Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][CH:8]([C:19]([O:21][CH3:22])=[O:20])[C:7](=O)[C:6]=2[CH:24]=1.[BH4-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:9][C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][C:6]=2[CH:24]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)c2ccc(Br)cc2C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Temperature: -15 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
In THF (150 ml) was dissolved methyl 7-bromo-1-(t-butoxycarbonyl)-1,2,3,4-tetrahydro-1-benzazepin-5-one-4-carboxylate (7.2 g). To the solution was added sodium borohydride (0.7 g) at −40° C., and then was added dropwise methanol (15 ml). The mixture was stirred at −15° C. for 1 hour. To the mixture was added 1M citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in THF (150 ml), and to the solution was added triethylamine (7.5 ml). To the mixture was added dropwise, under ice-cooling, methanesulfonyl chloride (2.1 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature for 1.5 hours, and to the mixture was added dropwise DBU (13.5 ml) at room temperature. The mixture was stirred at 90° C. for 10 minutes, and the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (5.18 g) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([Br:19])[CH:13]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Sodium hydride (9.9 g, 0.414 mol, 95% dry) was added in portions to a stirred solution of benzyl alcohol (41.0 g, 0.394 mol) in THF (1.0 L) at room temperature under a nitrogen atmosphere and stirred for 1 h. To this solution was added dropwise 1,3-dibromo-5-fluorobenzene (100.0 g, 0.394 mol). After stirring overnight, the mixture was partitioned with H2O (600 mL) and EtOAc (4×600 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with hexanes afforded the sub-title compound (101.3 g, 75%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:34])([F:35])[F:36])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1)=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: COC(=O)C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 40 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), methyl azetidine-3-carboxylate-HCl (7.54 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-methyl 1-(3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoyl)azetidine-3-carboxylate (11.9 mg, 0.020 mmol, 39.9% yield): LCMS=600.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.26 (2 H, m), 7.54-7.77 (7 H, m), 5.12 (1 H, s), 4.00-4.34 (4 H, m), 3.73 (3 H, d, J=5.27 Hz), 3.39-3.56 (3 H, m), 2.36 (2 H, q, J=6.44 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[C:4]#[N:5].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[N:14]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CN(C=O)C>[Br:12][C:13]1[N:14]=[C:15]([CH2:19][O:1]/[N:2]=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)\[C:4]#[N:5])[CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1cccc(Br)n1
Reactant: N#C/C(=N\O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#C/C(=N\OCc1cccc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (2Z)-(hydroxyimino)(phenyl)acetonitrile (6.0 g, 41.1 mmol, 1 eq.) in 80 ml of acetonitrile and 10 ml of DMF, was added 2-bromo-6-(bromomethyl)pyridine (10.3 g, 41.1 mmol, 1.0 eq.) followed by potassium iodide (681 mg, 4.11 mmol, 0.1 eq.) and caesium carbonate (20.1 g, 61.1 mmol, 1.5 eq.). The reaction was stirred 4 h at room temperature. The solvent was then evaporated and the residue dissolved in EtOAc, subsequently washed with H2O and brine. After separation, the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give (2Z)-{[(6-bromopyridin-2-yl)methoxy]imino}(phenyl)acetonitrile (11.3 g, 86% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[N:19]=[C:18]2[CH2:29][CH2:30][CH2:31][C:17]=12>CO.ClCCl>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:19]=[C:18]3[CH2:29][CH2:30][CH2:31][C:17]3=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[CH:21]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COC(=O)COc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)COc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 43.7 %

Procedure:
An 18-mL vial was charged with methyl 2-(4-aminophenoxy)acetate (24 mg, 0.13 mmol, 2 eq.) and 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture was dissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). After the volatile material was removed under reduced pressure, the residue was heated at 150° C. under argon for 1 hr. After cooling to room temperature, the reaction mixture was partitioned between NaHCO3 aq. (10 ml) and ethyl acetate (10 ml). The organics was separated and dried over MgSO4. The solvent was removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using dichloromethane followed by 0.1˜0.3% methanol in dichloromethane as eluent to give the desired product methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate as white solid (11.8 mg, 44% yield).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CCOC(C)=O.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 92.1 %

Procedure:
The olefin of Example 5 (2.6 g, 8.7 mmol) in EtOAc (50 mL) at room temperature is stirred under a hydrogen atmosphere (1 atm) in the presence of 10% Pd/C (500 mg) overnight. The reaction mixture is then purged with argon, followed by filtration through a Celite pad. Concentration of the filtrate followed by flash chromatography (10% EtOAc in hexane) gave the title ester (2.4 g, 92%) as a crystalline solid.
