Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]([C:14]2[N:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19](=[O:25])[C@@H:18]([CH2:26][CH3:27])[N:17]([CH:28]([CH3:30])[CH3:29])[C:16]=3[N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.N(OCCC(C)C)=O>C1COCC1>[CH2:26]([C@H:18]1[N:17]([CH:28]([CH3:30])[CH3:29])[C:16]2[N:15]=[C:14]([C:4]3[S:3][CH:2]=[N:6][C:5]=3[C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[N:23]=[CH:22][C:21]=2[N:20]([CH3:24])[C:19]1=[O:25])[CH3:27]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3sc(N)nc3-c3ccc(F)cc3)nc2N1C(C)C
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3scnc3-c3ccc(F)cc3)nc2N1C(C)C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-(2-amino-4-(4-fluorophenyl)thiazol-5-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 318, 0.14 g, 0.324 mmol) in 1.5 mL anhydrous THF, isoamyl nitrite (0.1 mL, 0.751 mmol) was added. The reaction mixture was place in an oil bath set at 85° C. for 2 h and then concentrated and purified by preparative HPLC. LCMS: 412.2 m/z (M+H)+; ret. Time: 4.84 min (Analytical Method A).
Reaction SMILES: [CH2:1]([C:3]([OH:20])([C:6]#[C:7][CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:4][CH3:5])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:38]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[CH2:1]([C:3]([O:20][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][O:38]1)([CH2:4][CH3:5])[C:6]#[C:7][CH2:8][O:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:2]
Reactant: CCC(O)(C#CCOS(=O)(=O)c1ccc(C)cc1)CC
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(C#CCOS(=O)(=O)c1ccc(C)cc1)(CC)OC1CCCCO1
Yield: 85.1 %

Procedure:
A solution of Compound 401 (6.5 g), PPTS (0.73 g) and 3,4-dihydro-2H-pyran (2 g) in dichloromethane (33 ml) was stirred at r.t. for 17 h. Dichloromethane (250 ml) was added and the solution was washed with brine (250 ml). Work-up with chromatography with ether/pentane 1:1 (v/v) gave the title compound (7.1 g). 1H NMR: 0.85 (t, 6H), 1.55 (q, 4H), 1.42-1.90 (m, 6H), 2.45 (s, 3H), 3.47 (m, 1H), 3.89 (m, 1H), 4.79 (s, 2H), 4.85 (m, 1H), 7.35 (d, 2H), 7.82 (d, 2H) .
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][C@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[CH2:7][OH:8])=[O:4].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:8][CH2:7][C@@H:6]([C:9]([NH:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:10])[NH:5][C:3](=[O:4])[C:2]([F:18])([F:1])[F:19])(=[O:22])[CH3:21]
Reactant: O=C(NCc1nccs1)[C@H](CO)NC(=O)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)NCc1nccs1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the solution of 1.518 g of 2-[(N-trifluoroacetyl-L-seryl)amino]methylthiazole in 18 ml of pyridine was added 1.8 ml of acetic anhydride, and the mixture was stirred at room temperature for 14 hours. After the reaction mixture was concentrated to dryness under reduced pressure, it was dissolved in 40 ml of methylene chloride and washed with 25 ml of a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was re-extracted with 30 ml of methylene chloride. The combined organic layer was dried with anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 1.733 g of 2-[(O -acetyl-N-trifluoroacetyl-L-seryl)amino]methylthiazole. Quantitative yield. NMR (CDCl3) δ: 2.06 (3H, s), 4.36-4.40 (2H, m), 4.75-4.85 (3H, m), 7.17-7.26 (1H, br), 7.34 (1H, d, J=3.3 Hz), 7.73 (1H, d, J=3.3 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([O:43]C)=[O:42])[CH:8]=[CH:9][CH:10]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl>CC(O)C.O>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[CH:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH2:29][CH2:30][CH3:31])[CH:26]=3)[CH:21]([C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[CH:20]2[C:41]([OH:43])=[O:42])[CH:8]=[CH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)OC)c1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1cccc(C(=O)O)c1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 26.2 %

Procedure:
