Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>ClCCl>[C:37]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:21])[CH3:22])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To the mixture of tert-butyl (2S,4S)-2-(aminomethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (202 mg, 0.5 mmol, step 2 of Example 17) and triethylamine (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added acetyl chloride (43 μL, 0.55 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting solution was added to water and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was PTLC eluting with dichloromethane/methanol (30:1 and 20:1 twice) to give 200 mg (90%) of the title compound as a colorless amorphous.
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:20]1[N:15]([CH2:14][CH2:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1
Yield: 78 %

Procedure:
10.0 g (25 mmol) of DTPA was dispersed in 20 ml of pyridine. 18 g (0.18 mol) of acetic anhydride was added to the dispersion, and a reaction was allowed to take place at 65□ for 24 hrs with stirring. After the reaction was completed, the reaction mixture was filtered to recover generated material. The recovered compound was washed with acetic anhydride and diethyl ether several times, and dried under pressure for 24 hrs, thereby obtaining a DTPA anhydride at a yield of 78%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:17]C2C=CC(C(OC)=O)=CC=2)[C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=NN(C[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[CH:43]=2)C=1Cl)=O)(C)(C)C>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:17][C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([O:50][CH3:51])=[O:49])[CH:43]=2)[C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)c1
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1cccc(C(=O)OC)c1

Procedure:
Compound prepared in an analogous manner to Intermediate #46, replacing 5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester with 5-Chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:17]([O:19][C:20](=[O:23])[CH2:21]Br)[CH3:18].Cl>C1C=CC=CC=1.[Zn]>[OH:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1)([CH3:13])[CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(C2CCCC2)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(C2CCCC2)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a refluxing mixture of 4′-cyclopentylacetophenone (17 g), I2 (5 mg) and Zn dust (12 g) in benzene (150 ml) was added ethylbromoacetate (11 ml) dropwise over 30 minutes. The mixture was refluxed for next 45 min and then cooled to room temperature. It was acidified with 10% aqueous HCl solution (150 ml) and organic layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to furnish 22 g (88.1% yield) of ethyl 3-hydroxy-3-(4′-cyclopentylphenyl)-butanoate (2a) as oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[CH3:18].Cl.[H][H]>[C].[Pd].C(O)C>[CH3:18][C:3]1[CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)[S:6][CH:2]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2n[nH]c(=O)c3ccccc23)sc1Br
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1csc(-c2n[nH]c(=O)c3ccccc23)c1
Yield: 90.6 %

Procedure:
300 mg of 4-(5-bromo-4-methyl-2-thienyl)-1-phthalazinone, 500 mg of 5% palladium carbon (Pd-C) and 1 ml of concentrated hydrochloric acid were added to 50 ml of ethanol, and hydrogen gas was reacted with the resulting mixture under ordinary pressure. After the end of the reaction, the mixture was filtered, and the filtrate was concentrated to obtain 205 mg of 4-(4-methyl-2-thienyl)phthalazinone.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[OH-].[Na+].[Cl:18][C:19]1[N:23]2[N:24]=[C:25](Cl)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1.O>COCCOC>[Cl:18][C:19]1[N:23]2[N:24]=[C:25]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Cl)n3n2)cn1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
