Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2.F[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)=[C:18]([CH3:23])[CH:17]=1)=[N:5][CH:6]=[N:7]2
Reactant: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1O
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
A mixture of 4-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-methylphenol (0.47 g, 1.5 mmol), 2-fluoro-4-trifluoromethylpyridine (0.371 g, 2.25 mmol), and potassium carbonate (0.31 g, 2.25 mmol) in DMSO (7 mL) was heated at 90° C. overnight. The reaction was complete, as determined by LC-MS. After cooling to room temperature, water was added and the mixture was stirred for 10 min. The solid precipitate was collected by filtration, washed with water, and dried under vacuum at 50° C. to provide 0.533 g (77%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-methyl-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as an off-white solid, M.P. 108-110° C. 1H NMR (CDCl3): δ 8.69 (s, 1H), 8.31 (d, J=5.1 Hz, 1H), 7.34 (m, 1H), 7.13-7.21 (m, 4H), 6.96-7.03 (m, 2H), 6.71-6.84 (br, 1H), 3.94 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.17 (s, 3H). LC/MS: 461.13 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:17]O)([O-:3])=[O:2].C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:17][C:5]1[CH:6]=[C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)cc1CCl

Procedure:
To a round bottom flask equipped with a nitrogen inlet and a water cooled condenser, 2-nitro-5-phenoxy-phenyl-methanol (2.7 g, 11.1 mmol) and triethylamine (4.7 mL, 33.9 mmol) were dissolved in dichloromethane (100 mL). Methane sulfonyl chloride (2.6 mL, 33.3 mmol) was added to the reaction mixture which was subsequently heated to reflux for 16 h. The next day the reaction was removed from the heating source, allowed to cool and poured into a separatory funnel which contained a water solution of 1N HCl. The organic phase washed 2 times with 1N HCl and one time with saturated brine solution. The phases were separated and the ethyl acetate layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using heptanes:ethyl acetate as the mobile phase (9:1) to yield a residue.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3S)-3-(aminooxy)piperidine-1-carboxylate 16 (0.19 g, 0.86 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 17 (0.28 g, 82%) as a white solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][NH2+:17][CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1.[N:22]([C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=1)[O:28][C:29]1[CH:34]=[N:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[C:23]=[O:24]>>[Br:8][C:9]1[C:21]2[C:20]3[CH2:19][CH2:18][N:17]([C:23]([NH:22][C:25]4[CH:38]=[CH:37][CH:36]=[C:27]([O:28][C:29]5[CH:34]=[N:33][CH:32]=[C:31]([CH3:35])[N:30]=5)[CH:26]=4)=[O:24])[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Reactant: Cc1cncc(Oc2cccc(N=C=O)c2)n1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cncc(Oc2cccc(NC(=O)N3CCc4c(cnc5[nH]nc(Br)c45)C3)c2)n1

Procedure:
The compound, 1-bromo-N-{3-[(6-methylpyrazin-2-yl)oxy]phenyl}-3,6,8,9-tetrahydro-7H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamide was prepared using 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium 2,2,2-trifluoroacetate and 2-(3-isocyanatophenoxy)-6-methylpyrazine as described in general procedure M. Yellow solid; M.p.=221-223° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.96 (s, 1H), 8.87 (s, 1H), 8.40 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.4-7.26 (m, 3H), 6.79-6.74 (m, 1H), 4.76 (s, 2H), 3.82 (t, J=6 Hz, 2H), 3.37 (t, J=6 Hz, 2H), 2.35 (s, 3H); LCMS [M+H]: 479.9.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](=O)([O:23]CC)[O:20][CH2:21][CH3:22]>>[CH3:18][CH2:17][O:16][C:14]([CH:13]([C:19]([O:20][CH2:21][CH3:22])=[O:23])[C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])=[O:15]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)cc1Cl
Yield: 85 %

Procedure:
Sodium (1.86 g, 0.081M) was added in portions to absolute ethanol (150 ml) with stirring. After all the sodium had dissolved a solution of ethyl 2,4-dichlorophenylacetate (20 g) in diethyl carbonate (50 ml) was added dropwise. The reaction mixture was heated until EtOH distilled over. The rate of addition was controlled such that it equalled the rate of distillation. After the completion of addition the reaction mixture was heated and distilled for further 4 hours. The cooled reaction mixture was partitioned between water (300 ml) and EtOAc (300 ml) and the organic layer dried and evaporated in vacuo to give a yellow oil (21 g, 85%).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[CH:36])#[N:29]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[C:36][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])#[N:29]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCCCCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
Under argon, to a solution of 2-iodoadenosine (200 mg, 0.51 mmol) and bis(triphenylphosphine)palladium dichloride (36 mg, 10 mol %) dissolved in N,N-dimethylformamide (5 mL), triethylamine (0.09 mL, 0.61 mmol, 1.2 eq.) and 7-cyano-1-heptyne (74 mg, 0.1 mmol, 1.2 eq.) were added, and, under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) was added thereto, followed by stirring at 60° C. for 24 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by dry packed silica gel column chromatography (chloroform:methanol=10:1), to thereby yield the above-titled compound as a pale yellow powder (yield: 77 mg, percent yield: 39%).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[O:14][CH2:15][C:16](=[O:23])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1.N1CCCCC1>CC(O)C>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:15]2[O:14][C:13]([NH:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2=[O:23])=[CH:26]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2OCCN(C)C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 21.6 %

