Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:5][CH:6]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[CH:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cc1ccc(/C=C\OC(C)(C)C)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(OC(C)(C)C)C1c1ccc(C)cn1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
The solution of (Z)-2-(2-tert-butoxyvinyl)-5-methylpyridine (12-3) (1.20 g, 6.27 mmol) in toluene (20 mL) and anhydrous copper sulfate (100 mg, 0.63 mmol) was heated to 75° C. Then the solution of ethyl diazoacetate (2.17 g, 18.8 mmol) in toluene (10 mL) was added dropwise over 2 h. It was heated for another 2 h after the addition was completed. The mixture was restored to room temperature for overnight. The solvent was removed under reduced pressure and the residue was purified by silca gel chromatography with gradient eluent (PE/EA=40/1; 20/1; 10/1). The product was obtained as a yellow oil (500 mg, 34%). LRMS (ES) calculated M+H for C16H24NO3: 278.3. Found: 278.2.
Reaction SMILES: [CH2:1]([C:8]1[N:9]([S:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:20])[CH2:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)C.[Pd]>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:11](=[C:12]([F:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][N:9]1[S:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)N1Cc2c(F)cccc2C=C1Cc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)CCS(=O)(=O)N1Cc2c(F)cccc2CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.5 %

Procedure:
Under a hydrogen atmosphere, 9 mg of methyl 3-[(3-benzyl-8-fluoroisoquinolin-2(1H)-yl)sulfonyl]propanoate and 9 mg of 10% Pd/C were dissolved in 1 mL of ethanol, followed by stirring at room temperature for 2 hours. After completion of the reaction, to the reaction liquid was added diethyl ether, followed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 10 mg (yield 100%) of a title compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].[CH:15]1([C@@H:21]([NH2:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:15]1([C@@H:21]([NH:23][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=2)[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: C[C@H](N)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 5 ml of ethyl acetate and 0.30 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.22 g of (1S)-1-(cyclohexyl)ethylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to obtain 0.37 g of N-((1S)-1-cyclohexylethyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 37 of the present invention) represented by the formula:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9]([C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[CH:10][NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].ClC1C2C(=CC([N+]([O-])=O)=CC=2)N=CC=1[C:38](OCC)=[O:39].COC1C=CC(NN)=CC=1>>[CH3:38][O:39][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:9]3=[CH:10][NH:11][C:12]4[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[C:8]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Reactant: O=c1c2c[nH]c3cc([N+](=O)[O-])ccc3c-2nn1-c1ccccc1
Agent: COc1ccc(NN)cc1
Product: COc1ccc(-n2nc3c4ccc([N+](=O)[O-])cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described 12a using 11a and 4-methoxyphenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 3.76 (3H, s), 7.02 (2H, d, J=9.34 Hz), 8.02 (2H, d, J=9.06 Hz), 8.27 (1H, dd, J=8.79, 2.19 Hz), 8.39 (1H, d, J=8.79 Hz), 8.52 (1H, q, J=2.20 Hz), 8.88 (1H, d, J=6.04 Hz). m/z 337.3 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=1[Cl:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.O>[NH2:27][C:22]1[C:21]([Cl:30])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:25]([Cl:26])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc([N+](=O)[O-])c1Cl)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
To a stirred mixture of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-nitrobenzene (433 mg), ferric chloride hexahydrate (17.5 mg) and activated carbon (17.5 mg) in a mixture of methanol (2.78 ml) and water (0.69 ml) was added hydrazine monohydrate (0.135 ml) dropwise at 60-70° C. After the addition was finished, the mixture was refluxed for half an hour. The mixture was allowed to cool and filtered. The filtrate was concentrated in vacuo. The residue was extracted with dichloromethane and the organic phase was dried over anhydrous magnesium sulfate. After being filtered, the filtrate was concentrated in vacuo and the resulting residue was washed with n-hexane to give 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzene (348 mg) as a white mass.
Reaction SMILES: [NH3:1].C(Cl)(Cl)Cl.[C:6]([N:11]=[C:12]=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]>ClCCCl>[C:6]([NH:11][C:12]([NH2:1])=[O:13])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: N
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(N)=O

Procedure:
Gaseous ammonia was blown into dry chloroform (50 g) to prepare a chloroform solution containing ammonia (0.18 g; 10.5 mmol). To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under-nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloylurea (1.28 g), which was recrystallized from a mixture of benzene and hexane to give colorless needles. M.P., 137°-138° C.
Reaction SMILES: [OH:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:9]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.Br[CH2:40][CH3:41]>[Ag]=O.CN1C(=O)CCC1>[CH2:40]([O:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:9]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23][CH2:22]5)=[CH:19][CH:20]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1)[CH3:41]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(O)nnc5c4cc3-c3ccccc3)cc2)CCC1
Reactant: CCBr
Agent: O=[Ag]
Solvent: CN1CCCC1=O
Product: CCOc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)nc3ccn12
Temperature: 80 °C

