Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].S(O)(=O)(=O)C.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1([CH2:25][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH2:24][O:23]1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]([OH:23])([CH2:24][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][N:26]1[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: O=C(O)CCS
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: CS(=O)(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCSCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 5 °C
Reaction time: 19 h

Procedure:
3-Mercaptopropionic acid (1.2 g, 1.1 equiv.) was dissolved in dimethylformamide (50 ml) and cooled to 5° C. in an ice bath. Sodium hydride (1.6 g of a 50% dispersion in oil, 3.3 equiv.) was added in portions over 10 minutes, followed by 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane mesylate (3.6 g). After stirring overnight (19 hours) the mixture was poured onto ice (200 ml) and extracted with methylene chloride (3×50 ml). The aqueous layer was adjusted to pH3 with hydrochloric acid (5N) and extracted with methylene chloride (3×50 ml). The organic extracts were combined, washed with saturated sodium chloride solution (2×50 ml), dried (Na2SO4), and evaporated under reduced pressure to a gum, 5.6 g.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([O:10][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(o1)CN(C)CC2O
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(C(F)(F)F)cc1

Procedure:
The same method as in Example 1 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[C:22]([Si:19]([O:13][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@:11]2([CH3:12])[C@H:6]1[CH2:5][CH2:4]/[C:3]/2=[CH:1]/[CH3:2])([CH3:21])[CH3:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C1/CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 8A (0.74 g, 4.1 mmol) was dissolved in 4 mL of dimethylformamide; 0.4 g of imidazole was added, followed by 0.7 g of tert-butyldimethylsilyl chloride. The resultant mixture was stirred at ambient temperature for 4 hours; equal portions of tert-butyldimethylsilyl chloride and imidazole were added, and the mixture was heated overnight at 60° C. Water was added; the mixture was stirred at ambient temperature for 30 minutes, and then extracted with ether. The organic phase was washed sequentially with 1 N aqueous H3PO4, water, and brine, and dried over Na2SO4. The solvents were removed in vacuo, and the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 0% to 10% ethyl acetate in hexanes. The titled compound was isolated contaminated with some unreacted starting material (0.31 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[Na+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:12]
Reactant: Cc1c(F)ccc(N)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc([N+]#N)c1Cl
Temperature: 5 °C
Yield: 83.6 %

Procedure:
2-chloro-4-fluoro-3-methylaniline (73 g) was added dropwise, with vigorous stirring to 50% hydrochloric acid (256 ml). The resulting white suspension was cooled to 5° C. and with stirring, sodium nitrite (34.5 g) in water (50 ml), added dropwise. The resultant yellow solution after filtration was cooled to 0° C. and with stirring sodium tetrafluoroborate (71 g) in water (140 ml), added dropwise. The yellow solid formed was filtered off and washed with petroleum ether (6.p 60°-80°) and combined with further similarly washed solid obtained by treating the filtrate, maintained at 0° C., with sodium tetrafluoroborate (71 g) in water (140 ml). The solid was dried overnight over phosphorus pentoxide in vacuo, giving a yield of 98.8 g 2-chloro-4-fluoro-3-methylbenzenediazonium tetrafluoroborate. This was divided into three portions each being placed in a round-bottomed flask (250 ml). The flasks were in turn heated with a naked bunsen flame until decompositio set in and an orange vapor was emitted, which was condensed and collected in a cooled receiver. The orange oil obtained from the three batches was dissolved in diethyl ether (200 ml) and washed with aqueous sodium hydroxide solution (10%, 300 ml) then saturated brine (200 ml). After drying the ethereal solution over anhydrous magnesium sulphate, filtering and evaporating at atmospheric pressure, the residual oil was distilled to give 2-chloro-3,6-difluorotoluene (45 g)
Reaction SMILES: [C:1]([O:8]C)(=O)[CH2:2][C:3](OC)=[O:4].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1](=[O:8])[CH2:2][C:3]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([F:10])=[CH:12][CH:13]=2)=[O:4])=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)CC(=O)OC
Product: O=C(CC(=O)Nc1ccc(F)cc1)Nc1ccc(F)cc1
Temperature: 200 °C

