Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[CH3:22])=[CH:3]\[C:4]([O:6][CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:5].[N+:23]([C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH:29]=[C:30]([C:38]([CH3:40])=O)[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:22][C:2]1[NH:1][C:38]([CH3:40])=[C:30]([C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[CH:29]([C:28]2[CH:41]=[CH:42][CH:43]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:3]=1[C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[NH:21][CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:5]
Reactant: COCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: C/C(N)=C/C(=O)OCC=Cc1ccc(Cc2ncc[nH]2)cc1
Solvent: Cc1ccccc1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
297 mg (1 mM) of 3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yl 3-aminocrotonate and 293 mg (1 mM) of 2-methoxyethyl 2-(3-nitrobenzylidene)acetoacetate were dissolved in 5 ml of toluene and refluxed for six hours. After cooling, the crystals produced were filtered off and recrystallized from methanol whereby the captioned compound was obtained. The yield was 502 mg (87.6%).
Reaction SMILES: C([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:38]1[C:50]2[CH:49]([CH2:51][O:52][C:53]([NH:55][C@@H:56]([C:61]([OH:63])=O)[CH2:57][CH:58]([CH3:60])[CH3:59])=[O:54])[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:53]([NH:55][C@@H:56]([C:61]([NH:18][C@H:19]([C:24]([S:26][NH:27][C@H:28]([CH2:36][OH:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:63])[CH2:57][CH:58]([CH3:59])[CH3:60])([O:52][CH2:51][CH:49]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]2[C:50]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:54]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)SN[C@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-S-Phe-CH2OH (1b) (2.0 g, 4.11 mmol) was taken in 20% piperidine in DMF (20 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-S-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×20 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (5 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-D-leucine (1.59 g, 4.52 mmol), DCC (931 mg, 4.52 mmol) and HOBt (610.0 mg, 4.52 mmol) in dry DMF (150 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (5% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2b with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 4% MeOH: CH2Cl2 to give 450 mg of the tripeptide Fmoc-NH-D-Leu-L-Ile-S-Phe-CH2OH (2b) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:21][C:22]([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33][C:34]([CH3:36])=[O:35])[C@@H:28]([O:37][C:38]([CH3:40])=[O:39])[C@@H:27]1[O:41][C:42]([CH3:44])=[O:43])=[O:23]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][C:5]1[N:10]=[C:9]([O:11][C@@H:30]2[O:31][C@H:26]([CH2:25][O:24][C:22](=[O:23])[CH3:21])[C@@H:27]([O:41][C:42](=[O:43])[CH3:44])[C@H:28]([O:37][C:38](=[O:39])[CH3:40])[C@H:29]2[O:33][C:34](=[O:35])[CH3:36])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCc1ccc(Cc2ccc(NC(C)=O)[nH]c2=O)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(NC(C)=O)nc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 3 h
Yield: 107.2 %

Procedure:
To a solution of 6-(N-acetylamino)-3-(4-ethylbenzyl)-1H-pyridin-2-one (0.034 g) in dichloromethane (2.5 mL) were added acetobromo-α-D-glucose (0.10 g) and silver carbonate (0.17 g), and the mixture was stirred under shading for 3 hours at 50° C. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/2) to give 6-(N-acetylamino)-2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-3-(4-ethylbenzyl)pyridine (0.081 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:20]1=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate (55 mg, 0.132 mmol) in dichloromethane (2 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 318.2 (M+1).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([F:20])([F:19])[F:18])=[C:12]([OH:22])[CH:11]=1>CO>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:7][OH:8])[C:17]([F:20])([F:19])[F:18])=[C:12]([OH:22])[CH:11]=1