0.61 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5.3 cm3 of a 1N aqueous solution of sodium hydroxide are added to a mixture of 0.5 g of commercial 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine in 15 cm3 of 1,2-dimethoxyethane. The reaction mixture is stirred at a temperature in the region of 20° C. for 30 minutes before the addition of 92 mg of palladium dichlorobis(triphenylphosphine). The reaction mixture is then stirred at 65° C. for 30 minutes, and then brought back to a temperature in the region of 20° C. and poured into 20 cm3 of water. The mixture obtained is extracted with 3×100 cm3 of dichloromethane and the combined organic phases are washed with 2×100 cm3 of a saturated aqueous solution of sodium chloride. The resulting organic phase is dried over sodium sulphate, filtered and concentrated by evaporation under reduced pressure. The yellow powder thus obtained is purified by chromatography on silica gel (eluent: 98/2 CH2Cl2/MeOH). 0.2 g of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo-[4,3-b]pyridazine is thus obtained in the form of a beige powder, the characteristics of which are as follows:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][CH:13]1[C:16]23[O:23][CH2:22][O:21][C:17]2=[CH:18][CH:19]=[CH:20][CH:15]3[CH2:14]1.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH3:36])[C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH2:26][CH2:25]1.N(CCO)(CCO)CCO>C1(C)C=CC=CC=1>[CH2:22]1[O:21][C:17]2[CH:18]=[CH:19][C:20]3[C:13]([CH2:12][N:24]4[CH2:25][CH2:26][CH:27]([N:30]([CH3:36])[C:31](=[O:35])[O:32][CH2:33][CH3:34])[CH2:28][CH2:29]4)=[CH:14][C:15]=3[C:16]=2[O:23]1
Reactant: CCOC(=O)N(C)C1CCNCC1
Reactant: CC1CC2C=CC=C3OCOC312
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)N(C)C1CCN(CC2=Cc3c2ccc2c3OCO2)CC1

Procedure:
4 g of the compound obtained in Stage H, 2.24 g of the compound obtained in Stage B of Example 6 and 1.7 ml of triethanolamine are refluxed in 40 ml of toluene for 24 hours. The reaction mixture is concentrated, taken up in ethyl acetate, washed with water and then extracted with 1 N hydrochloric acid, and the extract is rendered basic with concentrated sodium hydroxide solution and extracted with methylene chloride. The extract is dried to yield ethyl N-{1-[(3,4-methylenedioxybenzocyclobuten-1-yl)-methyl]-piperid-4-yl)-N-methylcarbamate. 23.5 ml of a 2% solution of fumaric acid in ethanol are added to yield the desired salt.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[NH3:26]>CO>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH2:26])[S:8]1(=[O:25])=[O:24]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Reactant: N
Solvent: CO
Product: NCCOCCN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.53 g, 1.2 mmol) was treated with 7N ammonia in methanol to give 2-{2-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethanamine which was treated with 1N hydrochloric acid in ether to afford its hydrochloride salt as a white solid (0.042 g, 8.6%). MS (ES) m/z 369.9 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:28])[CH3:27].O>C(O)C>[CH2:26]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:27]
Reactant: CCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and aqueous ethylamine solution (ca. 70%, 149 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (310 mg, 94.3% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15]C>N1CCCCC1.C(O)C>[CH2:12]([C:11]1[N:5]2[N:6]=[C:2]([CH3:1])[CH:3]=[C:4]2[N:7]=[C:9]([CH3:8])[CH:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cc(N)[nH]n1
Reactant: CCCCCC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCc1cc(C)nc2cc(C)nn12
Temperature: 80 °C

Procedure:
Add 5-methyl-2H-pyrazol-3-ylamine (217 mg, 2.17 mmol), nonane-2,4-dione (339 mg, 2.39 mmol) and piperidine (1 drop) to ethanol (10 mL) and heat at 80° C. overnight. Cool to room temperature and concentrate to dryness. Purify by silica gel column chromatography (0-20% ethyl acetate in hexane) to obtain a mixture of two isomers (2 g).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].C([Cu])#N.[C:9]1([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[O:27][CH2:28][O:29][C:18]3=[CH:17][C:16]=2[CH2:30][C@@H:31]2[O:33][CH2:32]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>CCCCC.C1COCC1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:32][C@@H:31]([OH:33])[CH2:30][C:16]1[CH:17]=[C:18]2[O:29][CH2:28][O:27][C:19]2=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [Li]C(C)(C)C
Reactant: c1ccc(-c2c(C[C@H]3CO3)cc3c(c2-c2ccccc2)OCO3)cc1
Agent: N#C[Cu]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCCCCC
Product: CC(C)(C)C[C@@H](O)Cc1cc2c(c(-c3ccccc3)c1-c1ccccc1)OCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
