Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+:22]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][N:10]2[C:15](=[O:16])[N:14]([Na:22])[C:13](=[O:17])[CH2:12][NH:11]2)=[O:7])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)OCN2NCC(=O)NC2=O)cc1
Reactant: [Na+]
Agent: C[O-]
Solvent: CO
Product: Cc1ccc(C(=O)OCN2NCC(=O)N([Na])C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methylbenzoyloxymethyl)-3,5-dioxo-hexahydro-1,2,4-triazine (1.0 g) is dissolved in methanol (60 ml), and the mixture is added with sodium methoxide (0.21 g) and stirred at room temperature for 30 minutes. The methanol is removed in vacuo, and the resulting white crystals are thoroughly washed with ethanol to give 2-(4-methylbenzoyloxymethyl)-3,5-dioxo-4-sodio-hexahydro-1,2,4-triazine (Compound No. 74). Yield, 0.84 g (77.8%). M.P., 225°-235° C. (decomp.).
Reaction SMILES: [CH:1]([C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)=[CH:2][CH2:3][CH3:4].[H][H]>CCOC(C)=O.[Pd]>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=Cc1cccc(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1cccc(C)n1
Yield: 92.5 %

Procedure:
The picoline from Step 1 (970 mg) was hydrogenated for 50 minutes at 20 psi of hydrogen in EtOAc (30 mL) using 5% Pd/C (90 mg) as catalyst. Filtration and concentration in vacuo gave 910 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:38]([CH:39]=[CH2:40])=[N:37][N:36]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][Si](C(C)(C)C)(C)C)=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:48]1[CH:53]=[CH:52][C:51]([C:54]([N:56]2[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]2)=[O:55])=[CH:50][CH:49]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:38](/[CH:39]=[CH:40]/[C:48]4[CH:49]=[CH:50][C:51]([C:54]([N:56]5[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]5)=[O:55])=[CH:52][CH:53]=4)=[N:37][N:36]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: O=C(c1ccc(I)cc1)N1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(C(=O)N4CCCCC4)cc2)nn3C2CCCCO2)CC1
Temperature: 125 °C
Yield: 75.4 %

Procedure:
To a solution of 4-[6-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 0.46 mmol) in DMF (2.1 mL) were added (4-iodo-phenyl)-piperidin-1-yl-methanone (0.175 g, 0.56 mmol), tri(o-tolyl)phosphine (28 mg, 0.09 mmol) and triethylamine (2.1 mL). The resulting solution was degassed using argon, palladium acetate (5 mg, 0.02 mmol) was then added and the reaction mixture was heated at 125° C. overnight. The reaction mixture was concentrated under vacuum and the residue taken up in water and then acidified to pH=1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of methanol (0-3%) in dichloromethane to yield the title compound as a light brown solid (0.25 g, 65%).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CN(C(ON1N=N[C:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCCC1>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:24]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:9])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1csc(Br)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1csc(Br)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
To a solution of 5-bromothiophene-3-carboxylic acid (1.03 g, 5.00 mmol) in acetonitrile (10 mL), were added HATU (2.09 g, 5.50 mmol), DIPEA (2.6 mL, 15.0 mmol) and piperidine (1.0 mL, 10.0 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (75 mL) and was washed with saturated aqueous citric acid (2×50 mL). The organic layer was concentrated in vacuo and the resultant residue was loaded onto an SCX-2 cartridge. Eluting with acetonitrile and evaporation of the organic fraction in vacuo afforded the title compound as an off-white solid (1.00 g, 73%). LCMS (Method B): RT=3.3 min, M+H+=274.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([OH:12])[C:6]1=[S:13])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:16][N:17]([CH:19]=[O:20])C>>[O:20]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:16]=2[N:17]=[C:19]1[O:12][C:7]1[C:6](=[S:13])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: CCCCn1cc(C)cc(O)c1=S
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(C)cc(Oc2nc3ccccc3o2)c1=S
Reaction time: 0.33 h
Yield: 73 %

