Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH2:3]1.ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Yield: 78.7 %

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 42 (445 mg) for the title product of Example 21. Trituration with ethyl acetate produced 317 mg of the titled compound as a solid, m.p. 126.5°-127.5° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([O:30]C)=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1.COC1C=CC2C=C(C)SC=2C=1.O[Li].O.Cl>C1COCC1.CO.O.O>[CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=[O:29])=[C:26]([CH3:32])[S:25][C:24]=4[CH:33]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc12
Agent: COc1ccc2cc(C)sc2c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a solution of methyl 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 1:1b (258 mg, 0.535 mmole) in a mixture of THF/MeOH/H2O (3:2:1, 6 ml) was added LiOH.H2O (224 mg, 5.35 mmole). The reaction was stirred 24 hours at ambient temperature. The mixture was diluted with H2O (10 ml) and acidified to pH 1 with 1 M HCl. The precipitate was collected by vacuum filtration, rinsed with MeOH, and dried at 50° C. under vacuum to afford 116 mg (45%) of a pale brown solid. 1H NMR (DMSO-d6) δ8.58 (1H, d, J=5.4 Hz), 8.44 (1H, d, J=8.9 Hz), 8.07 (1H, s), 8.00 (1H, d, J=24 Hz), 7.39 (1H, dd, J=2.4, 8.9 Hz), 6.78 (1H, d, J=5.4 Hz), 4.10-3.81 (3H, m), 3.69-3.54 (4H. m), 3.27, 3.24 (3H, s), 2.81 (3H, s).
Reaction SMILES: CN([CH:4]=[O:5])C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][C:8]=1[F:14].C([O-])([O-])=O.[K+].[K+].CI>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH3:4])=[CH:9][C:8]=1[F:14]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.[CH3:20][O-].[Na+].IC>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:20])[CH:18]=2)=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a suspension of 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2 g, 8.65 mmol) in methanol (44 ml) was added sodium methoxide (940 mg, 17.4 mmol) at room temperature under an atmosphere of nitrogen gas, followed by stirring. After 15 minutes, iodomethane (1.6 ml, 25.7 mmol) was added thereto, followed by stirring as it was for 22 hours. After concentrating the reaction mixture, water was added to the residue. Then, the precipitates were collected by filtration and washed with water, to give the crude crystals of the title compound (1.98 g). The crude crystals were suspended in ethanol, and then the precipitates were collected by filtration and washed with ethanol, to give the title compound (1.54 g, 66%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9](Cl)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CN(C=O)C.CCOCC>[O:22]([C:9]1[O:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Reactant: Oc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1oc(Oc2ccccc2)nc1C(F)(F)F
Reaction time: 1 h

