Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]2[O:16][C:15](=[O:17])[NH:14][C@H:13]2[CH3:18])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[Br:21][C:22]1[C:23]([CH2:29]Br)=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1>C1COCC1>[Br:21][C:22]1[C:23]([CH2:29][N:14]2[C@@H:13]([CH3:18])[C@@H:12]([C:4]3[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([F:1])[CH:3]=3)[O:16][C:15]2=[O:17])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reaction time: 1.5 h

Procedure:
To a cold (ice/methanol bath) mixture of (4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 93) (5000 mg, 19.00 mmol) in THF (100 ml) was added sodium hydride (912 mg, 22.80 mmol) all at once. The resulting mixture was stirred cold (ice bath) for 1.5 hrs followed by addition of 3-bromo-2-(bromomethyl)-6-chloropyridine (INTERMEDIATE 30) (5963 mg, 20.90 mmol). The reaction mixture was allowed to slowly warm to ambient in 3 hrs. The reaction was cooled (ice bath) and quenched by HCl (1N, aq.). The resulting mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure to afford an oil. This oil was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 40% ethyl acetate). Related fractions were pooled and concentrated in vacuo to afford a light amber gum of 8.2522 g as the titled compound. LCMS calc.=465.97. found=468.91.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=3)[S:10][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:16][N:12]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]=2)=[CH:15][N:14]=[CH:13]1
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: Nc1ccccc1
Product: Cn1cncc1-c1cc2nccc(Nc3ccccc3)c2s1

Procedure:
The title compound was prepared from 7-Chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine and aniline by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.18 (d, 1H), 7.77 (s, 1H), 7.39 (s, 1H), 7.37 (m, 3H), 7.28 (m, 2H), 7.18 (t, 1H), 6.80 (d, 1H), 3.86 (s, 3H); RP18-HPLC RT: 3.93 minutes; API MS: 307 (M+1).
Reaction SMILES: [C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25](OS(C(F)(F)F)(=O)=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[N:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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>[C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([C:51]3[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=3)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OS(=O)(=O)C(F)(F)F)O2
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
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1-c1ccncc1)O2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step 1 (50 mg, 0.073 mmol) in dioxane (5 ml) was added pyridine-4-boronic acid, (35.9 mg, 0.292 mmol), potassium phosphate tribasic (38.7 mg, 0.182 mmol) and tetrakis (16.85 mg, 0.015 mmol). After purging with N2 for 5 min, the reaction was stirred at 80° C. for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Purification by PTLC (40% EtOAc/hexane) provided the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]>O1CCCC1.[Cl-].[Zn+2].[Cl-].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:26][C:23]1[CH:22]=[C:21]([F:27])[CH:20]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: Fc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccccn2)c(F)c1
Temperature: -78 °C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
That is, under argon stream, 8.69 g (55.0 mmol) of 2-bromopyridine was dissolved in 200 ml of dry tetra hydrofuran and cooled to −78° C. To this was dripped 38.7 ml (61.9 mmol) of a 1.6 M hexane solution of n-butyllithium over 30 minutes. After completion of the dripping, further a solution of 7.5 g (55.0 mmol) of zinc chloride in 50 ml of dry tetra hydrofuran was dripped over 30 minutes. After completion of the dripping, the temperature of the mixture was slowly elevated to 0° C. and 9.65 g (55.0 mmol) of 1-bromo-2,4-difluorobenzene and 2.31 g (2.0 mmol) of tetrakis(triphenylphosphine)palladium (0) were added thereto. The mixture was stirred for 6 hours under reflux and then 200 ml of saturated saline was added to the reaction mixture, followed by extraction of the reaction mixture with diethyl ether. After drying the extract, concentration and purification by column chromatography (silica gel; chloroform/hexane (1/1:volume ratio)) afforded 6.00 g (31.4 mmol) of 2-(2,4-difluorophenyl)pyridine as color less transparent oil. Yield: 63%. Identification was performed by elementary analysis of 1H-NMR and elementary analysis of C, H and N.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([CH2:5][O:6][C:7]3[CH:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][C:8]=32)=[N:3][CH:2]=1.[C:16](=O)([O-])[O-].[K+].[K+].CO>C(Cl)Cl>[C:14]([C:12]1[CH:11]=[CH:10][C:8]2[N:9]3[CH:1]=[CH:2][N:3]=[C:4]3[CH2:5][O:6][C:7]=2[CH:13]=1)#[CH:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc2c(c1)OCc1nccn1-2
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc2c(c1)OCc1nccn1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
4H-Imidazo[2,1-c][1,4]benzoxazine-7-carbaldehyde (44 mg, 0.140 mmol) and anhydrous potassium carbonate (120 mg, 0.868 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (5 ml) was added. To the suspension was added dimethyl (1-diazo-2-oxopropyl) phosphonate (0.03 ml, 0.192 mmol). The reaction was stirred at rt for 2 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford desired product (11.9 mg, 0.061 mmol, 43.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C=O.CNC.CI.[Si](C#N)(C)(C)C.CC[CH2:26][CH2:27][N+:28](CCCC)(CCCC)CCCC.[F-]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:26][C:27]#[N:28]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Fc1ccc2[nH]ccc2c1
Agent: C=O
Agent: CNC
Agent: C[Si](C)(C)C#N
Solvent: CI
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.1 %

