtered through a bed of Celite, washed with methanol, the filtrate was dried over anhydrous Na2SO4, filtered and conc. in vacuo to yield a white solid as racemic tert-butyl-4-hydroxypyrrolidin-3-ylcarbamate (2.020 g, 100%). 1 H NMR (400 MHz, MeOD) δ ppm 4.13 (dt, 1 H), 3.89-3.75 (m, 1 H), 3.35 (brs, 1 H), 3.14 (dd, 1 H), 2.93-2.73 (m, 2 H), 1.46 (s, 10 H); m/z 203.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(#N)C>[C:11]([NH:15][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[N:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Fc1cc(F)c(F)nc1F
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(F)cc1F
Temperature: 60 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
To 40 ml of acetonitrile were added 11.0 g of 2,3,5,6-tetrafluoropyridine and 18.5 g of t-butylamine, and the mixture was stirred at 60° C. for 3 days, and the solvent and the like were distilled off. To the residue was added 100 ml of chloroform, and the mixture was washed with 50 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.7 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:33])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([Br:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1F

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz in carbontetrachloride. The title compound, ESI MS (m/z): 549 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=3[O:26][CH3:27])[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C.CO>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=3[O:26][CH3:27])[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)NCCN1CCc2ccc([N+](=O)[O-])cc2CC1
Solvent: CO
Solvent: CCO
Product: COc1cc(N)ccc1C(=O)NCCN1CCc2ccc(N)cc2CC1

Procedure:
7-Nitro-3-(2-[2-methoxy-4-nitrobenzamido]ethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine (0.52 g) was stirred under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)] in an ethanol/methanol (1:1) solution at room temperature for 3 hours. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give the title compound as a foam, yield 0.42 g, which was used directly without further purification.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.CO.O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of methyl 3-(2-((1R,2R)-2((S)-1-(6-trifluoromethyl)pyridin-3yl)piperidin-3-ylamino)cyclohexylamino) oxazol-5-yl)benzoate (69 mg, 0.127 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2M LiOH (1 mL, 2 mmol) in H2O. The reaction mixture was allowed to stir at rt overnight. The reaction mixture was cooled in an ice bath, 1M HCl was added dropwise to pH ˜3. The reaction mixture was concentrated. The resulting residue was purified using RP prep-HPLC method A. The desired fractions were concentrated and then lyophilized with water to give the desired product, 3-(2-((1R,2R)-2((S)-1-(6-trifluoromethyl)pyridin-3yl)piperidin-3-ylamino)cyclohexylamino)oxazol-5-yl)benzoic acid 3TFA salt (86 mg, 0.094 mmol, 74% yield) as a white foam. Anal. Calcd. for C22H30F3N5O3 m/z 529.23, found: 530.2 (M+H)+; 1H NMR (400 MHz, METHANOL-D3) δ ppm 8.26 (d, J=2.7 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.47-7.40 (m, 1H), 7.34 (dd, J=8.8, 2.7 Hz, 1H), 7.28-7.21 (m, 2H), 3.85 (dd, J=13.5, 4.7 Hz, 1H), 3.77-3.61 (m, 2H), 3.52 (dt, J=12.4, 4.5 Hz, 1H), 3.46-3.38 (m, 1H), 3.38-3.26 (m, 1H), 3.14-3.01 (m, 1H), 2.19 (d, J=12.6 Hz, 1H), 2.10-2.00 (m, 2H), 2.00-1.82 (m, 4H), 1.62-1.61 (m, 1H), 1.70-1.53 (m, 2H), 1.52-1.39 (m, 2H).
Reaction SMILES: C([NH:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](=[O:8])[CH3:7])(=O)C.[ClH:12]>C(O)C>[ClH:12].[O:8]=[C:6]([CH:5]([NH2:4])[CH:9]([CH3:11])[CH3:10])[CH3:7]
Reactant: CC(=O)NC(C(C)=O)C(C)C
Agent: Cl
Solvent: CCO
Product: CC(=O)C(N)C(C)C
Temperature: 25 °C

Procedure:
A mixture of N-acetyl-2-keto-3-amino-4-methylpentane (6.33 g, 40.3 mmol) and 6M hydrochloric acid (65 ml) was heated at reflux overnight. The reaction mixture was cooled to room temperature, ethanol (100 ml) was added and the mixture concentrated under reduced pressure The mixture was triturated with ether to give a precipitate which was collected by filtration. Crystallisation from acetone gave 2-keto-3-amino-4-methylpentane hydrochloride. (2.9 9, 63%) as a white crystalline solid.