Procedure:
To a solution of 1-butyl-3-hydroxy-5-methylpyridine-2-thione (2-035-05) (300 mg) in DMF (6.0 mL) was added sodium hydride (60% wt, 79 mg) at room temperature. After the reaction mixture was stirred for 20 min, to the reaction mixture was added 2-chlorobanzoxazole (432 mg), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was quenched with water, the solvent was removed. To the residue were added aqueous saturated ammonium chloride solution and ethyl acetate, and the organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (toluene/acetone=4/1) to give 3-(benzoxazol-2-yloxy)-1-butyl-4-methylpyridine-2-thione (2-035) 372 mg, 73%) as a yellow crystal. The obtained crystal was purified by recrystallization from methylene chloride and diethyl ether.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoate (74 mg, 0.16 mmol) in methanol (0.78 mL) and tetrahydrofuran (0.78 mL) was added 1 N aq sodium hydroxide (0.78 mL, 0.78 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 4 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoic acid. 1HNMR (400 MHz, DMSO-d6) δ 12.18 (br. s., 1 H), 8.56 (d, J=2.7 Hz, 1 H), 8.44 (t, J=5.6 Hz, 1 H), 7.78 (d, J=8.4 Hz, 2 H), 7.76-7.72 (m, 1 H), 7.54 (d, J=8.2 Hz, 2 H), 7.52-7.48 (m, 1 H), 7.37-7.27 (m, 2 H), 7.03 (d, J=7.8 Hz, 1 H), 6.86 (d, J=2.5 Hz, 1 H), 4.73-4.61 (m, 1 H), 3.46-3.37 (m, 2 H), 2.47 (t, J=7.0 Hz, 2 H), 2.39-2.23 (m, 1 H), 2.14-1.92 (m, 2 H), 1.20-1.13 (m, 1 H); (M+1): 446.2.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH2:15][OH:16])=[CH:11][C:12](O)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[CH:11][CH2:12][OH:13])[CH2:15][OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(=CC(=O)O)CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=CCO)CO
Temperature: 78 °C
Reaction time: 4 h

Procedure:
A 2.210 g (9.69 mmol) sample of 3-((t-butyldimethylsilyloxy)methyl)-4-hydroxybut-2-eneoic acid, 1,4-lactone, from Example 336A, was dissolved in 6 mL of methylene chloride, cooled in a dry ice bath, and 14.2 mL (21.3 mmol) of DIBAL was added. The mixture was stirred at 78° C. for 4 hours, allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to -78° C. and quenched with 1.53 mL of methanol and 2.55 mL of water. The mixture was filtered, and the filtrate concentrated and chromatographed on silica gel, eluting with 50% and 90% ethyl acetate in hexane. The solvent was removed and the product dried to afford 1.055 g of the title product, which was taken directly to the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([OH:28])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.I[CH3:31]>CC#N.[Ag]=O>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([O:28][CH3:31])[CH:5]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](O)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC(=O)[C@H](OC)C(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-hydroxy-butyric acid methyl ester (610 mg, 1.45 mmol) in CH3CN (20 mL) are added iodomethane (0.545 mL, 8.72 mmol and silver oxide (1.35 g, 5.81 mmol). After being stirred at room temperature for 16 h, additional iodomethane (0.545 mL, 8.72 mmol) and silver oxide (1.35 g, 5.81 mmol) are added and stirred for 3 days. The reaction mixture is filtered through celite pad and the filtrate is washed with brine. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash column chromatography (silica gel, eluent; heptane/EtOAc=100:0 to 0:100) to give (R)-3-tert-butoxycarbonylamino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg). HPLC retention time=1.20, 1.25 minutes (condition B): MS (m+1-Boc)=334. 1 H-NMR (400 MHz, CDCl3) δ ppm 1.37, 1.41 (s, 9 H), 2.72-3.03 (m, 2 H), 3.43, 3.71 (s, 3H), 3.63-3.82 (m, 1 H), 4.27-4.41 (m, 1 H), 4.68-5.04 (m, 1 H), 7.28-7.40 (m, 4 H), 7.41-7.61 (m, 4 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C1C=C(C=CC=1)CBr.C[C:20]([NH:45]C(OC(C)(C)C)=O)([CH2:24][C:25]1[CH:30]=[C:29]([Br:31])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[C:27]([Br:44])[CH:26]=1)[C:21]([OH:23])=[O:22]>CC(C)=O>[NH2:45][CH:20]([CH2:24][C:25]1[CH:26]=[C:27]([Br:44])[C:28]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=2)=[C:29]([Br:31])[CH:30]=1)[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NC(C)(Cc1cc(Br)c(OCc2cccc(C(F)(F)F)c2)c(Br)c1)C(=O)O
Agent: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(Cc1cc(Br)c(OCc2cccc(C(F)(F)F)c2)c(Br)c1)C(=O)O
Yield: 9 %