Procedure:
To a microwave vial was added tert-butyl {1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-5e) (113 mg, 0.223 mmol), silver oxide (310 mg, 1.336 mmol), bromoethane (0.062 mL, 0.826 mmol), and finally NMP (1 mL). The reaction mixture was then heated to 80° C. under microwave irradiation for 10 minutes. Upon completion the reaction mixture was filtered and then purified by reverse phase column chromatography (Sunfire C18) eluting with 20 to 100% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were then combined, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give tert-butyl {1-[4-(3-ethoxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (9-1) as a tan solid. MS (M+H)+: observed=536.4, calculated=536.64.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:27](Cl)(=[O:29])[CH3:28]>CCN(CC)CC>[C:27]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2F)C1
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-2-fluorophenyl)methyl)-piperidine-1-carboxylate (160 mg, 0.41 mmol) and Et3N (1 mL) at 0° C. was added acetyl chloride (32.3 mg, 0.41 mmol). The mixture was allowed to warm to rt and stirred overnight. The mixture was concentrated in vacuo to give crude (R)-tert-butyl 3-((R)-(2-acetamidoethoxy)-(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 54%), which was used in the next step without further purification. 1H NMR: (400 MHz, CDCl3): 1.20 (m, 1H), 1.40 (s, 9H), 1.70 (m, 2H), 1.98 (s, 3H), 2.60 (m, 2H), 3.48 (m, 4H), 3.90 (m, 1H), 4.42 (m, 1H), 5.82 (m, 1H), 7.10(m, 1H), 7.20 (m, 1H), 7.34 (m, 1H); MS (E/Z): 429 (M+1). MS (E/Z): 429 (M+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:17])=[N:4][C:5](F)=[C:6]([C:14]=1F)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[K+]>C1COCC1>[C:19]([O:21][C:5]1[N:4]=[C:3]([I:17])[C:2]([Cl:1])=[C:14]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([CH3:22])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1c(F)nc(I)c(Cl)c1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(OC(C)(C)C)nc(I)c(Cl)c1OC(C)(C)C
Yield: 86.4 %

Procedure:
Into a solution of tert-butyl 5-chloro-2,4-difluoro-6-iodonicotinate (0.4 g, 1.1 mmol) in THF (2.3 mL) at −78° C. was added a solution of potassium tert-butoxide (1.0 M×2.3 mL, 2.3 mmol). The temperature was allowed to rise to room temperature and the reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, evaporated and purified by silica chromatography (0-20% ethyl acetate in hexanes) to give tert-butyl 2,4-di-tert-butoxy-5-chloro-6-iodonicotinate (0.23 g, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[F:13]
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-6-chloropicolinate (12.0 g) in toluene (300 mL) was added a solution of 2-fluoro-5-methoxyphenylboronic acid (9.83 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.00 g) and sodium carbonate (14.8 g) in water (60 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and diluted with water. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude crystals were recrystallized from ethyl acetate to give the title compound (13.1 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][NH2:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]2[O:8][C:22](=[O:23])[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: NNC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 24 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
4-(Trifluoromethyl)benzoic acid hydrazide (commercially available from Maybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250 ml)/triethylamine (2.7 ml, 26 mmol) under N2 and 1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution was stirred for 18 h at 24° C., concentrated, and the residue was taken up in ethyl acetate, washed with 1N HCl solution, sat'd NaHCO3 solution, and brine prior to drying (MgSO4). Concentration gave 5 g (89%) of the title compound from which a sample was recrystallized from diethyl ether/hexanes: mp 214-216° C. MS m/z: 231 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[CH:19]=1.[CH3:20][N:21]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:14][CH2:13][C:12]([C:16]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([CH2:28][N:21]([CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH3:20])=[CH:30][CH:31]=3)=[O:18])=[CH:11][C:10]=2[CH:19]=1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccco3)ccc2OCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccco4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 7-(2-furyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.15 g) and triethylamine (0.25 ml) in dimethylformamide (10 ml) was added diethyl cyanophosphate (0.13 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetatehexane to give 7-(2-furyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 148) (0.1 g) as brown crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O:15]C(OCC)CCO)C.C(OC(OCC)C(O)CO)C>>[Br:1][C:2]1[C:7]2[O:8][CH2:9][CH:10]([OH:15])[CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCO)OCC
Reactant: Brc1cccc2c1OCCCN2
Agent: CCOC(OCC)C(O)CO
Product: OC1CNc2cccc(Br)c2OC1