Procedure:
The compound of Example 5, ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate (4.87 g; 0.02 mol) was added to a mixture of sodium phenol in 100 ml DMF. The reaction was allowed to progress at ambient temperature for 1 hour. Gas chromatographic analysis, at this point, indicated the completion of the reaction. The dark brown liquid was then slurried in ether and washed 5 times with NaOH (5%) and H2O. The resulting brown liquid was dried (MgSO4) and concentrated in vacuo to yield 5.2 g of a brown semi-solid. Bulb to bulb distillation at 75° C./25 mm gave 1.7 g of a colorless oil. Further distillation at 130° C./0.25 mm gave 2.8 g of a white solid. Recrystallization from methylcyclohexane gave 1.08 g of pure white solid, ethyl 2-phenoxy-4-trifluoromethyl-5-oxazolecarboxylate, mp 75°-77° C., yield 18%.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:19]([O:23][C:24](=[O:39])[NH:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[NH:38])[NH:36]O)=[CH:31][N:30]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24](=[O:39])[NH:25][C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:36]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:6][N:38]=3)=[CH:31][N:30]=2)[CH2:28][CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=N)NO)cn2)CC1
Reactant: O=C(O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3noc(C4CC4)n3)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
An 8-mL vial was charged with cyclopropanecarboxylic acid (78.5 μL, 0.99 mmol) and DMF (1.0 mL). Carbonyldiimidazole (176 mg, 1.09 mmol) was added to the vial at room temperature. The clear reaction mixture was stirred for 2 h and then added to another 8-mL vial containing {1-[5-(N-hydroxycarbamimidoyl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (430 mg, 1.47 mmol) in 1.0 mL of DMF. The resulting pale yellow reaction mixture was stirred at room temperature for 30 min and then heated at 100° C. for 16 h. The clear pale orange reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organics were washed with of water (2×15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to a crude oil. The crude oil was purified via normal phase flash chromatography on silica gel, eluting with 0-35% EtOAc/hexanes, to give {1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (86 mg, 26%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(Cl)c(Br)c1
Reactant: O[C@@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(3-chloro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 204.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.05 min, UPLC-MS (Condition 3) tR=1.24 min, m/z=480.1/482.1 [M+H]+.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([OH:24])[CH2:14][NH:15][CH2:16][C:17]([CH3:23])([CH3:22])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:42]([NH:45][C:46]1[CH:47]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:49]=[CH:50][C:51]=1[F:52])(=[O:44])[CH3:43]>C(Cl)Cl>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:32])[NH:11][C@@H:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([OH:24])[CH2:14][N:15]([S:53]([C:48]2[CH:49]=[CH:50][C:51]([F:52])=[C:46]([NH:45][C:42](=[O:44])[CH3:43])[CH:47]=2)(=[O:54])=[O:55])[CH2:16][C:17]([CH3:22])([CH3:23])[CH2:18][CH2:19][C:20]#[N:21])[CH2:2]1
Reactant: CC(=O)Nc1cc(S(=O)(=O)Cl)ccc1F
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCC#N)ccc1F
Yield: 39.3 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid (3R,3aS,6aR)hexahydro-furo[2,3-b]furan-3-yl ester (0.020 g, 0.05 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.025 ml, 0.13 mmol) and 3-acetamido-4-fluorobenzenesulfonyl chloride (0.012 g, 0.05 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by preparative thin layer chromatography (3% MeOH in CH2Cl2) gave 0.013 g of a white solid. MS (ES): 661 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=[O:6].[OH:15]O.Cl>CO.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])[C:5]([OH:15])=[O:6]
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (3.00 g, 11.2 mmol, 1 eq.) in MeOH (14 mL), a solution of hydrogen peroxide (30% wt solution in water, 14 mL, 11.2 mmol, 1 eq.) in 15% aq. NaOH soln. (14 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and further at r.t. for 18 hours. The reaction mixture was acidified by addition of conc. HCl. The suspension was filtered off and the filter cake was rinsed with H2O. The resulting white solid was dried under h.v. to give the title compound. The product was used without further purification.
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[C:22]([OH:29])=[C:23]([CH:25]=[CH:26][C:27]=2[Cl:28])[NH2:24])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH:37][C:38]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13][CH2:14]2)(=[O:19])=[O:20])[C:22]=1[OH:29])=[O:39]
Reactant: O=C=Nc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3ccccc3Br)c2O)CC1
Yield: 36.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-4-chloro-2-hydroxyaniline (110 mg, 0.28 mmol) and 2-bromophenylisocyanate (67 mg, 0.34 mmol) were coupled to form the desired urea (60 mg, 36%). Element Analysis Theory: C 44.80%, H 4.44%, N 9.50%, Found: C 44.65%, H 4.15%, N 9.20%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8].N(OC(C)(C)C)=O.C(Br)(Br)[Br:28]>ClCCl>[Br:28][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(N)c2)c(C)c1
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)c(Br)c2)c(C)c1
Temperature: 80 °C