Reactant: O=C(c1ccc(Br)cc1O)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C(c1ccc(Br)cc1O)C(F)(F)F
Temperature: 64 °C

Procedure:
To a round bottom flask were added sodium acetate (9.46 g, 115 mmol), hydroxylamine hydrochloride (7.09 g, 102 mmol) and MeOH (10 mL). To this mixture was added a solution consisting of 1-(4-bromo-2-hydroxy-phenyl)-2,2,2-trifluoro-ethanone (2.5 g, 9.3 mmol) and MeOH (62 mL). The reaction vessel was heated at 64° C. for 7 h before cooling to rt and pouring the reaction mixture into ice water (100 mL). The aqueous solution was then extracted with EtOAc (75 mL×2) and the organic layers dried (Na2SO4) and concentrated to yield the title compound as a mixture of the two possible oxime isomers (2.64 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:13]=1[NH:25][CH2:26][CH2:27][O:28][CH3:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:31])[NH:7][C@H:8]([C:10]1[N:25]([CH2:26][CH2:27][O:28][CH3:29])[C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[C:15]([F:18])[CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCNc1c(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc(F)c1-c1ccccn1
Solvent: CC(=O)O
Product: COCCn1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of {(S)-1-[4-fluoro-2-(2-methoxyethylamino)-3-pyridin-2-yl-phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (368 mg, 0.85 mmol) in AcOH (5 mL) was heated for 16 h at 70° C. in a sealed tube. After cooling to RT, the volatiles were removed in vacuo and the resulting residue taken up in DCM (15 mL) and washed with sat. NaHCO3 (30 mL). The aqueous was further extracted with DCM (2×15 mL). The combined organic fractions were washed with brine (15 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 20-75% EtOAc/cyclohexane) to afford the title compound as a white solid (239 mg, 68%). LCMS (Method C): RT 2.92 min [M+H]+ 415. 1H NMR (CDCl3, 400 MHz): δ 7.84 (1H, ddd, J=7.5, 7.5, 2.0 Hz), 7.71 (1H, dd, J=9.0, 5.0 Hz), 7.59-7.56 (1H, m), 7.38 (1H, ddd, J=7.5, 5.0, 1.5 Hz), 7.09 (1H, dd, J=10.5, 9.0 Hz), 5.29-5.19 (2H, m), 4.33-4.26 (1H, m), 3.91 (1H, ddd, J=15.0, 4.0, 4.0 Hz), 3.14-3.08 (2H, m), 3.07 (1H, s), 1.60 (3H, d, J=6.5 Hz), 1.41 (9H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+].IC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH3:10])[CH:7]=1
Reactant: Oc1cc(Cl)ccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 5-chloro-2-fluorophenol (4.68 g) and DMF (dry) (50 mL) were added K2CO3 (8.83 g) and iodomethane (3.99 mL) at room temperature. The mixture was stirred at room temperature for 4.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (4.60 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:28][C:27]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3)cc2)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCO
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(-c4ccccc4Cl)cc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution 2-(4-bromophenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile (1 eq.) from step 1,2-chlorophenylboronic acid (2 eq.) in n-propanol:dioxane (1:2; 0.17M) at room temperature was added palladium acetate/triphenyl phosphine (1:3; 0.05 eq.) and aqueous Na2CO3 (2M; 4 eq.). The mixture was stiffed 30 min at 150° C. in microwave (Smith Creator; Personal Chemistry), cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 5% afforded the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:47][CH2:48][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.41 mmol) in DMF (1 mL) was added chloromethyl pivalate (35 μL, 0.25 mmol) at rt. The reaction was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 1/1) to afford (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl pivalate (30 mg, 23%) and (N-(3-(5-(4-chlorophenyl)-1-((pivaloyloxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propylsulfonamido) methyl pivalate (20 mg, 13.3%) as white solids. The title compounds were characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([N:40]([CH:42]([CH3:44])[CH3:43])[CH3:41])[CH2:36][C@H:35]1[CH2:45][OH:46]>C1COCC1.O>[OH:46][CH2:45][C@@H:35]1[CH2:36][C@H:37]([N:40]([CH:42]([CH3:43])[CH3:44])[CH3:41])[CH2:38][CH2:39][C@@H:34]1[NH:33][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:17])[F:16])[CH:4]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N)[C@H](CO)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Reaction time: 0.08 h