t-Butyl lithium (21.4 mL of a 1.7M solution in pentane, 36.4 mmol) was added dropwise to a suspension of CuCN (1.63 g, 18.2 mmol) in 120 mL of THF at -78° C. The mixture was stirred for 30 min and allowed to warm to -10° C. A soultion of 8.01 g (2S)-3-(2,3-diphenylmethylenedioxyphenyl)-1,2-epoxypropane (24.2 mmol) of (from step 3 above) in 20 mL of THF was added dropwise. The reactions was stirred for 18 hr, then quenched by addition of 100 mL of 9:1 saturated NH4Cl: conc. NH4OH. The mixture was stirred vigorously for 30 min and partitioned between 50 mL of water and 150 mL of ether. The aqueous phase was extracted twice with 50 mL of ether, and the combined layers were washed with water and saturated NH4Cl and dried over MgSO4. The solvents were removed under vacuum to give an amber oil. The oil was purified by flash chromatography over silica gel, eluting with 20% ethyl acetate:hexane to afford 5.95 g (63% yield) of the title compound as a yellow oil. MS (DCI/NH3) M/Z: 389 (M+H)+, 406 (M+NH4)+. 1H NMR (CDCl3, 300 MHz) δ: 0.95 (s, 9H), 1.45 (m, 2H), 2.73 (dd, 1H), 2.85 (dd, 1H), 4.08 (m, 1H), 6.65-6.8 (m, 3H), 7.37 (m, 6H), 7.57 (m, 4H).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.CN(C=O)C>[CH2:28]([O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH:17]([OH:19])[CH2:18][N:11]1[C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
N-Cbz-4-hydroxyproline (40.00 g, 150.8 mmol) 8 was dissolved into 110 mL DMF. To this mixture was added 45.85 g of K2CO3 (2.2 eq; 331.7 mmol) and 2.30 g of NaI (0.1 eq). The reaction flask was purged with argon and 55.4 mL of benzylbromide (3 eq; 452 mmol) was added dropwise. This mixture was then stirred over night at room temperature. The reaction was then diluted with 300 mL ethyl acetate and washed with water (8×200 mL) to remove DMF, followed by washing with 100 mL brine. The organic layer was dried over Na2SO4 and concentrated to a yellow oil. The oil was then washed several times with 100 mL hexanes to remove any remaining benzyl bromide and then separated by silica gel in hexanes:ethyl acetate, 3:2, isolating N-Cbz-4-hydroxyproline benzyl ester at Rf=0.25 in nearly quantitative yield. 1H and 13C NMR spectra were in agreement with 1H and 13C NMR spectra previously reported (Robinson et al., 1998).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[C:14]=3OC)[CH:9]=[C:8]2[C:22]([O:24]C)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:28]([OH:30])C>>[C:1]1([N:7]2[C:15]3[C:10](=[C:11]([O:30][CH3:28])[C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=[C:8]2[C:22]([OH:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: COC(=O)c1cc2cc(OC)c(OC)c(OC)c2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(cc(C(=O)O)n2-c2ccccc2)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
Methyl 1-phenyl-5,6,7-trimethoxyindole-2-carboxylate (280 mg) was dissolved in ethanol (5 mL), a 10% aqueous solution (2 mL) of potassium hydroxide was added to the solution, and the mixture was stirred for 30 minutes under reflux. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and washed with ether. The water layer was then neutralized with hydrochloric acid and extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(Cl)Cl>[SH:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCOCC
Product: O=c1c2ccccc2nc(S)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 ml, three-neck round bottom flask equipped with magnetic stirrer, 25 g (0.17 moles) methyl anthranilate in 100 ml methylene chloride was placed. Into that mixture 23.0 g (0.17 moles) phenyl isothiocyanate in 50 ml methylene chloride was dropped in. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was refluxed at 40° C. for one hour. Ether (about 50 ml) was added; a precipitate formed which was removed by suction filtration to give the above-identified product.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(OCC(O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(C)(C)C.[I:23][CH2:24][CH2:25]O.C(OCC)=C>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([O:19][CH:17]([O:18][CH2:25][CH2:24][I:23])[CH3:16])[CH3:21]
Reactant: CCOC(=O)CC(O)COC(C)(C)C
Reactant: OCCI
Agent: C=COCC
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OCCI
Temperature: -20 °C
Yield: 150 %

Procedure:
