Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][C@H:24]([C:44]([OH:46])=[O:45])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:38][C:39]3[S:40][CH:41]=[CH:42][N:43]=3)[CH2:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)OC(=O)CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccs1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)CN(CCCC[C@H](N)C(=O)O)Cc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
Piperidine (0.20 mL) was added to a solution of (S)-1-(9H-fluoren-9-yl)-14,14-dimethyl-3,12-dioxo-10-(thiazol-2-ylmethyl)-2,13-dioxa-4,10-diazapentadecane-5-carboxylic acid (72.5 mg, 0.125 mmol) in DMF (1.0 mL). The mixture was stirred at room temperature for 2 hrs. Solvent was evaporated under reduce pressure to afford a residue, which was purified by flash chromatography over silica gel to afford (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)(thiazol-2-ylmethyl)amino)hexanoic acid (25 mg, 35%). 1H NMR (400 MHz, CD3OD) 7.70 (d, J=3.6 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 4.15 (s, 2H), 3.52 (dd, J=7.2, 5.2 Hz, 1H), 3.38 (s, 2H), 2.73 (t, J=7.2 Hz, 2H), 1.91-1.76 (m, 2H), 1.60-1.44 (m, 13H); MS (ESI), 358 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]([CH2:26][CH3:27])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:26]([N:24]([CH3:25])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N(C)CC)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCN(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 18 h
Yield: 96.6 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(Ethyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (337, 650 mg, 1.77 mmol) is charged with 1,4-dioxane (10 mL) and MeOH (10 mL). A stirring bar is added and stirring is initiated. After dissolution, water (5 mL) is added followed by the LiOH monohydrate (187 mg, 4.46 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (1 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 18 h, the contents of the flask are filtered through a pad of celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed under reduced pressure. This process is repeated 1 time. Pumping to constant weight gives beige solid (0.58 g, 97%).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][CH:20]=1)[O:9][CH2:10][CH2:11][CH:12]1[O:17]CCCO1)([CH3:5])([CH3:4])[CH3:3]>C1COCC1>[C:2]([C:6]1[CH:7]=[C:8]2[C:18]([CH:12]([OH:17])[CH2:11][CH2:10][O:9]2)=[CH:19][CH:20]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)OCCC2O
Temperature: 0 °C

Procedure:
Concentrated hydrochloric acid (70 mL) was cooled in an ice bath and then about 40 mL of THF was added and stirred. At 0° C. with stirring was added 2-[2-(3-tert-Butyl-phenoxy)-ethyl]-[1,3]dioxane (8.48 g, 32.1 mmol) slowly in THF (30 mL). After the addition was complete the ice bath was removed and the resulting mixture was stirred vigorously at room temperature for 3 hours. Then ether was added (300 mL) and the layers were separated, and the organic layer was extracted with water (3×100 mL) and finally dried over magnesium sulfate, filtered and concentrated to give the title compound as a light yellow oil and used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@@H:16]1Br)(=[O:13])[CH3:12]>C(Cl)Cl.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:11]([O:14][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:16]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: CC(=O)c1ccc(O)cc1
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C(C)=O)cc1
Yield: 15.9 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 2 g (14.7.10-3 mol) of 1-(4-hydroxyphenyl)ethanone, 2.8 g (16.10-3 mol) of silver imidazolate, 5.74 g (16.1.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4 g (29.3.10-3 mol) of zinc chloride in 100 ml of methylene chloride, 0.96 g (yield: 18%) of the expected product is obtained after purification by chromatography on silica gel using a toluene/ethyl acetate mixture (6/1 v/v) as the eluent.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][C:20]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][N:34]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:28]=2)=[N:21][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[CH3:26][O:25][C:23]([C:22]1[N:21]=[C:20]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33][N:34]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:28]=2)[CH:19]=[CH:18][C:17]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[O:24]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (1.93 g, 6.86 mmol) was added dropwise to tert-butyl 7-(5-hydroxy-6-(methoxycarbonyl)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29D) (2.40 g, 6.23 mmol) and TEA (0.95 g, 9.35 mmol) in anhydrous DCM (25 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hours, diluted with DCM, washed with 10% citric acid, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 88:12-82:18 to provide tert-butyl 7-(6-(methoxycarbonyl)-5-(trifluoromethylsulfonyloxy)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29E): 1H NMR (300 MHz, CDCl3) δ 8.40 (1H d), 7.95 (1H, d), 7.71 (1H, d), 7.66 (1H, dd), 7.19 (1H, d), 4.04 (3H, s), 3.75 (2H, m), 2.82 (2H, t), 1.96 (2H, m), 1.56 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Yield: 37 %