Methyl(1RS,2SR,3RS)-3-[2-(3-Carbomethoxyphenyl)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.08 g, crude) was dissolved in propan-2-ol (1 ml) and aqueous sodium hydroxide (1M, 1 ml, 1 mmol) added. The mixture was refluxed for 12 hr. then cooled, diluted with water, acidified with 3M-aqueous hydrochloric acid and extracted with ethyl acetate (3×). The combined organic extract was purified by column chromatography on silical-gel (eluant: 30% EtOAc/hexane/5% AcOH) to give the title compound as a colorless solid (20 mg)
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]([C:17]([CH3:34])([CH3:33])[CH2:18][CH2:19][C:20]([O:22]CC2C=CC([N+]([O-])=O)=CC=2)=[O:21])=[O:16])=[CH:11][CH:10]=1>O.O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][C:15]([C:17]([CH3:33])([CH3:34])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[CH:35][CH:36]=1
Reactant: COc1ccc(COC(=O)C(C)(C)CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COC(=O)C(C)(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
To a solution of sodium sulfite hydrade (12.35 g) in water (70 ml) was added a solution of p-nitrobenzyl 4-p-methoxybenzyloxycarbonyl-4-methylvalerate (25.4 g) in tetrahydrofuran (140 ml). The reaction mixture was stirred at room temperature for 7.5 hours, diluted with water and washed with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4-p-methoxybenzyloxycarbonyl-4-methylvaleric acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33](O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:63]([NH2:67])([CH3:66])([CH3:65])[CH3:64]>CN(C=O)C.CC#N>[C:63]([NH:67][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:38]=[CH:37][CH:36]=1)=[O:34])([CH3:66])([CH3:65])[CH3:64]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)N
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: CC#N
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
DIEA (50 μL, 0.29 mmol) was added to a suspension of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (50 mg, 0.13 mmol) and HATU (60 mg, 0.16 mmol) in DMF (0.5 mL). The solids dissolved over 5 min, at which point tert-butylamine (20 μL, 0.19 mmol) was added. The solution was stirred at r.t. for 1 h, then diluted with CH3CN (1 mL), filtered, purified by prep HPLC, concentrated, and dried in a vacuum oven over the weekend at 40° C. to give the title compound (39 mg, 69% yield) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (q, J=4.37 Hz, 1H) 8.08 (s, 1H) 8.01 (dd, J=8.24, 5.80 Hz, 2H) 7.92 (d, J=7.93 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.77-7.82 (m, 2H) 7.73-7.77 (m, 1H) 7.55 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87 (d, J=4.58 Hz, 3H) 1.42 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ ppm 166.20 (s) 163.22 (s) 162.66 (d, J=246 Hz) 152.56 (s) 152.52 (s) 140.06 (s) 136.53 (s) 135.76 (s) 129.38 (d, J=12 Hz) 129.36 (s) 128.70 (s) 127.86 (s) 126.27 (s) 125.86 (s) 125.70 (d, J=2.5 Hz) 124.83 (s) 118.90 (s) 115.93 (d, J=20 Hz) 113.88 (s) 111.60 (s) 50.85 (s) 28.60 (s) 26.19 (s). LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column. XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.57, (ES−) m/z (M−)=443. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=11.71 min, purity=100%; column: Waters Xbridge Phenyl column 3.5 μm 4.6×150 mm, Rt=9.53 min, purity=100%.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]1=[O:25])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:25])[C@@H:8]1[O:14][C:15](=[O:24])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)S[C@H]1NC(=O)[C@@H]1OC(=O)COc1ccccc1

Procedure:
A solution of 129 mg (0.34 mmole) of (3S,4R)-2-(4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl)-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred for 4 hours at room temperature. The reaction mixture is diluted with 50 ml of methylene chloride, washed in succession with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]
Reactant: Sc1ncccn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCSc1ncccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A mixture of 2-mercaptopyrimidine (7.3 g), N-(2-bromoethyl)phthalimide (16.5 g), potassium carbonate (10.8 g) and N,N-dimethylformamide (DMF) (85 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and the crystals separated were collected by filtration to obtain N-[2-(2-pyrimidinylthio)ethyl]-phthalimide (17.3 g, 93%). The resultant was recrystallized from ethanol-isopropyl ether to obtain pale yellow prisms, m.p. 149°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8]1)=[O:6].[CH:32]1N=CN(C(N2C=NC=C2)=O)C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[C:5]([N:7]1[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([C:23]([O:25][CH:26]([CH3:32])[CH3:27])=[O:24])=[CH:8]1)=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
Ethyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylate was saponified, converted to the corresponding isopropyl ester using CDI and isopropanol, and then oxidized as described previously in Step D of Example 63 to give the title compound; 1H-NMR (DMSO-d6): δ 10.83 (1H, s), 7.76 (1H, d), 7.71 (1H, app t), 7.64 (1H, s), 7.52-7.61 (2H, m), 7.40 (1H, m), 7.08 (1H, app t), 6.98 (1H, app t), 5.05 (1H, sept), 1.52 (6H, s), 1.18 (6H, d); MS(ESI): 439 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:35])[CH3:34])[CH3:33]
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 82.3 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol (0.11 g, 0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% EtOAc/Hex to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=7.6, 1,7 Hz, 2H), 7.45-7.39 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.3, 2.0 Hz, 1H), 4.25-4.17 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.56 (s, 6H), 1.43 (quintet, J=7.7 Hz, 2H), 1.30-1.22 (m, 5H), 0.86 (t, J=7.3 Hz, 3H), MS (ES) m/e 466 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[C:26]([O:30][C:31]([N:33]1[CH2:41][CH2:40][CH:36]([C:37](O)=[O:38])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCCP(=O)=O.CN1CCOCC1>CCOC(C)=O.O.C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:41][CH2:40][CH:36]([C:37](=[O:38])[NH:1][CH2:2][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1cccc(C(F)(F)F)c1
Agent: CCCP(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Charge (2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1:1) (913 g, 2.43 mol) and 1-tert-Butoxycarbonylisonipecotic acid (623 g, 2.73 mol, 1.12 eq) along with THF (2.75 L) and EtOAc (5.5 L) and cool to 0-5° C. Add 1.2 equivalents of propylphosphonic anhydride (T3P) (1.2 eq, 2.91 mol, 1.512 L of a 50% solution in EtOAc) and maintain the reaction temperature at 0-5° C. during addition. Stir for 10 min, then add N-methylmorpholine (566 g, 5.6 mol, 2.3 eq) holding the temperature below 5° C. during addition. Warm the reaction to room temperature and after 10 hours, cool in an ice bath and add water (7.3 L). Separate the layers and wash the aqueous layer with EtOAc (2.75 L). Combine the organic layers and wash with 0.5M aqueous sodium bicarbonate solution (2.75 L). Wash the organic layer with saturated aqueous sodium chloride (2.75 L), then treat the resulting organic layer with sodium sulfate and filter. Remove the solvent via distillation down to ˜4.6 L. Add back heptane (11 L) while removing solvent via distillation until the final volume reaches ˜11 L. Cool to 50° C. and seed. Hold the resulting slurry at 50° C. for 3 h, then cool the slurry to room temperature and stir for 2 h. Filter the solids and wash the cake, first with 10% EtOAc in heptane (2 L) then with heptane (2 L). After drying in a vacuum oven at 60° C. for 3 h, 800 g (79%) of 4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester is obtained as a white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH:25]=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCOc1cccc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Product: CCOc1cccc(SC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield (1.29 g, yellow oil) from tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.60 g, 5.73 mmol) and 3-ethoxybenzenethiol (1.06 g, 6.87 mmol) by the similar manner in Step-1 of Intermediate-4.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:27]2[S:31][C:30](=[S:32])[N:29]([CH2:33][C:34]([O-:36])=[O:35])[C:28]2=[O:37])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2+]1CCCCC1.Cl>O1CCOCC1>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH:26]=[C:27]2[S:31][C:30](=[S:32])[N:29]([CH2:33][C:34]([OH:36])=[O:35])[C:28]2=[O:37])[N:25]=1
Reactant: O=C([O-])CN1C(=O)C(=Cc2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)SC1=S