Procedure:
To a stirred mixture of methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl) propionate (0.20 g, 0.44 mmol), potassium carbonate (0.15 g, 1.1 mmol) and acetone (15 mL) was added 3-trifluormethyl benzylbromide (0.26 g, 1.1 mmol). The procedure followed was the same as described in Example 1, but the isolation on column chromatography of the intermediate methyl-2-tert-butoxycarbonylamino-3-[3,5-dibromo-4-(3-trifluormethylbenzyloxy)phenyl]propionic acid was not done. Purification of the final residue by HPLC, using the same conditions as described in Example 1(b), gave 20 mg (9%) of 2-amino-3-[3,5-dibromo-4-(3-trifluormethylbenzyloxy)phenyl]propionic acid. LC-MS (electrospray): m/z 498 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([N:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]3[C:30]([F:29])([F:41])[F:40])[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(C(F)(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(trifluoromethyl)-1H-benzo[d]imidazole to give 156. 1H NMR (400 MHz, DMSO) δ 8.20 (d, J=8.6 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.94 (d, J=8.6 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 4.56 (s, 4H), 4.04 (s, 1H), 3.86-3.79 (m, 4H), 3.75 (s, 2H), 2.93 (d, J=11.0 Hz, 2H), 2.00 (t, J=10.9 Hz, 2H), 1.67 (d, J=12.1 Hz, 2H), 1.38-1.12 (m, 3H), 1.04 (s, 6H). LCMS: 556.3
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-c3ccc(C(F)(F)F)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.15 g, 0.58 mmol) and 3-methoxyphenol (0.10 g, 0.81 mmol, Aldrich) in DMF (6 mL), was added NaH (32 mg, 0.81 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (10 mL) was added to the residue, and the mixture was washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (5:1 hexanes/EtOAc) afforded the title compound as a white solid. Mp: 87–88° C. MS (ESI, pos. ion) m/z: 347 (M+1). Anal. Calcd for C18H13F3N2O2: C, 62.54; H, 3.75; N, 8.09. Found: C, 62.54; H, 3.75; N, 7.99.
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][CH3:29])=[O:27])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[N:10]=[N:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:29][O:28][C:26]([NH:25][C@@H:14]([CH2:13][C:11]1[N:10]=[N:9][NH:8][CH:12]=1)[C:15]([OH:17])=[O:16])=[O:27]
Reactant: COC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](Cc1c[nH]nn1)C(=O)O

Procedure:
(S)-benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate (502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) in MeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filtered through diatomaceous earth (Celite®) and concentrated in vacuo. (S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid was obtained as a colorless gum (266 mg, 111%) which was contaminated with ca. 10% of the methyl ester. The material was used as is without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([CH3:15])[C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][NH:17][C:18]([NH:20][NH2:21])=[S:19].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C1S(=O)(=O)CCC1.O>[SH:19][C:18]1[N:20]([NH2:21])[C:12]([C@H:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH3:15])=[N:16][N:17]=1
Reactant: NNC(=S)NN
Reactant: C[C@H](C(=O)O)c1ccc2ncccc2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: C[C@@H](c1ccc2ncccc2c1)c1nnc(S)n1N
Temperature: 90 °C
Yield: 63.8 %