Procedure:
Intermediate 27(a) (3.6 g, 13.2 mmol) and a 5% aqueous KOH solution (90 mL, 80.0 mmol) were stirred in tetrahydrofuran (30 mL, 0.44 M) at 22° C. for 2 hours. The volatiles were removed in vacuo and treatment with strongly acidic Dowex-50™ (WX8-200), elution with ammonium hydroxide (1.0 N), and treatment with Amberlite™ CG-50 afforded Intermediate 27(b) (1.2 g) in 37% yield.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[N:6]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:7]=[CH:8][C:9]=1[N:10](C)C)(=O)[CH3:2].[NH2:18]N>C(O)C>[C:13]([N:6]1[C:5](=[O:17])[C:4]2[C:1]([CH3:2])=[N:18][NH:10][C:9]=2[CH:8]=[N:7]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: NN
Reactant: CC(=O)c1c(N(C)C)cnn(C(C)(C)C)c1=O
Solvent: CCO
Product: Cc1n[nH]c2cnn(C(C)(C)C)c(=O)c12

Procedure:
4-Acetyl-2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (2.5 g) was added to hydrazine (3.2 g)/ethanol (30 ml) and the mixture was refluxed for 6 hours. After the ethanol-hydrazine was distilled off, the residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane and diethyl ether and dried. White powder, 1.7 g. 1H-NMR (CDCl3) 6: 1.70(9H,s), 2.74(3H,s), 8.10(1H,s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>FC(F)(F)C(O)=O.O=[Pt]=O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc2c(n1)CCCC2)OCC

Procedure:
A solution of compound 58a (6.0 g, 17 mmol) in trifluoroacetic acid (20 mL) was hydrogenated at about 2 to 3 atm over PtO2 (0.4 g, 1.8 mmol) at 30° C. for 20 h. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:2 v/v)) to obtain compound 58b as a colorless oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H27N5O3: 284.1 (M+H). Found: 284.2.
Reaction SMILES: [C:1]12([CH2:8][OH:9])[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[C:1]12([CH2:8][O:9][C:12]3[C:11]([Cl:10])=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[C:14]([F:24])[CH:13]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OCC12CCCCC1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A mixture of bicyclo[4.1.0]heptan-1-ylmethanol (0.86 g, 6.80 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (1.69 g, 6.80 mmol) and cesium carbonate (4.40 g, 13.7 mmol) in anhydrous dimethylsulfoxide (15 mL) was heated at 100° C. under nitrogen for 16 hours. The reaction mixture was filtered through a pad of diatomaceous earth and rinsed with ethyl acetate (100 mL). The organic layer was washed with 1.0 M hydrochloric acid (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was purified by column chromatography with a mixture of hexanes in ethyl acetate (9:1) to afford the title compound as a white solid (1.30 g, 54%): 1H NMR (300 MHz, CDCl3) 7.85 (d, J=18.4 Hz, 1H), 6.54 (d, J=12.20 Hz, 1H), 3.81 (d, J=9.1 Hz, 1H), 3.68 (d, J=9.1 Hz, 1H), 1.98-1.79 (m, 4H), 1.39-1.29 (m, 3H), 1.56 (s, 9H), 1.02-0.94 (min, 1H), 0.89-0.83 (m, 1H), 0.67-0.62 (m, 1H), 0.40-0.37 (m, 1H); MS (ES+) m/z 377.2, 379.2 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccncc2F)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccncc2F)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 3-(3-fluoro-pyridin-4-yl)-5-methyl-isoxazole-4-carboxylic acid (0.41 g, 0.0019 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.55 g, 0.0019 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.36, 0.0019 mol), 1-hydroxy-7-azabenzo-triazole (0.25 g, 0.0019 mol), and N,N-diisopropylethyl amine (0.96 mL, 0.0055 mol), in N,N-dimethylformamide (10 mL). Stir the mixture overnight at ambient temperature. Concentrate in vacuo and take up the residue in water and extract with ethyl acetate. Concentrate and elute over silica gel using methanol/dichloromethane resulting in the isolation of 0.66 g (76%) of the desired amide as a light yellowish solid. MS(ES): (M+1)+ 467.0, 468.1 m/z.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=3)[N:17]=2)=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(-c2cncc(CCc3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.8 %

Procedure:
To a solution of 4-methyl-2-{6-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-pyrazin-2-yl}-thiazole-5-carboxylic acid benzylamide (40 mg, 0.08 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd(OH)2 (10 mg, 20%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 3 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 4-methyl-2-{6-[2-(4-trifluoromethyl-phenyl)-ethyl]-pyrazin-2-yl}-thiazole-5-carboxylic acid benzylamide (20 mg, 50%). 1H NMR (400 MHz, CD2Cl2) δ 9.16 (s, 1H), 8.39 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.28-7.37 (m, 7H), 6.25 (bs, 1H), 4.60 (d, J=8.0 Hz, 2H), 3.19 (apparent s, 4H), 2.72 (s, 3H); HRMS (M+H)+=483.14.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cccc(Cl)c2Cl)c1Br
Yield: 75 %

Procedure:
2,3-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3-dichlorobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 166°-169° C., yield 75%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]([Sn](CCCC)(CCCC)CCCC)=[N+:26]=[N-:27]>C1(C)C=CC=CC=1>[N:25]1[NH:26][N:27]=[N:18][C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: Cc1ccccc1
Product: Nc1cccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1