Agent: C1CC[NH2+]CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(C=C2SC(=S)N(CC(=O)O)C2=O)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising 2.2 g of piperidinium 5-(2-tritylaminothiazol-4-ylmethylene)rhodanine-3-acetate and 30 ml of a 4N dioxane solution of hydrogen chloride was stirred at room temperature for 30 minutes, and the resulting mixture was left to stand overnight. The crystalline product which precipitated out was collected by filtration and washed with dioxane, giving the desired compound as a brownish-orange powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](C=O)=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C1C=C(Cl)C=C([C:22]([O:24]O)=[O:23])C=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:24][CH:22]=[O:23])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C=O)ccc1OC(C)=O
Solvent: ClCCl
Product: COc1cc(OC=O)ccc1OC(C)=O
Temperature: 50 °C
Yield: 98.9 %

Procedure:
To a solution of 4-formyl-2-methoxyphenyl acetate (15 g, 77 mmol) in CH2Cl2 (100 mL) was added m-CPBA (31 g, 154 mmol). The solution was refluxed at 50° C. for 2.5 h. The solution was washed with saturated Na2SO3 solution (50 mL), saturated Na2CO3 solution (50 mL) and brine(50 mL), dried over Na2SO4, filtrated and concentrated in vacuo to afford 16 g of crude product as a white solid, which was used for next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23]Br)=[CH:22][C:16]=2[CH:15]=1)=[O:13].O>CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][C:21]([CH2:23][O:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: Oc1cccnc1
Reactant: COC(=O)c1cc2cc(CBr)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(COc3cccnc3)ccc2s1

Procedure:
3-Hydroxypyridine (0.40 g.) was dissolved in dry N,N-dimethylformamide (10 ml.) and sodium hydride (0.20 g. of 50% dispersion in mineral oil) was added portionwise with stirring and the resulting mixture was stirred at room temperature for 30 minutes. 5-(Bromomethyl)benzo[b]thiophene-2-carboxylic acid methyl ester (1.20 g.) in a few mls of dry N,N-dimethylformamide was then added and the mixture was stirred at room temperature for 30 minutes, and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with a mixture of chloroform and toluene (1:1) first gave mineral oil followed by pure product. Evaporation of the product-containing fractions gave a solid (0.40 g.) which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 5-(3-pyridyloxymethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, m.p. 106°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11](C(OC(C)(C)C)=O)[CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][N:10]=1)=[O:4]
Reactant: COC(=O)c1ncc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 50.7 %

Procedure:
(+/−)-5-{tert-Butoxycarbonyl-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butyl]-amino}-pyrimidine-2-carboxylic acid methyl ester (1.498 g impure) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added. This was stirred at room temperature. At 70 min, another 3 mL of trifluoroacetic acid was added. At 90 min, the reaction was concentrated and the material was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave (+/−)-5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (0.620 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.16 (s, 2 H) 7.67-7.73 (m, 2 H) 7.61-7.66 (m, 2 H) 7.56 (d, J=8.2 Hz, 2 H) 7.39 (d, J=8.2 Hz, 2 H) 4.68 (d, J=5.7 Hz, 1 H) 4.46-4.57 (m, 1 H) 3.98 (s, 3 H) 1.79-1.92 (m, 1 H) 1.64-1.79 (m, 2 H) 1.05 (d, J=6.2 Hz, 3 H) 0.99 (d, J=6.2 Hz, 3 H); MS (M+1): 444.3.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[CH:27][N:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[CH:35][C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[CH:27][N:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2ccncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-ethyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (42 mg, 0.084 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.258 mL, 3.34 mmol) and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to afford a yellow oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield the title compound as a yellow solid (34 mg).