Procedure:
As shown in step v of Scheme 1, (S)-2-(quinolin-6-yl)propanoic acid (50 g, 248.5 mmol) and 1,3-diaminothiourea (29.02 g, 273.4 mmol) were suspended in a mixture of tetramethylene sulfone (sulfolane, 38 mL) and water (57 mL). Methane sulfonic acid (35.5 ml, 546.7 mmol) was added to the mixture, whereupon all solids dissolved. The reaction temperature was slowly increased to 90° C. and the reaction was heated at 90° C. for 40 hours, at which time a 68% conversion of starting material to product was observed by HPLC analysis. The reaction mixture was cooled in an ice bath and water (75 mL) was added, followed by the careful addition of saturated sodium bicarbonate (500 mL) until a pH 8 was achieved. The resulting fine purple precipitate was collected by vacuum filtration, washed with water, saturated sodium bicarbonate, water, and methyl t-butyl ether, respectively. The product was dried in a vacuum oven at 55° C. for 2 days to afford 6-((S)-1-(5-mercapto-4-amino-4H-1,2,4-triazol-3-yl)ethyl)quinoline (compound 1005, 43 g): ESMS (M+1), 272.09; 1H NMR (300.0 MHz, DMSO-d6) δ 13.65 (1H, br s), 8.86 (1H, dd, J=1.8, 8.4 Hz), 8.34 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.7, 13.7 Hz), 7.82 (1H, d, J=1.5 Hz), 7.70 (1H, dd, J=1.8, 8.7 Hz), 7.50 (1H, dd, J=1.8, 8.7 Hz), 5.44 (2H, s), 4.57 (1H, q, J=7.2 Hz), 1.65 (3H, d, J=7.2 Hz). The product was 92% pure by 1H NMR analysis, with the major impurities being compound 1004 and sulfolane. Chiral HPLC analysis showed 92% ee (ChiralPak® AD-H, 70% i-propanol/hexanes; retention time: 4.98 min for S-enantiomer, 12.33 min for R-enantiomer). The product was used as is in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.CCN=C=NCCCN(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[O:44][C:45]([CH3:51])=[C:46]([C:48](O)=[O:49])[N:47]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:2][O:3][C:4](=[O:24])[CH2:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][C:48]([C:46]3[N:47]=[C:43]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[Cl:36])[O:44][C:45]=3[CH3:51])=[O:49])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: Cc1oc(-c2ccccc2Cl)nc1C(=O)O
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-aminopropionylamino)-phenyl]cyclohexyl}acetic acid methyl ester HCl salt (60 mg, 0.169 mmol), EDCI (81.05 mg, 0.423 mmol), 2-(2-chloro-phenyl)-5-methyl-oxazole-4-carboxylic acid (44.2 mg, 0.186 mmol), HOBt (34.28 mg, 0.254 mmol) and ethyldiisopropylamine (76.68 mg, 0.592 mmol) were put into dichloromethane solvent (10 mL) and stirred at room temperature for 24 hours. After the reaction, aqueous NaHCO3 was added thereto, and extracted with dichloromethane. The organic layer was washed with brine, then the product was dried with anhydrous sodium sulfate, and the solvent was removed. Column chromatography was conducted on the crude material to obtain trans-{4-[4-(3-{[2-(2-chlorophenyl)-5-methyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (80 mg, 88%).
Reaction SMILES: [OH:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH:4]([N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:3]1.CO.O.NN>CC(OC)(C)C.O>[NH2:7][CH:4]1[CH2:5][CH2:6][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:1])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)(c2ccccc2)C1
Agent: NN
Solvent: CO
Solvent: O
Solvent: COC(C)(C)C
Product: NC1CCC(O)(c2ccccc2)C1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A solution of Example 58B (107 mg, 0.348 mmol), MeOH (5.5 mL), and hydrazine monohydrate (0.424 mL, 8.70 mmol) was heated at 50° C. for 1 hour, cooled to ambient temperature, and diluted with MTBE (50 mL) and water (25 mL). The layers were separated. The organic layer was washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated to provide the title compound (34 mg, 0.19 mmol, 55% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([F:37])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:30]=[C:31]([F:37])[C:32]([OH:36])=[C:33]([F:35])[CH:34]=4)[CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-acetyl-6-(3,5-difluoro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (30 mg, 0.059 mmol) was reacted with TFA (2 mL) to afford the desired product (14.2 mg, 59%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.98 (s, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.07-8.00 (m, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.0, 1.6 Hz, 2H), 4.29 (s, 1H), 3.23 (s, 1H), 2.71 (s, 3H), 2.41 (d, J=12.2 Hz, 2H), 2.19 (d, J=12.1 Hz, 2H), 1.76-1.67 (m, 2H), 1.63-1.54 (m, 2H); ESI MS m/z 412 [C23H23F2N3O2+H]+; HPLC 98.7% (AUC), tR=8.13 min.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCc1ccccc1

Procedure:
A solution of 5.6 g of 2-fluoro-5-nitrobenzoic acid and 14.5 g of 2-phenylethylamine in 20 ml of dimethylacetamide is reacted and worked up in analogy to Example 1. Yellow crystals from isopropanol, melting point 116°-118° C.