Procedure:
Methyl 3′-amino-4′-chloro-2-methylbiphenyl-4-carboxylate (946 mg, 3.43 mmol) was dissolved in a mixture of CHBr3 (5 mL) and dichloromethane (5 mL). To the above stirred mixture was added t-butyl nitrite (680 μL, 530.6 mg, 5.145 mmol). The reaction mixture was heated to 80° C. for 30 minutes. Aliquot (LCMS) indicated complete consumption of starting material. Crude mixture was purified by flash chromatography (SiO2, Biotage 40+S cartridge) to afford methyl 3′-bromo-4′-chloro-2-methylbiphenyl-4-carboxylate. LCMS calc.=339.97; found=340.98 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[B:9]([OH:14])[OH:10]
Reactant: Cc1ccncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccncc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirring solution of 3-bromo-4-methylpyridine (5.9 g, 34.3 mmol) in toluene (30 mL) and THF (7.5 mL) was added triisopropyl borate (10.3 mL, 44.6 mmol). The resulting mixture was cooled to −78° C. under a nitrogen atmosphere followed by the addition of n-butyllithium (17.83 mL, 44.6 mmol, 2.5 M in hexanes) over a period of 1 hour. The reaction mixture was allowed to stir for an additional 30 min and then the dry ice bath was removed. The reaction mixture was quenched by the addition of 2N HCl (60 mL). Upon reaching room temperature, the resulting yellow solution was transferred to a 500 mL separatory funnel and the layers were separated. The aqueous layer was neutralized to pH 7.0 with sodium hydroxide and then extracted with THF (3×60 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solid material was vigorously stirred with acetonitrile and filtered to yield Intermediate 1A (2.2 g, 16.06 mmol, 48.8% yield) as an off-white solid. MS (ES): m/z=138.0 [M+H]+. 1H NMR (400 MHz, MeOD) δ ppm 8.45 (1 H, s), 8.33 (1 H, d, J=5.77 Hz), 7.50 (1 H, d, J=5.27 Hz), 2.62 (3 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:33][C:34]1[C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[S:37][CH:38]=1)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:33][C:34]2[C:35]3[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=3[S:37][CH:38]=2)[C@@H:24]([CH3:32])[CH:25]([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[C:19]([O:23][C:24](=[O:28])[C@H:25]([CH3:27])[NH2:26])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:19]([O:23][C:24](=[O:28])[C@@H:25]([NH:26][CH:14]1[CH2:15][CH2:16][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12][CH2:13]1)[CH3:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.5 %

Procedure:
To a solution of N-Cbz-4-piperidinone (3.497 g, 15.0 mmol) in dichloroethane (100 mL) was added L-alanine tert-butyl ester hydrochloride (2.731 g, 15.03 mmol) and sodium triacetoxyborohydride (6.47 g, 30.5 mmol). The mixture was stirred for 20 hours at room temperature, then quenched by the addition of saturated ammonium chloride (100 mL). The mixture was poured into ethyl acetate (500 mL), washed with water (2 times 100 mL), dried (MgSO4) and concentrated to yield the desired product (5.30 g, 97% yield). LC/MS: m/z 325.25 [M+H]+
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].Cl.O.[Cl-].[Na+]>C(OCC)(=O)C.O>[C:13]([NH:3][C@H:4]([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A reaction flask was charged with 120 ml distilled water, 48.0 g (1.2 mol) of sodium hydroxide and 58.8 g (0.4 mol) of glutamic acid. After cooling to 0° C., acryloyl chloride, 36 g (0.4 mol) was added over 1 hour to the stirred solution. After stirring for an additional 1 hour, the solution was acidified to pH of 2 with the addition of a concentrated HCl-H2O (1:1) solution. After saturation of the solution with sodium chloride, ethyl acetate was used to extract the product. After drying the combined extracts over anhydrous magnesium sulfate, the ethyl acetate was evaporated to recover the crude product in greater than 60% yield. After recrystallization from ethyl acetate the white, crystalline N-acryloylglutamic acid had a melting point of 125°-127° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][CH2:13][NH2:14])[CH2:11][CH2:10]1.[CH3:15][C:16]1[N:17]=[C:18]([N:24]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[C:25]2=[O:41])[S:19][C:20]=1[C:21](O)=[O:22]>>[CH:9]1([CH2:12][CH2:13][NH:14][C:21]([C:20]2[S:19][C:18]([N:24]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=4)[C:25]3=[O:41])=[N:17][C:16]=2[CH3:15])=[O:22])[CH2:11][CH2:10]1
Reactant: NCCC1CC1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCCC1CC1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-cyclopropylethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 26% yield: mp 195-196° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.76 (s, 1H), 4.47 (s, 2H), 4.12-4.07 (m, 2H), 3.49-3.42 (m, 4H), 2.59 (s, 3H), 1.50-1.43 (m, 2H), 0.72-0.62 (m, 1H), 0.47-0.41 (m, 2H), 0.14-0.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.1, 155.4, 152.0, 148.9, 134.3, 129.7, 121.4, 120.4, 118.0, 47.3, 42.1, 41.8, 40.2, 34.3, 17.0, 8.6, 4.1; MS (ES+) m/z 469.3 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].S(Cl)(Cl)=O.[CH3:23][C:24]1[N:25]=[CH:26][C:27]([CH2:30][NH2:31])=[N:28][CH:29]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:31][CH2:30][C:27]1[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][N:28]=1)=[O:11])#[N:2]
Reactant: Cc1cnc(CN)cn1
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cnc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)cn1
Reaction time: 3 h