Procedure:
To a solution of 5-fluoroindole (0.9 g, 6.8 mmol, 1.0 eq.) in a mixture of acetic acid (2 mL) and water (1 mL) were added, at 0° C., formaldehyde (720 μL, 37% in H2O, 8.9 mmol, 1.3 eq) and dimethylamine (1.23 mL, 40% in H2O, 10.9 mmol, 1.7 eq). The mixture was stirred at room temperature for 6 hours and then, quenched with ice and 5 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane and then, the organic layer was dried over MgSO4 and partially evaporated. To the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere, anhydrous toluene (40 mL) and methyl iodide (824 μL, 13.2 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (60 mL) were added, under an argon atmosphere, TMSCN (1.25 mL, 9.9 mmol, 1.5 eq.) and TBAF (19.9 mL, 1M, 19.9 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: heptane/CH2Cl2, 80:20 to 40:60) to afford (5-fluoro-1H-indol-3-yl)-acetonitrile as beige oil (0.70 g, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]1[C:9]3([C:17]4[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=4)[NH:11][C:10]3=[O:19])[NH:8][CH:7]([CH3:25])[CH2:6][C:5]2=1.[C:26]([Cu])#[N:27].CCOC(C)=O>CN1CCCC1=O.CCCCCC>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]12[C:20]2[NH:21][C:22]3[C:4](=[CH:3][C:2]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:5]=2[CH2:6][CH:7]([CH3:25])[NH:8]1
Reactant: CC1Cc2c([nH]c3ccc(Br)cc23)C2(N1)C(=O)Nc1ccc(Cl)cc12
Reactant: N#C[Cu]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1Cc2c([nH]c3ccc(C#N)cc23)C2(N1)C(=O)Nc1ccc(Cl)cc12
Reaction time: 0.5 h

Procedure:
Compound 63 (30 mg, (1072 mmol), CuCN (9.67 mg, 0.108 mmol) in N-methylpyrrolidone (0.12 mL) was refluxed for 16 hr. The solvent was removed under reduced pressure overnight and the black residue was stirred for 30 minutes with 30% aq. ammonia (0.2 mL), followed by addition of chloroform. An insoluble material was tittered off and washed 5 times with boiling chloroform. The organic phases were combined, washed with water and dried with sodium sulfate. The product was isolated using flash column chromatography with 10% 35% EtOAc in hexane (3.0 mg, 11.5%). 1H NMR (300 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.54 (s, 1H), 7.99 (s, 1H), 7.92-7.83 (m, 3H), 7.05 (d, J=2.1 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.98-3.85 (m, 1H), 2.85 (dd, J=15.5, 3.6 Hz, 1H), 2.42 (dd, J=15.3, 10.5 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H); MS (ESI) m/z 363.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH:20]([CH3:22])[CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH:20]([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)c1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC(C)c1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 48 h