Yield: 43 %

Procedure:
A solution of (3-Trifluoromethyl-benzoylamino)-acetic acid (1.76 g, 0.0071 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine(0.80 g, 0.0080 mol) and then drop-wise with isobutyl chloroformate (1.0 g, 0.007 mol). The resulting mixture was stirred for 5 min and then treated with a solution of ((1R,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)methanol (1.3 g, 0.0065 mol) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 5-8% [NH4OH/MeOH]/CH2Cl2) to give 1.2 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ(TMS): 8.15 (s, 1 H), 8.05 (d, J=7.8 Hz, 1 H), 7.76 (d, J=7.8 Hz, 1 H), 7.76 (bs, 1 H), 7.57 (t, J=7.8 Hz, 1 H), 7.17 (bs, 1 H), 4.26 (m, 1 H), 4.26 (dd, J=5 Hz, J=16 Hz, 1 H), 4.13 (dd, J=5 Hz, J=16 Hz, 1 H), 3.27 (m, 1 H), 3.17 (m, 1 H), 2.57 (m, 2 H), 2.24 (s, 3 H), 1.92-1.60 (m, 7 H), 1.05 (d, J=6.5 Hz, 6 H); MS found: (M+H)+=430.48.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[S:6][CH:7]=1>C(Cl)(Cl)Cl.CO.O=[Mn]=O>[O:13]=[C:9]1[N:8]([C:5]2[S:6][CH:7]=[C:3]([CH:2]=[O:1])[N:4]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1OCCN1c1nc(CO)cs1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1csc(N2CCOC2=O)n1

Procedure:
MnO2 (7.2 g; 83.6 mmol) was added to a solution of 3-(4-hydroxymethylthiazole-2-yl)oxazolidin-2-one (0.56 g; 2.8 mmol), prepared as described in the above step, in chloroform (60 ml) and methanol (6 ml).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@@H:16]3[CH2:20][C@@H:19]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH2:18][NH:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:29]1[N:30]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:29]1[N:30]([CH2:34][C:35]([N:17]2[CH2:18][C@H:19]([CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[CH2:20][C@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)=[CH:12][CH:11]=2)=[O:15])=[O:36])[N:31]=[CH:32][CH:33]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccs2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2cccs2)CN1C(=O)Cn1nccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 5.7 %

Procedure:
A flask was charged with (2S,4S)—N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide (84 mg, 0.21 mmol), 2-(2H-1,2,3-triazol-2-yl)acetic acid (29 mg, 0.23 mmol), DIEA (0.5 mL, 2.9 mmol), HATU (81 mg, 0.21 mmol) and DMF (3 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 64, (2S,4S)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(thien-2-ylmethyl)pyrrolidine-2-carboxamide (6.1 mg, 0.012 mmol, 6% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 9.15 (s, 1H), 7.72 (s, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.18-7.16 (m, 1H), 7.03-6.82 (m, 8H), 5.29 (s, 2H), 4.86 (d, J=8.0 Hz), 3.63-3.58 (m, 1H), 3.25-3.20 (m, 1H), 3.12 (dd, J=13.6, 4.8 Hz, 1H), 3.01-2.87 (m, 2H), 2.73 (dd, J=12.4, 5.2 Hz, 1H), 1.75-1.68 (m, 1H). MS (EI) for C26H24FN5O3S. found 506.2 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[O:19].[CH2:24]([N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[N:34][C:35](Cl)=[C:36]([NH:41][CH:42]([CH3:44])[CH3:43])[N:37]=2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:24]([N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[N:34][C:35]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:3]=4[F:2])[CH2:11][CH2:10]3)=[C:36]([NH:41][CH:42]([CH3:44])[CH3:43])[N:37]=2)[CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:18]([OH:19])([C:20]([F:23])([F:22])[F:21])=[O:17]
Reactant: Fc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