Procedure:
A solution of 2-(3-Cyano-phenoxy)-nicotinic acid (0.0067 grams, 0.03 mmole) in thionyl chloride (500 μl, 6.9 mmole) was stirred at room temperature for 3 hours and concentrated under reduced pressure to give a white solid. To the residue was added pyridine (300 μl) and C-(5-Methyl-pyrazin-2-yl)-methylamine (0.0038 grams, 0.03 mmole). The mixture stood at room temperature for 3 hours and then was concentrated under reduced pressure to white solid. (0.0093 g); Anal. calcd. for C19H15N5O2: C, 66.08; H, 4.38; N, 20.26. Found: C, 56.89; H, 5.02; N, 18.31.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=O)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1CCCCC1.[Ti](Cl)(Cl)(Cl)Cl>[O:12]1[CH2:13][CH2:14][N:9]([C:1]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[CH2:2])[CH2:10][CH2:11]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccsc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCCCC1
Product: C=C(c1ccsc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.4 %

Procedure:
A solution of 57 g of titanium tetrachloride (TiCl4) in 100 ml of cyclohexane is added dropwise to a stirred solution of 75 g of 3-acetylthiophene and 160 g of morpholine in a liter of cyclohexane. When the addition is complete, the reaction mixture is further stirred at room temperature for 12 hours, then the precipitate is filtered off and the filtrate is concentrated by evaporation. The residue is distilled and has a boiling point of 98°/0.04 millibar. In this manner 36.5 g of 1-morpholino-1-(thiophen-3-yl)-ethylene are obtained in the form of a colourless oil.
Reaction SMILES: [ClH:1].C([S:6][CH2:7][C@@:8]([CH3:13])([C:10]([OH:12])=[O:11])[NH2:9])(C)(C)C>>[ClH:1].[CH3:13][C@@:8]([C:10]([OH:12])=[O:11])([CH2:7][SH:6])[NH2:9]
Reactant: CC(C)(C)SC[C@](C)(N)C(=O)O
Agent: Cl
Product: C[C@](N)(CS)C(=O)O

Procedure:
Conc. hydrochloric acid (345.3 g) was added to S-tert-butyl-α-methyl-L-cysteine (38.4 g, 201 mmol) produced by the method in EXAMPLE 11, and the resultant mixture was refluxed for 24 hours to obtain an aqueous solution of α-methyl-L-cysteine hydrochloride.