Procedure:
The title compound was prepared from 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.273 g, 0.86 mmol), azidotributyl tin (0.314 g, 0.260 mL, 0.95 mmol) in toluene (10 mL). The reaction mixture was heated to reflux temperature for 12 hours resulting in partial conversion to the desired product along with partially and fully deprotected final products. An additional amount of azidotributyl tin was added (0.260 mL) and the reaction was heated to reflux temperature for 18 hours. Toluene was removed under reduced pressure and the crude was dissolved in 5 mL of 1,4-dioxane, 5 mL of 6.0 N aqueous hydrogen chloride, and 2 mL of methanol. The reaction was then heated to 60° C. for 2 days. The reaction was concentrated under reduced pressure and the pH was made basic by adding 2.0 N aqueous NaOH. The aqueous phase was washed with ethyl acetate (3×10 mL). The aqueous phase was then acidified using 6.0 N aqueous hydrogen chloride. The compound was filtered and purified by preparative HPLC (10-100% acetonitrile in H2O, 20 min) (0.050 g, 0.18 mmol, 21% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.8 (br s, 1H), 8.9 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.8 (d, 1H), 7.6 (t, 1H), 7.3 (d, 1H); ES-MS (m/z) 278 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])C(OCC)=O)=[CH:5][CH:4]=1.Br.O>CC(O)=O>[F:18][C:17]([F:19])([F:20])[C:16](=[O:21])[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)C(F)(F)F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCc1ccc(O)cc1)C(F)(F)F
Temperature: 120 °C

Procedure:
A 100 mL round bottom flask, fitted with reflux condenser, magnetic stirrer and argon inlet was charged with 2.05 g (6.7 mM) of ethyl 3-(4-methoxyphenyl)-2-(1-oxo-2,2,2-trifluoroethyl)propionate, 20 mL of 31% HBr in AcOH, and 10 mL of water. This mixture was heated overnight at 120° C., concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was extracted with aqueous bisulfite, saturated sodium bicarbonate, dried (anhydrous MgSO4), and the solvent removed under reduced pressure. The crude reaction mixture was chromatographed on a 50×300 mm silica gel column with 1:1 ethyl acetate:hexane. Similar fractions were combined and solvent was removed under reduced pressure to yield 600 mg (41%) as a clear oil. nmr(CDCl3)--α2.95(m, 4H), 4.90(bs, 1H), 6.93(dd, 4H) J=4, 60 Hz.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH2:27][CH3:28])[N:9]=1.ON1C2C=CC=CC=2N=N1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH2:27][CH3:28])[N:9]=1
Reactant: CCC1N=C(c2ccccc2Cl)c2cc(CCC(=O)O)sc2-n2c(C)nnc21
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC1N=C(c2ccccc2Cl)c2cc(CCC(=O)N3CCOCC3)sc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1 g of 3-[4-(2-chlorophenyl)-6-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.23 ml of morpholine and stirred at room temperature for 10 minutes. To the mixture is added 0.6 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 18 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 100 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from a mixture of isopropyl ether-ethyl acetate (1:1) to give 0.8 g of 3-[4-(2-chlorophenyl)-6 -ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-2-yl]propionic acid morpholide as colorless crystals, melting at 145°-147° C.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.Cl.[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C.C(N(CC)CC)C.ClCCl>[CH3:29][O:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][C:37]([S:41]([NH:8][C@H:9]3[CH2:13][CH2:12][N:11]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=5)[CH2:19][CH2:20]4)[C:10]3=[O:27])(=[O:43])=[O:42])=[CH:38]2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(NC4CCN(c5ccncc5)CC4)C3=O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) in methanol (10 ml) was combined with a 4N solution of hydrochloric acid in ethyl acetate (10 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue obtained was combined with dichloromethane (20 ml) and triethylamine (700 ml), followed by 7-methoxynaphthalene-2-sulfonyl chloride (150 ml) at 0° C., and then stirred at room temperature for 1 hour. The reaction mixture was combined with an aqueous solution of sodium carbonate, extracted with dichloromethane, dried, concentrated and purified by a column chromatography dichloromethane: 10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (123 mg) as a colorless amorphous material.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:31].[Na+].[K+]>C1(C)C=CC=CC=1>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:31])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C#N)cc1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (which may be prepared as described in Preparation of Intermediate 16; 15.21 g, 61.5 mmol) in toluene (100 mL) at 0° C. under argon was added dropwise di-isobutylaluminum hydride (1.0 M in toluene, 15 mL, 15 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, after which it was cooled to 0° C. and charged with 100 mL of saturated aqueous Rochelle salt solution. The mixture was allowed to stir for 14 hours after which the mixture was extracted three times with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde which was used without further purification. To a solution of the aldehyde in ethanol was added hydroxylamine hydrochloride (4.66 g, 67 mmol) and pyridine (5.4 mL, 67 mmol). The reaction mixture was stirred until no starting material was observed by TLC and then all volatiles were removed under reduced pressure. The resulting product was suspended in water and the aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde oxime (14.60 g, 90%) as a white solid. LRMS (ESI+): m/z [M+H]+ 266.1; 1H NMR (300 MHz, CDCl3) δ ppm 11.12 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.24 (d, 1H), 4.64 (s, 2H), 0.82 (s, 9H), 0.03 (s, 6H).