Reaction SMILES: [OH:1][C:2]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)([CH3:7])[C:3]([NH:5][NH2:6])=O.[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[S:30])=[N:24]2)=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].S(=O)(=O)(O)O.N>C(O)C.O.C(OCC)(=O)C>[F:14][C:15]1[C:16]([CH2:22][N:23]2[CH:27]=[CH:26][C:25]([NH:28][C:29]3[S:30][C:3]([C:2]([C:8]4[S:9][CH:10]=[C:11]([CH3:13])[N:12]=4)([OH:1])[CH3:7])=[N:5][N:6]=3)=[N:24]2)=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccnc(Cn2ccc(N=C=S)n2)c1F
Reactant: Cc1csc(C(C)(O)C(=O)NN)n1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1csc(C(C)(O)c2nnc(Nc3ccn(Cc4nccc(C)c4F)n3)s2)n1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A mixture of Intermediate 107, 2-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)propanohydrazide (82 mg, 0.407 mmol), and Intermediate 79, 3-fluoro-2-[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]-4-methylpyridine (84 mg, 0.340 mmol) in ethanol (6 mL) was heated under reflux for 3 h. Reaction mixture was concentrated and residue was treated with sulfuric acid (2 mL, 37.5 mmol) at 0° C., and the resulting mixture was allowed to reach room temperature overnight. Reaction mixture was placed in an ice-bath and treated slowly and dropwise with 37% aq. NH3 (10 mL) until pH was basic. Mixture was diluted with water and ethyl acetate (60 mL). Organic phase was separated, washed with brine, dried over sodium sulfate and concentrated. Crude was loaded on a silica cartridge and eluted with a linear gradient, 0-5% MeOH-DCM, affording 100 mg (68.3% yield) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.81 (s, 1H), 8.19 (d, 1H), 7.71 (s, 1H), 7.33-7.31 (m, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 5.93 (s, 1H), 5.33 (s, 2H), 2.28 (br s, 6H), 1.96 (s, 3H). [ES+MS] m/z 432 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.CO[C:11](=O)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[CH:30][C:24]=4[C:23]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1(C)C=CC=CC=1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[O:28][C:25]3[CH:26]=[CH:27][N:22]([C:18]4[CH:17]=[C:16]5[C:21](=[CH:20][CH:19]=4)[N:13]([CH2:12][C:11]4[NH:3][CH2:2][CH2:1][N:4]=4)[N:14]=[CH:15]5)[C:23](=[O:38])[C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21
Reactant: NCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CC2=NCCN2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a 0° C. solution of ethylenediamine (68 mL, 1.0 mmol) in toluene (0.36 mL) was slowly added trimethyl aluminium (0.50 mL, 10 M in toluene) over ten minutes. The solution was allowed to stir at 0° C. for 5 minutes; then a suspension of methyl-2-(5-(2-(4-chlorophenyl)-4-oxofuro[3,2-c]pyridin-5(4H)-yl)-1H-indazol-1-yl)acetate (0.22 g, 0.50 mmol) in toluene (7.27 mL) was added and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 18 h; then the reaction mixture was diluted with H2O (2 mL) and the solids were removed by filtration. The filtrate was extracted with CH2Cl2 (3×20 mL) and the extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/9:1 EtOH with NH4OH, 100:0 to 90:10) yielded the title compound (47.6 mg, 21%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (s, 1H), 7.57-7.55 (m, 2H), 7.42 (dd, J=9.0, 2.0 Hz, 2H), 6.89 (d, J=7.0 Hz, 1H), 5.21 (s, 2H) 3.51 (br s, 1H), 3.30 (s, 4H); ESI MS m/z 444 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.8 min.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)#[N:2].C(O)=[O:28]>Cl>[C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)(=[O:28])[NH2:2]
Reactant: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1F
Reactant: O=CO
Agent: Cl
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1F
Reaction time: 24 h
Yield: 65 %

Procedure:
3.73 g of 3-cyano-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one was dissolved in 100 ml of formic acid saturated with hydrogen chloride. The mixture was stirred for 24 hours at 25°-30° C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of water. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 2.54 g (yield: 65%) of 3-carbamoyl-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. The properties (melting point and IR) of this compound agreed with those of the compound obtained in Example 4.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH:31]C(=O)C1C=CC=CC=1)=[N:21]2>CO>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]12[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]1[CH2:24][S:23][C:22]([NH2:31])=[N:21]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 65 °C
Yield: 104.2 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.99 mL, 6.6 mmol) was added to a stirred suspension of N-((4aS,5S,7aS)-7a-(2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (1.34 g, 3.30 mmol) in dry MeOH (10 mL) at RT under nitrogen. The reaction was stirred and heated at 65° C. overnight, under nitrogen. The reaction was allowed to cool to RT and the volatiles were removed in vacuo. The residue was purified by column chromatography (normal phase, 25 g, Biotage SNAP cartridge KP-Sil, 25 mL per min, gradient 20% to 100% EtOAc in n-hexane) to give the title compound (1.04 g). 1H NMR (400 MHz, CDCl3) δ ppm: 2.78 (dd, J=13.33, 4.03 Hz, 1 H) 2.93-3.01 (m, 1 H) 3.09 (dd, J=13.39, 3.61 Hz, 1 H) 3.83 (dd, J=8.44, 2.45 Hz, 1 H) 4.44-4.56 (m, 3 H) 4.62 (d, J=4.40 Hz, 1 H) 6.75-6.92 (m, 2 H) 7.36-7.47 (m, 1 H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)[C:5](=[O:22])[NH:4][NH:3]1>CO.[Pd]>[NH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:2](=[O:1])[NH:3][NH:4][C:5]1=[O:22]
Reactant: O=C(NCCCCn1c(=O)[nH][nH]c1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCCCn1c(=O)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To benzyl 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)butylcarbamate (I-9b: 369 mg, 1.205 mmol) in methanol (4.819 mL) was added 10% Pd/C (51.3 mg, 0.048 mmol). The mixture was stirred at room temperature for 1 hour under 1 atm of H2, filtered over celite, rinsed with more methanol, concentrated in vacuo and dried to give 4-(4-aminobutyl)-1,2,4-triazolidine-3,5-dione (I-9c: 105 mg, 51%) as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.51-1.79 (m, 4 H) 2.94 (t, J=7.20 Hz, 2 H) 3.50 (t, J=6.57 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13](S(C)(=O)=O)[C:14]=3[N:15]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[N:33]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:33])[C:14]=3[N:15]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1nc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 2-(1-Methyl-2,4-diphenyl-1H-imidazol-5-yl)-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 40) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Yellow solid (21 mg, 91%);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 92 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(4-fluorobenzyl)-4-methylthiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 92% yield: mp 223-225° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.67 (t, J=8.1 Hz, 1H), 7.38-7.35 (m, 5H), 7.32-7.27 (m, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.23 (dd, J=8.1, 2.3 Hz, 1H), 6.11 (t, J=5.5 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.03 (s, 2H), 4.54 (d, J=5.5 Hz, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 163.9, 162.2, 160.6, 153.5, 152.3, 134.5, 133.6, 131.5, 129.6, 128.8, 128.7, 127.7, 122.1, 115.8, 104.1, 97.3, 70.8, 43.3, 17.3; (ES+) m/z 450.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:30])([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:30])([F:16])[F:29])=[CH:21][CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(c1ccc(OCC(F)(F)F)nc1)N1Cc2c(ccnc2Cl)C1=O
Temperature: 25 °C
Yield: 32.3 %

Procedure:
A mixture (suspension) of ethyl 3-(bromomethyl)-2-chloroisonicotinate (698 mg, 2.5 mmol, Step-1), 1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (643 mg, 2.5 mmol, Amine-1, single enantiomer) and cesium carbonate (3.3 g, 10.0 mmol) in THF (20 mL) is heated at refluxed temperature overnight. After cooling to rt, the reaction mixture is filtered through a pad of Celite™, and washed with EtOAc. The filtrate is concentrated to give a brown suspension. The residue is purified by column chromatography on NH-gel eluting with n-hexane/EtOAc (4:1) to give 300 mg (32% yield) of the title compound as clear brown oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:14])[CH:3]=1.N(OCCC(C)C)=O.[I:23]CI>>[I:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:14])[CH:3]=1
Reactant: ICI
Reactant: Cc1cc(N)ccc1-c1ccccc1
Agent: CC(C)CCON=O
Product: Cc1cc(I)ccc1-c1ccccc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A stirred solution of 4-amino-2-methyl-1-phenylbenzene (10.49 gm, 57.2 mmol) in diiodomethane (100 mL) was treated with iso-amyl nitrite (27 mL, 200.2 mmol) over 5 mins. The mixture was heated to 75° C. for 45 mins, then at 65° C. for 1 h. After being cooled, the mixture was concentrated under reduced pressure (95° C./30 mmHg) and the residue was purified by flash chromatography (eluting with hexane) to give 4-iodo-2-methyl-1-phenylbenzene (11.6 gm, 66%) as an oil.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:23][CH2:24][CH2:25][OH:26])(=[O:22])[CH3:21]>C(OCC)C.B(F)(F)F.CCOCC>[C:20]([O:23][CH2:24][CH2:25][O:26][C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])(=[O:22])[CH3:21]
Reactant: CC(=O)OCCO
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(OCCOC(C)=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.95 g (31.3 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 20 ml of diethyl ether under N2 and cooled to 0° C., and 5.87 ml (31.3 mmol) of 2-hydroxyethyl acetate (50% strength) and 3 drops of BF3.Et2O were added. After removal of the ice bath, the mixture was stirred at RT for 2 h.
Reaction SMILES: O[C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH2:8]([C:3]1[C:4](=[O:7])[CH2:5][CH:6]([O:17][C:14](=[O:16])[CH3:15])[C:2]=1[CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)O
Reactant: CCCCCC1C(=O)C=CC1(C)O
Product: CCCCCC1=C(C)C(OC(C)=O)CC1=O

Procedure:
In the same apparatus as in Example 1, 3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g) and acetic acid (55 ml) were charged and heated under reflux for 15 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (80 ml) and water (50 ml) and treated as in Example 1 to obtain 2-n-pentyl-3-methyl-4-acetoxy-2-cyclopentenone (20.6 g). Yield, 92%. B.P., 125°-135° C./0.2-0.5 mmHg.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:21]3[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:18]=[CH:17][C:16]=3[NH:15]/[C:14]/2=[N:31]\C(C2C=CC3C=CSC=3C=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][C:52]=1[F:53])[C:47]([OH:49])=O>>[Cl:43][C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][C:52]=1[F:53])[C:47](/[N:31]=[C:14]1/[N:13]([C@H:10]2[CH2:9][CH2:8][C@@H:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:2])[CH3:3])[CH2:12][CH2:11]2)[C:21]2[CH:20]=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:18]=[CH:17][C:16]=2[NH:15]/1)=[O:49]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc4ccsc4c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)c(Cl)c3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Yield: 45.4 %

Procedure:
The title compound was prepared using a method analogous to the preparation of (E)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzo[b]thiophene-6-carboxamide, using 3-chloro-4-fluorobenzoic acid. The material was purified via preparative HPLC (0.1% NH4OH in ACN/H2O) to provide (E)-3-chloro-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (45.4% yield). MS m/z=585.4 [M+H], calc 585.12 for C30H38ClFN6O3.