Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:49])[CH:3]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:4]([N:6]1[C@H:10]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:36][C:35]([C@@H:37]7[CH2:41][CH2:40][C@H:39]([CH3:42])[NH:38]7)=[N:34][CH:33]=6)=[CH:28][CH:27]=5)=[CH:22][CH:21]=4)[C:13]=3[N:12]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:43])=[O:5].[CH3:50][O:51][C:52]([NH:54][C@@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])=[O:53].N1C(C)=CC(C)=CC=1C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:47][O:46][C:45]([NH:44][CH:3]([CH:2]([CH3:49])[CH3:1])[C:4]([N:6]1[C@@H:7]([CH3:43])[CH2:8][CH2:9][C@H:10]1[C:11]1[NH:12][C:16]2[CH:17]=[CH:18][C:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[N:36]=[C:35]([C@@H:37]6[CH2:41][CH2:40][C@H:39]([CH3:42])[N:38]6[C:56]([C@@H:55]([NH:54][C:52](=[O:53])[O:51][CH3:50])[CH:59]([CH3:61])[CH3:60])=[O:57])[NH:34][CH:33]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:13][C:14]=2[N:15]=1)=[O:5])=[O:48]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)NC(C(=O)N1[C@@H](C)CC[C@H]1c1nc2c(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6)[nH]5)cc4)cc3)cccc2[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1[C@@H](C)CC[C@H]1c1nc2cc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)cc3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.4 %

Procedure:
To a mixture of methyl N-[2-methyl-1-[(2S,5S)-2-methyl-5-[4-[4-[4-[2-[(2S,5S)-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-benzimidazol-2-yl]pyrro-lidine-1-carbonyl]propyl]carbamate (88 mg, 0.126 mmol), (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (22 mg, 0.126 mmol) and 2,4,6-collidine (50.11 μl, 0.38 mmol) in DMF (3.5 ml) is added HATU (52.8 mg, 0.14 mmol) at 0° C. The reaction mixture is stirred at rt for 5 hours, diluted with EtOAc, washed with H2O and brine. The organic phase is dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography on silica gel (1 to 20% MeOH in CH2Cl2) and repurified by reverse phase HPLC using a gradient of CH3CN/water to afford the methyl N-[(1S)-1-[(2S,5S)-2-[4-[4-[4-[2-[(2S,5S)-1-[2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]-5-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (22 mg, 19.9%) as a white fluffy powder.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[Si]([O:34][CH2:35][C:36]1[S:40][C:39]([C:41](=[N:43]O)[NH2:42])=[CH:38][CH:37]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]2[O:14][N:43]=[C:41]([C:39]3[S:40][C:36]([CH2:35][OH:34])=[CH:37][CH:38]=3)[N:42]=2)=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)s1
Yield: 55 %

Procedure:
To a solution of 4-phenoxybenzoic acid (0.12 g, 0.55 mmol) in acetonitrile (5 ml) were added successively 1-hydroxybenzotriazole (88 mg, 0.65 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.60 mmol), 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-2-carboximidamide (0.14 g, 0.5 mmol) that was obtained in Example 4 (4b) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with 0.1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained in tetrahydrofuran (4.0 ml) was added tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 1.0 ml, 11.0 mmol) with stirring, and the resulting mixture was stirred at 60° C. for 3 hours. After stirring, the reaction mixture was poured into water (20 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (97 mg) in a yield of 55% as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[N:7][N:6]2[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:25]=[CH:24]C=C[C:19]=4[C:20]#[N:21])[CH:13]=3)=[CH:10][N:11]=[C:5]2[N:4]=1.N1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:8]=[N:7][N:6]2[C:9]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:25]=[CH:24][N:21]=[CH:20][CH:19]=4)[CH:13]=3)=[CH:10][N:11]=[C:5]2[N:4]=1
Reactant: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccncc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnn2c(-c3ccnc(-c4ccncc4)c3)cnc2n1
Temperature: 90 °C
Yield: 24.8 %

Procedure:
A mixture of 7-(2-chloropyridin-4-yl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.10 g, 0.33 mmol) (prepared as described in Example 1), pyridine-4-boronic acid (50 mg, 0.40 mmol) and sodium carbonate (600 μl of a 2 M solution) in 1,4-dioxane (3 ml) was degassed by bubbling nitrogen through for 20 min. Tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.04 mmol) was added and the mixture heated at 90° C. for 4 h. Solvent was removed in vacuo from the mixture and the residue partitioned between dichloromethane (50 ml) and water (30 ml). The organic layer was washed with saturated brine then dried (MgSO4), filtered and evaporated in vacuo. Purification by chromatography (silica gel, 5% MeOH/CH2Cl2) gave 28 mg of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.98–7.99 (2H, m), 8.06 (1H, dd, J 1.6, 5.1), 8.59 (1H, s), 8.79–8.84 (3H, m), 8.94 (1H, dd, J 0.8, 4.3), 8.95 (1H, s); MS (ES+) m/z 343 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[CH:10].O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[C:11]1([C:9]2[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Product: C[Si](C)(C)Cn1cc(-c2ccccc2)nn1
Reaction time: 96 h