Procedure:
A mixture of dimethyl malonate (0.5 g, 3.78 mmol) and 4-fluoroaniline (0.93 g, 8.33 mmol) was heated neat to 200° C. for 20 min in the microwave system. After cooling, the solid was filtered and washed with ethyl acetate to provide the desired malonamide which was used without further purification. MS: Cal'd (MH+) 291, exp (MH+) 291.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:16][C:17]2[O:21][C:20]([C:22]([Cl:27])=[O:24])=[CH:19][CH:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1Cc1ccc(C(=O)O)o1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1Cc1ccc(C(=O)Cl)o1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution containing 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoic acid 7 (20.15 g, 61.77 mmol) in methylene chloride (310 mL), thionyl chloride (45 mL, 617 mmol) is added. The reaction is refluxed for 5 hours and another batch of thionyl chloride (45 mL, 617 mmol) is added. The reaction is stirred overnight at room temperature. The solution is concentrated to a syrup and passed through a pad of silica gel (50 g), washed with 3% hexanes, and concentrated in vacuo to afford 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-2-furoyl chloride 8 (17 g, 80% yield). NMR 1.26 (s, 6H), 1.28 (s, 6H), 1.68 (s, 4H), 2.25 (s, 3H), 4.00 (s, 2H), 6.11 (d, 1H), 7.10 (s, 1H), 7.11 (s, 1H), 7.41 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(Cl)c1

Procedure:
A solution of 3-chlorophenylacetic acid (10.0 g) in methanol (80 ml) containing 2 drops of concentrated sulphuric acid was heated at reflux for 3 hours. The reaction mixture was concentrated and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was dried over magnesium sulphate and evaporated to give the title compound (9.8 g) as a colourless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>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>[OH:31][CH2:32][C:33]1[CH:38]=[C:37]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:36]=[CH:35][CH:34]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of (3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate). (3.0 g, 6.0 mmol), 3-hydroxymethylphenylboronic acid (1.5 g, 10 mmol), K3PO4 (3.0 g) and Pd(PPh3)4 (0.30 g) in dioxane (30 ml) was heated to reflux. After 3 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc, dried, concentrated to give an oil which was purified by column chromatography (eluent 30% EtOAc/Hexane) to give the title compound as a foam (2.6 g, 96%); MS (ESI) m/z 407([M+H]+); 1H NMR (DMSO) δ 9.149 (s, 1H), 8.33 (d, 1H, J=7.1 Hz), 7.96 (d, 1H), 7.8 Hz), 7.80 (t, 1H, J=7.4 Hz), 7.62 (d, 2H, H=7.1 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.40-7.28 (m, 5H), 7.18-7.14 (m, 1H), 5.23 (t, 1H, J=5.6 Hz), 4.41 (d, 1H, J=5.6 Hz).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2.[CH2:24]([O:26]C=O)C>>[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH:24]=[O:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:3][CH2:2]2
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Reactant: CCOC=O
Product: O=CNc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1

Procedure:
A mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone (0.50 g; 1.6 mmol) and ethylformate (30 ml) was stirred at reflux for 9 days. The mixture was evaporated. Aqueous sodium hydroxide (20 ml; 1M) was added followed by extraction with dichloromethane (3×20 ml). The crude mixture was purified by silica gel chromatography, using a mixture of dichloromethane:methanol (9:1) and 1% methanol as eluent. The product was isolated as the free base. Yield 0.29 g (53%). Mp. 236° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:15][C@@H:14]5[CH2:28][O:29][CH2:30][CH2:31][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[ClH:32]>>[ClH:32].[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][C:21]([OH:23])=[O:22])[CH2:15][C@@H:14]5[CH2:28][O:29][CH2:30][CH2:31][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Agent: Cl
Product: O=C(O)CN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 113.1 %