Procedure:
1.49 g of 4-dimethylamino-benzaldehyde are added to a solution of 0.88 g of 1,3-diamino-2-isopropyl-imidazolium chloride in 15 ml of glacial acetic acid. After allowing the reaction mixture to stand at room temperature for 2 days, the product is crystallized out by the addition of ether and then recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-isopropyl-imidazolium chloride of melting point 241°.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][C:9]2(C(OCC)=O)[CH2:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:31]([O:33]CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][CH:9]2[CH2:13][C:12]3[CH:14]=[C:15]([CH2:31][OH:33])[CH:16]=[CH:17][C:11]=3[O:10]2)=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: CCOC(=O)C1(COCc2ccc(F)cc2)Cc2ccccc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc2c(c1)CC(COCc1ccc(F)cc1)O2
Yield: 83 %

Procedure:
Following the process described in example 18 (point C), starting from ethyl 2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-2-carboxylate (7.00 g, 23.2 mmol), LiAlH4 (3.51 g, 92.6 mmol) and dry ethyl ether (300 ml), the title compound was prepared (83% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17]C3CCCCO3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(C)c21
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of crude [1-hydroxy-4-methyl-6-(tetrahydro-pyran-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester in THF (30 mL), was added dilute hydrochloric acid (6M, 3 mL) at 0° C. The mixture was allowed to warm to room temperature over 1 hour then concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane=1:1) to give the product as a light brown gum (2.1 g, 62%, 2 steps). 1H NMR (400 MHz, DMSO-d) δ ppm 9.21 (s, 1H), 9.01 (s, 1H), 6.86 (d, J=2.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 5.40-5.37 (m, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.35-3.01 (m, 1H), 2.19-2.13 (m, 4H), 1.10 (t, 3H). MS (ESI) m/z=251 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](=O)([O:17]CC)[NH2:16]>[Cl-].[Zn+2].[Cl-]>[C:8]1([C:7]2[C:6]3[CH:5]=[CH:4][S:3][C:2]=3[NH:1][C:15](=[O:17])[N:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(N)=O
Reactant: Nc1sccc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 10.0 g of 2-amino-3-benzoylthiophene, 16.57 g of ethyl carbamate and 1.00 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is washed with chloroform, then with water, and filtered to give a solid of 4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one. Recrystallization from a mixture of ethanol and dimethylformamide gives crystals having a melting point of 247° - 249°C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[C:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:5][N:4]=1.[BH4-].[Na+]>C(O)C>[C:12]1([CH:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]3[C:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:5][N:4]=[C:3]3[CH2:2][O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCCCCc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccccc1)OC2
Yield: 38.5 %