A mixture of 4-(2,4-difluorophenoxyl)piperidine hydrochloride (62.6 mg, 0.251 mmol), 6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (90 mg, 0.209 mmol), sodium tert-butoxide (60.2 mg, 0.627 mmol), BINAP (19.5 mg, 0.031 mmol) and Pd2(dba)3 (9.6 mg, 10.4 μmol) in toluene (1.04 mL) was heated at 100° C. for 16 h. The mixture was purified by HPLC Method A to afford 6-benzyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine as its TFA salt (73.0 mg, 57.5%) as a yellow oil. ESI-MS m/z [M+H]+ 494.4.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[Cl-].[CH3:10][CH2:11]O>>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCO
Agent: [Cl-]
Product: CCOC(=O)[C@@H]1CCCN1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Into a 500 ml 3-necked roundbottom flask, was placed a solution of proline (20.0 g, 174. mmol) in EtOH (100 ml). To the above was added thinyl chloride (40 ml). The resulting solution was heated to 70° C., with stirring, for 12 hours. The mixture was concentrated by evaporation. To afford ethyl prolinate that was used without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:23])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[C:31]([C:30]1[CH:35]=[CH:36][C:27]([CH2:26][NH:25][C:13](=[O:23])[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (3.71 g) is added to an ice-cold stirred solution of cinnamic acid (3.13 g) in 30 mL tetrahydrofuran. After stirring for an additional 1 hr, methyl 4-(aminomethyl)benzoate hydrochloride (4.7 g) and triethylamine (3.23 mL) are added and the final mixture stirred while immersed in an ice water bath for an additional 30 min, followed by stirring overnight at room temperature. After removal of the solvent by rotary evaporation, the residue is taken up in chloroform (250 mL) and extracted with water (200 mL), 1N HCl (3×50 mL), water (100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) and the final chloroform layer dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo, the crude product (2.74 g) is suspended in 100 mL tetrahydrofuran and 20 mL 2N NaOH and the mixture stirred at room temperature overnight. The mixture is then made acidic by addition of excess 1N HCl, and the precipitate recovered by filtration. After washing the filter cake with water and pressing to remove as much water as possible, the white solid is crystallized from methanol/2N HCl as N-(4-carboxybenzyl)cinnamamide,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1>COC(OC)N(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25](/[N:27]=[CH:12]/[N:13]([CH3:14])[CH3:9])=[O:26])=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C(N)=O)cc2)c1Sc1ccc(Cl)cc1
Agent: COC(OC)N(C)C
Product: CN(C)/C=N/C(=O)c1ccc(-c2nc(-c3ccccc3)n(C)c2Sc2ccc(Cl)cc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzamide (Example 71, 35 mg, 0.083 mmol) in 3 mL of dimethylformamide-dimethylacetal was heated at 120° C. for 30 min. The volatiles were removed to afford 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}-N-[(1E)-(dimethylamino)methylene]benzamide, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH2:21])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:22]([CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])=[C:23]=[S:24]>C(Cl)(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][CH:10]([NH:21][C:23](=[S:24])[NH:22][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(=O)OCCN=C=S
Reactant: Cc1cc(C)cc(CC(N)c2cccc3c2CCCC3)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCNC(=S)NC(Cc1cc(C)cc(C)c1)c1cccc2c1CCCC2

Procedure:
A solution of 2-(3,5-dimethylphenyl)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)-ethylamine (2.18 g) in 40 ml of chloroform was treated with acetic acid 2-isothiocyanato-ethyl ester (1.13 g) at room temperature and the mixture heated under reflux for 2 hours. After completion of the reaction the solvent was evaporated in vacuo and the residue was purified on silica gel with a gradient of cyclohexan/ethyl acetate. This yielded the title compound in 2.74 g (83%).