Procedure:
A mixture of (R)-tert-butyl 2-(2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (250 mg, 0.593 mmol), HCl (4M in 1,4-dioxane) (10 mL, 40.0 mmol) and 1 N hydrochloric acid (2 mL, 2 mmol) was stirred at 70° C. for 1 hour. The mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound as a brown solid (245 mg, 103%). 1H NMR (400 MHz, DMSO-d6) δ 3.17-3.74 (m, 5H), 3.90-4.03 (m, 2H), 4.06-4.17 (m, 2H), 4.46 (d, J=18.19 Hz, 1H), 4.73 (d, J=12.13 Hz, 1H), 7.00 (br s, 1H), 7.29 (t, J=7.83 Hz, 1H), 7.52-7.62 (m, 2H), 7.69 (d, J=7.83 Hz, 2H), 11.61 (br s, 1H), 13.14 (br s, 1H) 14.22 (br s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H19N5O3, 366.15. found 366.2.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: Nc1ncc(F)cc1I
Reactant: C#CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#Cc1cc(F)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Propyne (15.4 g, 0.39 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (80 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (61.0 g, 0.26 mol), bis(triphenylphosphine)dichloropalladium(0) (9.0 g, 13.0 mmol), copper (I) iodide (2.95 g, 15.6 mmol) and triethylamine (77.7 g, 107 mL, 0.78 mol) in THF (650 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (32.2 g, 84%). 1H NMR (400 MHz, CDCl3): 7.90 (s, 1H), 7.24 (dd, J=8.4, 2.8 Hz, 1H), 4.84 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1.[CH2:13]([CH:16]([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([C:16]([CH2:3][N:4]1[CH:8]=[N:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5]1)([C:19]#[N:20])[C:17]#[N:18])[CH:14]=[CH2:15]
Reactant: C=CCC(C#N)C#N
Reactant: CC(C)(C)c1ncn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(C)(C)C)n1
Yield: 10.8 %

Procedure:
1.28 g of 1-(chloromethyl)-3-t-butyl-1H-1,2,4-triazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 1.01 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.16 g of allyl [(3-t-butyl-1H-1,2,4-triazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (31), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=O)[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:47])=CC=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:36]#[N:37])[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[S:47])[CH3:32])[O:26][C:25]4=[O:34])=[CH:20][C:19]=3[F:35])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=O)OC4=O)cc3F)CC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)c1ccc(NC2(C#N)CCN(c3ccc(N4C[C@H](CNC(C)=S)OC4=O)cc3F)CC2)cc1
Yield: 61 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)—N-{3-[4-(4-(4-methoxycarbonylphenylamino)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 61% yield.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][N:17](C(=O)C(F)(F)F)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.CCOCC>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(C(=O)C(F)(F)F)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A mixture of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 4) (0.250 g, 0.464 mmol) and K2CO3 (0.064 g, 0.464 mmol) in MeOH was stirred at room temperature for 24 h. The reaction was diluted with Et2O (50 mL), washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give a pale yellow residue which was purified by reverse phase preparative-HPLC, eluting with MeCN/H2O, to afford methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (0.117 g, 57% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.28-7.32 (1H, m), 7.15-7.20 (1H, m), 7.13 (2H, d, J=6.7 Hz), 4.79 (1H, s), 3.75 (1H, d, J=16.2 Hz), 3.69 (3H, s), 3.48 (1H, quin, J=6.6 Hz), 3.42 (1H, d, J=16.5Hz), 2.94-3.05 (2H, m), 2.17 (1H, br. s.), 1.39 (6H, s), 1.26 (3H, d, J=6.4 Hz), 1.09 (3H, d, J=6.7 Hz), 0.95 (9H, s). LCMS (M+H) calcd for C26H36FN2O3: 443.2. found: 433.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:18](O)=[O:19])=[CH:16][N:15]=[C:14]2[N:21]([CH3:25])[N:22]=[C:23]([CH3:24])[C:13]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2=NC=CC=C2N=N1.C(N(CC)CC)C.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][NH:64][C:18]([C:17]2[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[C:13]3[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:19])=[CH:59][CH:58]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nn(C)c2ncc(C(=O)O)c(NCCNC(=O)OC(C)(C)C)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cnc3c(c(C)nn3C)c2NCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 279.4 %