Procedure:
9-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ol was prepared using a procedure analogous to 9-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine except that 3,3-diethoxypropan-1-ol was replaced by 3,3-diethoxypropane-1,2-diol. LCMS, [M+H]+=246.1. 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J=7.7, 1.8 Hz, 1H), 6.81-6.69 (m, 2H), 4.37 (ddd, J=12.3, 3.7, 1.3 Hz, 1H), 3.99 (br. s., 1H), 3.93 (dd, J=12.3, 2.2 Hz, 1H), 3.57 (br. s., 1H), 3.40 (dd, J=13.0, 4.0 Hz, 1H), 3.22 (dd, J=13.0, 2.4 Hz, 1H), 3.01 (br. s., 1H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[C:8]2=[N:9][C:10]3[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([OH:17])=[C:7]2[C:6](=[N:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[O:5]1)[CH3:3].[C:29]([OH:32])(=[O:31])[CH3:30]>>[C:29]([O:32][CH:4]([C:8]1[C:7]([C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:5])=[C:16]([OH:17])[C:15]2[C:10](=[C:11]([C:18]([F:21])([F:19])[F:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH:2]([CH3:3])[CH3:1])(=[O:31])[CH3:30]
Reactant: CC(C)C1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: CC(=O)O
Product: CC(=O)OC(c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1ccccn1)C(C)C

Procedure:
Using the procedure of Example 23, 6 g of 1,3-dihydro-3-(1-methylethyl)-1-[(2-pyridinyl)-imino]-5-trifluoromethyl furo-[3,4-b]-quinolin-9-ol and 120 ml of acetic acid were reacted to obtain 3.5 g of 1-[4-hydroxy-3-[(2-pyridinyl)-aminocarbonyl]-8-trifluoromethyl-2-quinolinyl]-2-methylpropyl acetate melting at 230° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16](=O)[CH2:17][CH3:18]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([CH2:17][CH3:18])[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: CCC(=O)CBr
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Product: CCc1cn2c(N)c(Cl)cc(C(=O)OC)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 4 in EXAMPLE 1 from methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, Step 3) and 1-bromo-2-butanone.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:80])[CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])=[CH:66][CH:65]=1>>[C:76]([Si:73]([CH3:75])([CH3:74])[O:72][CH2:71][C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:80])([CH3:79])([CH3:78])[CH3:77]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(=O)CO[Si](C)(C)C(C)(C)C)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 26.5 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.53 mmol), was reacted with diisopropylethylamine (0.28 g, 2.1 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 1-(4-amino-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethanone (0.21 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {4-[2-(tert-butyl-dimethyl-silanyloxy)-acetyl]-phenyl}-amide as a yellow foam (Yield 0.1 g, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N:10]([Si](C)(C)C)=[N+:11]=[N-:12].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[N:11][NH:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1cccc(-c2nn[nH]n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
3-Bromobenzonitrile (2.49 g, 13.7 mmol) and azidotrimethylsilane (3.14 g, 27.3 mmol) were stirred in anhydrous toluene (100 mL) under argon at ambient temperature. To this was added dibutyltin oxide (341 mg, 1.37 mmol) and the resulting reaction was fitted with a reflux condenser and heated with stirring at 110° C. for 3 h. Upon cooling, the reaction mixture was concentrated in vacuo, and then concentrated to dryness twice following the addition of MeOH (ca. 25 mL each). The crude reaction mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The organic phase was washed with 1N aqueous NaOH (4×75 mL), the combined basic aqueous portions were treated with 4N HCl to obtain an endpoint of pH=4 and the acidic aqueous phase was extracted with EtOAc (4×100 mL washes). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo to obtain 5-(3-bromophenyl)-2H-tetrazole as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][OH:27])[O:23][C:22]4=[O:28])=[CH:17][C:16]=3[F:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O[C:31]1[CH:35]=[CH:34][O:33][N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[C:1]([C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][C@H:24]([CH2:26][O:27][C:31]5[CH:35]=[CH:34][O:33][N:32]=5)[O:23][C:22]4=[O:28])=[CH:17][C:16]=3[F:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nn1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](COc5ccon5)OC4=O)cc3F)CC2)nn1
Yield: 25.8 %

Procedure:
3-(4-(4-(6-Cyano-3-pyridazinyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-hydroxy methyloxazolidin-2-one (398 mg, 1 mmol), 3-hydroxyisoxazole (93.5 mg, 1.1 mmol) and triphenylphosphine (328 mg, 1.25 mmol), were suspended with stirring in dry tetrahydrofiran (10 ml). Diisopropylazodicarboxylate (242 mg, 1.2 mmol) was added dropwise by syringe, and the mixture stirred at ambient temperature for 30 minutes. The reaction mixture was filtered, evaporated to dryness, dissolved in EtOAc/isohexane (1:1), and applied to a 10 g silica Mega Bond Elut® column, eluting with a gradient from 75 to 100% EtOAc in isohexane. Relevant fractions were combined and evaporated to give the title compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:13][C:6]=12
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of the iodide 408 (4.5 g, 10.8 mmol) in dry THF (120 ml) at was added CuI (205 mg, 0.1 eq, 1.08 mmol), TEA (2.73 g, 2.5 eq, 27 mmol), ethynyltrimethylsilane (2.12 g, 2 eq, 21.6 mmol) and Pd(PPh3)2Cl2 (212 mg, 0.028 eq, 0.30 mmol) and the reaction mixture was heated to reflux for 2 hours. It was then cooled to RT and partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and adsorbed onto silica gel. Purification by column chromatography (30% EtOAc/hexane) afforded 409 (2.2 g, 53% yield). LCMS: 387.1 (M+H).