Ethyl 4-t-butoxyacetoacetate (20.0 g) synthesized according to the method described in Heterocycles 26, 2841 (1987) was dissolved in methanol (150 mL) and sodium borohydride (1.68 g) was added at a temperature of from 5° C. to 15° C. The mixture was stirred for 1 hr and water (100 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (150 mL) was washed well with water. MTBE was evaporated to give ethyl (±)-4-t-butoxy-3-hydroxybutanoate (16.9 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (73 mL) in THF (100 mL) was added a solution of ethyl (±)-4-t-butoxy-3-hydroxybutanoate (10.66 g) in THF (30 mL) at a temperature of from −58° C. to −48° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (21.5 g) and ethyl vinyl ether (11.4 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (10 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (19.1 g) and 15.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (100 mL), MTBE (100 mL) was added and the mixture was extracted and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and ethanol (150 mL) and p-toluenesulfonic acid monohydrate (1.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with MTBE (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to flash chromatography using heptane/ethyl acetate (3:1) as an eluent to give the title compound (2.0 g) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[Si:13]([O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1cc([N+](=O)[O-])cn1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 4-nitro-1H-pyrazole (500 mg, 4.42 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (2.12 g, 8.85 mmol), cesium carbonate (5.76 g, 17.7 mmol) and anhydrous DMF (5 mL). After heating at 70° C. for 1 h, the mixture was cooled to room temperature and diluted with methylene chloride (50 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 92% yield (1.11 g) of 116a as a white solid: mp 63-64° C.; 1H NMR (500 MHz, CDCl3) d 8.20 (s, 1H), 8.08 (s, 1H), 4.24 (t, 2H, J=4.5 Hz), 3.95 (t, 2H, J=4.5 Hz), 0.84 (s, 9H), −0.04 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[C:8]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:26][CH2:25]3)=[O:23])[C:7]=2[CH:36]=1)#[N:2].[Cl-].[OH:38][NH3+].C[O-].[Na+]>CS(C)=O.CO>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])=[C:8]([NH:21][C:22]([C@H:24]3[CH2:25][CH2:26][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:28][CH2:29]3)=[O:23])[C:7]=2[CH:36]=1)=[O:38]
Reactant: N#Cc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Reactant: [NH3+]O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: NC(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Trans-5-cyano-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (107 mg) obtained in Example 6 is suspended in dimethyl sulfoxide (2 ml), and thereto are added hydroxy-ammonium chloride (36 mg) and a 28% sodium methoxide in methanol (100 μl). The mixture is heated at 50° C. for 2 hours, and further at 80° C. for 2 hours. The reaction solution is poured into ice-water, and the precipitates are collected by filtration, and purified by recycle HPLC to give the title compound (25 mg; APCI-MS M/Z: 539/541 [M+H]+) and trans-5-aminocarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (18 mg; APCI-MS M/Z: 524/526 [M+H]+).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C1COCC1.[Br-].[CH2:36]([Zn+])[CH:37]([CH3:39])[CH3:38]>O.CCOC(C)=O>[CH2:36]([C:2]1[C:3]([CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C[Zn+]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CC(C)C)cc(C)c32)cc1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (2.7 g, 6.2 mmol) in isobutylzinc(II) bromide in THF (0.5 M, 24.9 mL, 12.4 mmol) was added Pd[(t-Bu)3P]2 (0.5 g, 0.98 mmol), and then the mixture was stirred at 70° C. for 14 h. The mixture was then stirred under reflux for 7 h. The reaction was then diluted with H2O and EtOAc. The mixture was then filtered through a Celite® pad. The filtrate was partitioned. The organic phase was washed with H2O, and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by SiO2 column chromatography (heptane/EtOAc=88/12) to afford the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.74 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.31 (d, J=8.60 Hz, 2H), 6.86-6.94 (m, 2H), 4.90 (d, J=11.12 Hz, 1H), 4.64 (d, J=11.12 Hz, 1H), 4.60-4.64 (m, 1H), 3.81-3.91 (m, 1H), 3.45-3.54 (m, 1H), 2.57 (d, J=7.33 Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H), 1.79-1.88 (m, 1H), 1.56-1.75 (m, 2H), 1.39-1.55 (m, 4H), 0.84-0.89 (m, 6H).