Procedure:
To a solution of 4-[2-(tert-butoxycarbonylamino)ethylamino]-1,3-dimethyl-pyrazolo[3,4-b]pyridine-5-carboxylic acid (96.1 mg, 0.275 mmol) in N,N-dimethylformamide (2.5 ml) was subsequently added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (91.8 mg, 0.479 mmol), 3-hydroxytriazolo[4,5-b]pyridine (39.7 mg, 0.292 mmol) and triethylamine (0.115 ml, 0.825 mmol). The reaction mixture was stirred for five minutes after which (4-methoxyphenyl)methanamine (0.072 ml, 0.550 mmol) was added. The reaction mixture was stirred at room temperature over night. The reaction mixture was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was separated and the aqueous phase was further extracted with EtOAc (3×40 ml) and dichloromethane (1×50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 360 mg of a yellow liquid which was purified by column chromatography (silicagel using a gradient of MeOH (1-7%) in dichloromethane) to give 43 mg of a colorless sticky oil (0.092 mmol, 33%) MS (ESI) m/z=469.3 [M+1]+.
Reaction SMILES: [C:1]([O-:7])(=O)[CH2:2][C:3]([CH3:5])=[O:4].[Li+].C(N(CC)CC)C.[CH2:16]([NH:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:17][CH3:18].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClC(Cl)C>[CH:21]1([CH2:20][N:19]([CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:23][CH2:22]1
Reactant: CCCNCC1CC1
Reactant: CC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A stirred mixture of lithium acetoacetate (scheme 2: (G)) (1.00 g, 9.26 mmoles), triethylamine (2.58 mL, 18.5 mmoles), and n-propylcyclopropylmethyl amine (scheme 2: (E)) (1.32 mL, 9.26 mmoles) in dry dichloroethane (60 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) (2.36g, 9.26 mmoles). The mixture was stirred overnight at room temperature, and then acidified (pH˜1) with 1M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over MgSO4. Concentration in vacuo and purification by silica gel chromatography (30% ethyl acetate/hexane) gave 900 mg of a yellow oil.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:31]([C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1)[CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[F:2][CH2:3][CH2:4][CH:5]=[CH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C@H:39]2[CH2:40][CH2:41][C@H:36]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38]2)[CH2:43][CH2:44]1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C=CCCF)CC2)CC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (6.9 g, 17.1 millimols) with THF (40 ml) was cooled down to -20° C., followed by adding t-BuOK (1.9 g, 17.1 millimols) to the mixture, stirring the mixture for 30 minutes, dropwise adding to the mixture, a THF (30 ml) solution of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarbaldehyde (4.1 g, 15.5 millimols) so as to keep the temperature at -20° C., stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 1, except that the quantity of ethyl acetate used for extraction was made 150 ml, to obtain raw trans-(trans-4-(4-fluorobutenyl)cyclohexyl)-4-pentylcyclohexane (4.2 g).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17]O>>[S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc2c(s1)CCNC2
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(s1)CCNC2

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (1 eq) obtained in step IV in methanol was added thionyl chloride (1.5 eq) at 0° C., and the reaction was refluxed for 3.0 h Reaction mixture was concentrated and neutralized to afforded the methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH3:25])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:27](=[O:29])[CH3:28]>>[C:27]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH3:25])[C:19]=1[OH:18])(=[O:29])[CH3:28]
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Product: CC(=O)c1ccc(OCc2ccc(Sc3cncc(C#N)c3)cc2)c(C)c1O
Yield: 40.7 %

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (0.86 g, 5.20 mmol) affords the title compound (787 mg, 41%): 1H NMR (d6-DMSO) δ 2.06 (s, 3H), 2.58 (s, 3H), 5.30 (s, 2H), 6.72 (d, J=9.0 Hz, 1H), 7.51-7.55 (m, 4H), 7.81 (d, J=9.0 Hz, 1H), 8.23 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 2H), 8.91 (d, J=2.0 Hz, 1H), 12.85 (s, 1H).