Procedure:
2-(3-Hydroxymethyl-5-undecyl-1,2,4-triazol-4-yl)benzophenone (2.7 g) obtained in Example 23 was dissolved in ethanol (30 ml). Thereto was added sodium borohydride (240 mg) with stirring and the mixture was stirred at room temperature for 2 hours. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added thereto and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (150 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography. The oily substance obtained was crystallized from hexane to give 1 g of 6-phenyl-1-undecyl-4H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazepine, melting point 83°-84° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:26][CH:27]2[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]2)=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:9]=1[NH2:10])(=O)[CH3:2].O.[NH2:39]N>CN1C(=O)CCC1>[CH3:2][C:1]1[C:4]2[C:5]([CH2:26][CH:27]3[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[N:6][C:7]3[N:8]([N:11]=[CH:12][C:13]=3[C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:9]=2[NH:10][N:39]=1
Reactant: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(C)=O)CC1
Reactant: NN
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1n[nH]c2c1c(CC1CCC(C(=O)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 4-((6-acetyl-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4o, 72 mg, 0.144 mmol). To this vial was added NMP (2 mL) followed by hydrazine monohydrate (1 mL). The reaction was stirred at room temperature for 18 hours. At 18 hours, the hydrazine monohydrate was removed in vacuo and the crude 4-((7-amino-6-(1-hydrazonoethyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarbohydrazide (Int-4p) was transferred into 2-5 mL microwave vessel. The vial was sealed and heated to 200° C. for 45 minutes in microwave. After 45 minutes, the NMP was removed in vacuo using chlorobenzene as a cosolvent. The residue was dried on high vacuum over night. The crude 4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarbohydrazide (Int-4q) was taken up in 4 N HCl in 1,4-dioxane (2 mL). To this was added H2O (1 mL). This solution was stirred at 70° C. for 2 hours. After 2 hours, the solvent was removed in vacuo. The residue was purified via reverse-phase preparatory HPLC to yield 4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylic acid (5) (m+H=467.23, retention time=3.66 min).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([N:25]=[N+]=[N-])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([NH2:25])[N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nc(N=[N+]=[N-])cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Nc1nc(N)cc(-n2cnc3ccccc32)n1)c1ccccc1
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a suspension of of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-azidopyrimidine (11 mg, 0.03 mmol) in ethanol (1 mL) was added 10% palladium on carbon (11 mg), then the mixture was charged with H2 via balloon. The reaction mixture was stirred for 2 h, then filtered over packed Celite and rinsed thoroughly with EtOAc. The solvent was concentrated under reduced pressure, and the crude material was purified by preparative thin layer chromatography eluting with 3% MeOH/CH2Cl2 to afford 6.2 mg of the title compound. Mass spectrum 331.2 (CI, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](O)([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([CH3:15])=[CH2:14])[CH:9]=2)[CH:4]=1
Reactant: COc1ccc2cc(C(C)(C)O)ccc2c1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=C(C)c1ccc2cc(OC)ccc2c1

Procedure:
A solution of 1.22 g 2-methoxy-6-(1-hydroxy-1-methylethyl)naphthalene in 25 ml hexamethylphosphoramide (HMPA) was heated to 240° C. for 15 minutes. The solution was cooled, poured into water, and the brown solid which had formed was filtered off and washed with isopropanol. Recrystallization of the brown solid from isopropanol gave 2-methoxy-6-isopropenylnaphthalene, mp 101° to 103 5° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:63])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:26]([O:57][CH3:58])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:55][CH3:56])[C@@H:36]([CH3:54])[C:37]([NH:39][C@@H:40]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[C:41]([NH2:43])=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:3])=O.[O:64]=[C:65]1[CH:69]=[CH:68][C:67](=[O:70])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH2:79])=[O:77]>>[O:70]=[C:67]1[CH:68]=[CH:69][C:65](=[O:64])[N:66]1[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][C:76]([NH:78][NH:79][C:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:63])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:26]([O:57][CH3:58])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:55][CH3:56])[C@@H:36]([CH3:54])[C:37]([NH:39][C@@H:40]([CH2:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[NH:47][CH:46]=1)[C:41]([NH2:43])=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:77]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(N)=O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157, from N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O>C1COCC1.CCOCC>[C:7]1([C:13]2([CH2:18][NH2:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CC1(c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCC1(c2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirring (mechanical stirring) suspension of 12 gm (0.315 mol) of lithium aluminum hydride in THF (600 ml) in a 2000 ml reaction flask at 0° C. (ice-bath), 35 gm (0.20 mol) of phenylcyclopentane carbonitrile in 100 ml THF is added dropwise via an addition funnel. The ice bath is replaced with a heating mantle and the reaction is heated at reflux for 16 hours. The reaction mixture is diluted with 500 ml ether and cooled down to 0° C. The reaction is worked up by adding 50 ml of 15 wt. % NaOH aqueous solution dropwise with vigorous stirring. Then 20 ml water is added and the mixture is stirred for an addition 10 minutes. The resulting two-phase mixture (a colorless liquid and a white precipitate) is filtered and the filtrate dried over anhydrous MgSO4. Filtration and concentration at reduced pressure on a rotary evaporator gave 33 gm of [(phenylcyclopentyl)methyl]amine.