Procedure:
To a solution of ethyl 2-({2-[2-(dimethylamino)ethoxy]phenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.010 g, 0.031 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0042 g, 0.029 mmol) in 2-propanol (0.3 mL), piperidine (0.00028 mL, 0.0028 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0029 g, y. 22%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:3]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:31][CH2:32]3)[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:5]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)nc(-c3ccncc3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(-c3ccncc3)n2)cc1Cl

Procedure:
Dissolve 4-chloro-6-(3-chloro-4-fluorophenyl)-2-(pyridin-4-yl)pyrimidine (64 mg, 0.2 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (46 mg, 0.2 mmoles) in DMA (2.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (55 mg, 0.4 mmoles) to this mixture and heat at 140° C. for 20 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product. Wash the crude product with Et2O (2.0 mL) to afford the title product as cream colored solid. NMR (CDCl3) δ 3.34 (4H, s), 3.99 (4H, s), 7.20 (1H, m), 7.47 (1H, s), 7.43 (1H, t), 8.09 (1H, d, J=2.0), 8.30 (2H, m), 8.35 (1H, m), 8.55 (2H, m), 8.70 (2H, m). Mass spec m/z=515.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-].COCCOC.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH:11]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(C)CCC1CSc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: CC1CCC(CSc2ccc(F)cc2)C(C(=O)O)C1
Temperature: 70 °C

Procedure:
A solution of (1R/S,3R/S,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methyl-cyclohexanecarboxylate and (1R/S,3S/R,6R/S)-ethyl 2-{[(4-fluorophenyl)sulfanyl]-methyl}-5-methylcyclohexanecarboxylate (1:1 mixture, 54 mg, 0.17 mmol) in a mixture of aqueous LiOH (2 M, 1.7 mL, 3.4 mmol), DME (1 mL) and ethanol (0.3 mL) was heated at 70° C. for 7 h. The solution was cooled to room temperature, acidified with aqueous 2 M HCl (0.5 mL) and extracted with ethyl acetate. The organic extracts were concentrated in vacuo to yield (1R/S,3R/S,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid and (1R/S,3S/R,6R/S)-2-{[(4-fluorophenyl)sulfanyl]methyl}-5-methylcyclohexanecarboxylic acid as a 1:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH2:17][O:18][CH2:19][CH2:20][C:14]=2[N:13]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]2[CH2:17][O:18][CH2:19][CH2:20][C:14]=2[N:13]=1
Reactant: COC(=O)c1ccc(C)c(-c2nc3c([nH]2)COCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1nc2c([nH]1)COCC2
Temperature: 60 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
A mixture of methyl 4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate (compound 1.10, 210 mg, 0.73 mmol, 1.00 equiv, 95%) and sodium hydroxide (92.65 mg, 2.32 mmol, 3.00 equiv) in 12 mL methanol/H2O (2:1) was stirred for at 60° C. in an oil bath. After 2 h, the reaction mixture was concentrated under reduced pressure and the residue was taken up in 5 mL of H2O. The resulting mixture was washed with 3×10 mL of ethyl acetate and the pH of the aqueous layer was then adjusted to 2-3 using hydrogen chloride (aq., 2 M). The resulting mixture was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield 0.21 g (89%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=O)[C:10]([OH:12])=[O:11].C1CCN2C(=NCCC2)CC1.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][N:29]=[C:28]([S:34][CH3:35])[N:27]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]([OH:12])=[O:11])=[N:25][C:26]2[N:27]=[C:28]([S:34][CH3:35])[N:29]=[CH:30][C:31]=2[CH:32]=1
Reactant: O=C(O)C(=O)Cc1ccccc1Br
Reactant: CSc1ncc(C=O)c(N)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3ccccc3Br)c(C(=O)O)nc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
3.372 g 3-(2-bromophenyl)2-oxopropionic acid in 20 ml DMF were treated with 4.434 g DBU under cooling and stirred for 10 min at RT. 2.728 g 4-amino-2-methylsulfanylpyrimidine-5-carbaldehyde were added and the mixture was stirred at 85° C. for 4.5 hrs. Stirring was continued over night at RT, then the solvent was evaporated and the residue dispensed in aqueous sodium carbonate solution. The mixture is extracted with ethyl acetate, then acidified to pH 2 and again extracted with chloroform. The chloroform extracts were dried and evaporated and the residue triturated with hot ethyl acetate. 2.786 g of the title product were thus obtained after filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][Mg]Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[C@H:22]([OH:23])[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC[C@@H]([C@@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (71 mg, 0.154 mmol) (Example 210, StepA) in THF (2 mL) was sparged with argon for 5 minutes. The mixture was cooled to 0° C. and methylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml, 0.339 mmol) was added at such a rate that the internal temperature did not get above 4° C. The mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (2×4 g stacked columns, eluent: 5 to 15% isopropanol/hexanes) to give the title compound as the more polar diastereomer.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[OH:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C@H:14]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]5[N:38]=[CH:37][C:36]([N:39]6[CH:43]=[C:42]([CH2:44][C:45]([OH:47])=[O:46])[CH:41]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[CH2:15][O:16][C@H:10]12>CO.C(Cl)Cl>[OH:8][C@@H:9]1[CH2:13][O:12][C@@H:11]2[C@H:14]([O:17][C:18]3[N:19]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:55])([CH3:54])[CH3:56])[C:20]4[C:21]([N:48]=3)=[N:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]5[N:38]=[CH:37][C:36]([N:39]6[CH:43]=[C:42]([CH2:44][C:45]([O:47][CH3:2])=[O:46])[CH:41]=[N:40]6)=[CH:35][CH:34]=5)=[CH:29][CH:28]=3)=[C:24]([Cl:26])[CH:25]=4)[CH2:15][O:16][C@H:10]12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccc(-n5cc(CC(=O)O)cn5)cn4)cc3)c(Cl)cc21
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1cnn(-c2ccc(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)n(COCC[Si](C)(C)C)c5cc4Cl)cc3)nc2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TMS-Diazomethane (2 M in hexanes, 0.15 mL, 0.300 mmol) was added to a stirred solution of 2-[1-[6-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-pyridyl]pyrazol-4-yl]acetic acid (27.3 mg, 0.039 mmol) in MeOH (0.5 mL) and DCM (0.5 mL). The reaction mixture was stirred at room temperature. After 3.5 hours, the reaction mixture was evaporated under reduced pressure to give the desired compound as a yellow residue. This material was used in the next step without further purification. LC-MS: calculated for C35H39ClN6O7Si 718.23 observed m/e: 719.31 (M+H)+ (Rt 1.26/2 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[S:14])[NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:16][C:17](=O)[CH2:18][CH3:19]>C(O)(C)(C)C>[CH2:18]([C:17]1[N:13]=[C:12]([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:14][CH:16]=1)[CH3:19]
Reactant: CCC(=O)CBr
Reactant: NC(=S)CCc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)(C)O
Product: CCc1csc(CCc2ccc([N+](=O)[O-])cc2)n1
Yield: 94.9 %