Procedure:
(Azidomethyl)trimethylsilane (1.6 g, 12.38 mmol), ethynylbenzene (1.30 g, 12.73 mmol), copper(II) sulfate (0.060 g, 0.376 mmol) and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.135 g, 0.681 mmol) were added to a 1:2 solution of waterbutan-1-ol. The reaction was stirred for 4 days and t-butanol and water were removed, producing a 4-phenyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]1[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]([C:41]4[N:46]=[C:45]([C:47]([F:49])([F:50])[F:48])[C:44]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43][N:42]=4)[CH:36]([CH:37]([CH3:38])[CH3:39])[C:24]3=[CH:23][C:22]=2[CH:21]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The intermediate 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole was prepared following a procedure analogous to that described in Preparation 4. The mixture of compound 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (0.19 mmol), ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (97 mg, 0.38 mmol) and DIEA (100 μL, 0.57 mmol) in i-PrOH/CH2Cl2 (1 mL/0.5 mL) was stirred at 50° C. for 8 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1) to give racemic ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate. LC-MS m/z 563 [M+Na]+. 1H NMR (400 MHz, CD3OD): δ 9.31 (s, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 6.55 (s, 1H), 6.02-5.92 (m, 1H), 5.23-5.17 (m, 1H), 5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.19-4.06 (m, 1H), 4.00-3.93 (m, 1H), 3.27 (s, 3H), 2.42-2.32 (m, 1H), 1.36 (t, J=7.2 Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:74])[C:62]4[C:66]([CH:67]=3)=[N:65][N:64](C3CCCCO3)[CH:63]=4)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:67]=[C:66]4[C:62]([CH:63]=[N:64][NH:65]4)=[C:61]([NH:74][C:14]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[N:13]=4)=[O:16])[CH:60]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1cccc(CN2CCCCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(CN2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.7 %

Procedure:
To a solution of 6-(1-piperidinylmethyl)-2-pyridinecarboxylic acid (33 mg, 0.15 mmol) in DMF (0.6 ml) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (57 mg, 0.15 mmol) and DIPEA (0.052 ml) and the mixture was stirred for 5 mins at room temperature. 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (33 mg, 0.10 mmol) was added and the mixture was stirred for 3 h and then overnight. The mixture was then treated with saturated sodium bicarbonate solution (10 ml) and extracted with dichloromethane (3×10 ml). The extracts were passed through a hydrophobic frit and blown to dryness under a stream of nitrogen. The crude product was dissolved in methanol (2 ml) and hydrochloric acid (5M, 2-3 drops) were added. The solution was shaken for 2 h then blown to dryness under a stream of nitrogen then purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound (17 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[O:20][CH3:21])[CH:6]=[C:7]([Br:10])[C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)c(F)c(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
3,5-dibromo-4-fluoroaniline (1.6 g, 4.16 mmol) was dissolved in DCM (41.6 ml). Pyridine (0.90 ml, 11.13 mmol) was added and the reaction mixture cooled to 0-5° C. Methyl chloroformate (0.66 ml, 8.52 mmol) was added dropwise via syringe. The reaction mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was diluted with additional 50 ml dichloromethane and washed with 0.5 M citric acid twice, NaHCO3 solution once and brine once, then dried over MgSO4, filtered and evaporated to dryness. Chromatography on silica (gradient from 100% hexanes to 100% DCM) gave methyl (3,5-dibromo-4-fluorophenyl)carbamate (1.22 g) as a colorless fluffy solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CCC(=O)O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a mixture of ethyl 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.00 g), tetrahydrofuran (3 mL) and ethanol (3 mL) was added a 1N aqueous sodium hydroxide solution (4.2 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.61 g, 66%) of 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 157-158° C.
Reaction SMILES: P(=O)([O-])[O-].P(=O)(O)O.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][NH:10]1.N.[Li]>C(O)(C)(C)C>[CH2:9]1[C:18]2[CH:13]([CH2:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][NH:10]1
Reactant: C1=Cc2ccccc2CN1
Agent: N
Agent: O=[PH](O)O
Agent: O=[PH]([O-])[O-]
Solvent: CC(C)(C)O
Product: C1=CCC2CCNCC2=C1
Temperature: -78 °C