Procedure:
A mixture of 3-(4-nitrophenyl)propanethioamide (1.25 g), 1-bromo-2-butanone (0.98 g) and tert-butanol (30 mL) was heated under reflux for 30 min. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-ethyl-2-[2-(4-nitrophenyl)ethyl]-1,3-thiazole as a yellow oil (1.48 g, yield 95%) from a fraction eluted with hexane-ethyl acetate (4:1-2:1, v/v).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.O.[OH-].[Na+]>O1CCCC1>[C:9]1([CH3:12])[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][OH:2])=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CCCO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
1.24 g of 3-p-tolyl-propionic acid methyl ester (40ab) prepared by above Step 2 was dissolved in 100 ml of tetrahydrofuran under Argon atmosphere. Then 27 ml of lithium aluminium-hydride was added thereto with stirring for 2 hrs at 0° C. After 3 ml of distilled water, 3 ml of NaOH (1N) and 9 ml of distilled water were added to the reaction mixture sequentially, the mixture was stirred for 30 min and filtered using cellite in glass filter and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:2) as an eluant to give 971 mg of 3-p-tolyl-propane-1-ol (40ac) (yield: 93%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)n1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 70.7 %

Procedure:
The title compound (95 mg) was prepared as in Example 177, Steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 211 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C17H20N4, 280.17. found, m/z 281.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.79-2.77 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]([N:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl>[C:1]([N:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:25])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(Cc1ccc(S(C)=O)cc1)C(=O)c1ccccc1
Yield: 56.9 %

Procedure:
To a solution of N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g) in dichloromethane (120 ml) is added gradually m-chloroperoxybenzoic acid (5.5 g) with stirring at a temperature below 5° C. and the mixture is stirred at the same temperature for 15 minutes. After the reaction, the reaction mixture is washed successively with 5% aqueous potassium carbonate solution and aqueous sodium chloride solution, and subsequently dried over magnesium sulfate. After dichloromethane is distilled off from the mixture, the residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol=100:0-100:5) to give N-benzoyl-N-methyl-N-(4-methylsulfinylbenzyl)amine (4.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](O)=[O:33]>C1(C)C=CC=CC=1>[CH:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH2:23][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[CH:30][CH:29]=1)=[O:33]
Reactant: Nc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: O=CNc1ccc(CCc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 97.7 %

Procedure:
The 4-[2-(3,4-dibenzyloxyphenyl)ethyl]benzenamine (4.5 g, 11 mmole) is dissolved in toluene (75 ml) containing formic acid (0.51 g, 11 mmole) and refluxed for two hours. The reaction mixture is evaporated to dryness, and the residue is recrystallized from toluene to afford 4.7 g (97%) of N-formyl-4-[2-(3,4-dibenyloxyphenyl)ethyl]benzeneamine, mp 119°-122° C.