Procedure:
The procedures of Examples 1 and 2 are followed without isolation of the intermediate phosphonate of formula (III). The reaction solution resulting from the Wittig reaction of Example 2 is cooled to -78° C. and the procedure of Example 4 is followed with the addition of ammonia followed by 15 molar equivalents each of tert-butanol and lithium metal. The solution is refluxed at -33° C. for no more than 15 minutes and is then worked up as in Example 4 to yield the hexahydro-isoquinoline derivative of formula (X) wherein R4 is --OCH2CH3 ; R2, Z and Z1 are hydrogen; and X and Y are H3CO--.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.F[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 130 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (105 mg, 0.300 mmol) and methyl 2-fluorobenzoate (0.0382 mL, 0.300 mmol) were added to dimethylsulfoxide (5 mL). To this mixture, potassium carbonate (82.9 mg, 0.600 mmol) was added and the mixture was stirred for 6 hours at 130° C. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 29.5 mg (20%) of the desired compound as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:13][C@H:12]2[C@H:8]([N:9]=[C:10]([NH:14][CH2:15][CH3:16])[S:11]2)[C@@H:7]([OH:17])[C@@H:6]1[OH:18])=[N+:2]=[N-:3].C(O)C.CC(O)(C)C.[C:27]1([C:33]([OH:37])([C:35]#[CH:36])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.[Cu].O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:15]([NH:14][C:10]1[S:11][CH:12]2[O:13][CH:5]([CH2:4][N:1]3[CH:36]=[C:35]([C:33]([OH:37])([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:34])[N:3]=[N:2]3)[CH:6]([OH:18])[CH:7]([OH:17])[CH:8]2[N:9]=1)[CH3:16]
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN=[N+]=[N-])O[C@@H]2S1
Reactant: C#CC(C)(O)c1ccccc1
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CC(C)(C)O
Product: CCNC1=NC2C(OC(Cn3cc(C(C)(O)c4ccccc4)nn3)C(O)C2O)S1
Reaction time: 24 h
Yield: 21 %

Procedure:
In a 10 mL rb flask was added (3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (40 mg, 0.15 mmol, 1.00 eq.), copper turnings (66 mg; 1.05 mmol; 7.00 eq.) and copper(II)sulfate pentahydrate (7.5 mg; 0.03 mmol; 0.20 eq.). The flask was evacuated and filled with nitrogen. This procedure was repeated twice before ethanol (0.5 ml)/water (0.7 ml)/2-methylpropan-2-ol (1.3 ml) and 2-phenylbut-3-yn-2-ol (22 mg; 0.45 mmol; 3.00 eq.) was added into the mixture and stirred for 24 h to get the reaction completed. Product formation was confirmed by LCMS. The solution was diluted with 2 mL H2O, dried and separated with mass based prep HPLC to afford the desired product.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:26])([CH3:25])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20](OCC)=O)[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[CH2:28]([Al+]CC(C)C)C(C)C.[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([S:7]([C:10]([CH3:25])([CH3:26])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]#[CH:28])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)CC1
Reactant: CC(C)C[Al+]CC(C)C
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Product: C#CC1CCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
1-(4-Benzenesulfonyl-4-methylpentyl)-4-ethoxycarbonylpiperidine (0.3 g, 0.79 mmol) was dissolved in dichloromethane (5 ml) and cooled to −78° C. Diisobutylaluminium hydride (1.0M in dichloromethane, 1.0 ml, 1.0 mmol) was added. The reaction was stirred for 30 minutes at −78° C. then quenched by the addition of ethyl acetate (0.5 ml) and water (0.1 ml). The mixture was stirred at room temperature for 10 minutes then filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in methanol (20 ml). Dimethyl (1-diazo-2-oxopropyl)phosphonate (0.3 g, 1.56 mmol) and potassium carbonate (0.23 g, 1.65 mmol) were added and the reaction stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2–4% methanol/dichloromethane, to give the title compound (90 mg, 34%). NMR of hydrochloride salt:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:8]([CH3:25])[CH2:7][C:6]2=[O:26].[CH:27](OCC)=[O:28].[O-]CC.[Na+].[H-].[Na+]>C1C=CC=CC=1.C(O)C>[OH:28][CH:27]=[C:7]1[C:6](=[O:26])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]1[CH3:25]
Reactant: CCOC=O
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)CC2=O
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)C(C)C(=CO)C2=O

Procedure:
Following the procedure of Examples 1-E, 16-B and 17-B, 9.5 g. of benzyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate, 10.95 ml. of ethyl formate and sodium ethoxide prepared from 2.57 g. of sodium hydride and 3.23 ml. of ethanol in 120 ml. of benzene gave on work-up a yellow oil which on crystallization afforded 6.0 g. of crude product, m.p. 106°-110°C. The analytical same is recrystallized several times from methanol, m.p. 116°-118°C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:8]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 81.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3-trifluoromethyl-phenyl)-propionic acid (286 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 1.25 h. The reaction mixture was then treated with a solution of 2-aminothiazole (175 mg, 1.75 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.41 mmol) in tetrahydrofuran (10 mL). This solution was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 60/40 heptane/ethyl acetate) afforded 3-cyclopentyl-N-thiazol-2-yl-2-(3-trifluoromethyl-phenyl)-propionamide (299.2 mg, 81.4%) as a light yellow solid: mp 134-136° C.; EI-HRMS m/e calcd for C18H19F3N2OS (M+) 368.1170, found 368.1165.