Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[OH:7][CH:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CC(C)=O>[O:7]=[C:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1
Reactant: C=CCC1C(=O)C=CC1O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: C=CCC1C(=O)C=CC1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a mixture of 150 ml of dried benzene and 100 ml of acetone, was dissolved 1.5 g of 4-hydroxy-5-allyl-2-cyclopentenone. After adding 3 g of freshly distilled aluminum isopropoxide, the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, washed twice with 30% sulfuric acid, then with water until the washings had become neutral. After drying over anhydrous sodium sulfate, the mixture was stripped of the solvent by distillation and the residue was distilled in vacuo to obtain 1.2 g (81% yield) of 4-keto-5-allyl-2-cyclopentenone boiling at 53° C./4 mmHg.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][CH:13]1[N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17][NH:16][C:15](=[O:31])[CH2:14]1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:33][C:22]1[C:21]2[N:30]=[C:18]3[CH2:17][NH:16][C:15](=[O:31])[CH2:14][CH:13]([CH3:12])[N:19]3[C:20]=2[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: [NH4+]
Reactant: CC1CC(=O)NCc2nc3cnc4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1CC(=O)NCc2nc3c(N)nc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MCPBA (2.73 g of 77% purity, 16 mmol) was added to a solution of 12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one (1.3 g, 4.9 mmol) in chloroform (20 mL), and the reaction mixture was stirred for 15 minutes at room temperature. Concentrated ammonium hydroxide (30 mL) and p-toluenesulfonyl chloride (1.12 g, 5.86 mmol) were sequentially added, and the resulting mixture was stirred at room temperature for two hours. An analysis by LC/MS indicated the presence of the 5N-oxide, and additional p-toluenesulfonyl chloride (1 equivalent) was added. The mixture was stirred at room temperature overnight. The organic layer was separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 0% to 15% 2 N methanolic ammonia in chloroform over a period of 42 minutes) followed by recrystallization from acetonitrile to provide 389 mg of 6-amino-12-methyl-8,9,11,12-tetrahydro-10H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-10-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[CH2:6][CH2:5]2
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2cc(F)ccc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(F)ccc2C1=O
Yield: 90.2 %

Procedure:
6-Fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-78d: 250 mg, 1.5146 mmol) was reacted with 3-iodo-4-methyl-pyridine (365 mg, 1.66 mmol), 1,4-dioxane (10 mL), copper iodide (29 mg, 0.151 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (21.5 mg, 0.151 mmol) and potassium phosphate (965 mg, 4.54 mmol) for 14 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 350 mg of the product (90.4% yield).
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17]C4C=CC([N+]([O-])=O)=CN=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=CC(O)=CC=3OC2)C=CC=CC=1.Cl[C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=1>>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:45]4[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Product: O=[N+]([O-])c1cccnc1Oc1ccc2c(c1)OCC(c1ccccc1)O2

Procedure:
2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-3-nitropyridine was prepared in the same way as 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine above from 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and 2-chloro-3-nitropyridine (56 mg). Yield is 30 mg and mp <60° C. 1H NMR (DMSO-d6) δ=4.16 (dd, J=8.6, 11.4 Hz, 1H), 4.46 (dd, J=11.4, 2.5 Hz, 1H), 5.27 (dd, J=2.5, 8.6 Hz, 1H), 6.73 (dd, J=2.5, 8.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 7.34-7.52 (m, 6H), 8.43 (dd, J=1.9, 4.8 Hz, 1H), 8.55 (dd, J=7.8, 1,9 Hz, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([N:9]=[C:10]=[O:11])[CH2:6][CH2:7][CH3:8]>ClCCl>[OH:2][CH2:1][CH2:3][NH:4][C:10]([NH:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: NCCO
Reactant: CCCCN=C=O
Solvent: ClCCl
Product: CCCCNC(=O)NCCO
Temperature: 30 °C
Yield: 113 %

Procedure:
61.7 grams (1 mole at 99% purity) of ethanolamine and 170 grams of dichloromethane were charged to a flask eguipped with stirrer, thermometer, feed tank, distillation head and condenser. 101 grams (1 mole at 98% purity) of butyl isocyanate were fed to the flask dropwise with stirring and cooling (utilizing a dry ice bath) over a period of 1.5 hours such that the temperature of the reaction mixture was maintained at about 30° C. At this time some solid had been formed and it was redissolved by heating to 46° C. The flask contents were stirred at 46° C. for an additional two hours and then freed of volatile materials by stripping at 90° C. and 2 mm Hg, leaving 181 g of solid product. This material was recrystallized from 2-butanone giving tiny white crystals melting at 67° C. The HLB value of N-(2-hydroxyethyl)-N'-1-butyl urea is 12.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(F)cc1[N+](=O)[O-]
Yield: 58.7 %

Procedure:
By using 0.59 g of N-(4,5-difluoro-2-nitrophenyl)glycine ethyl ester, 155 mg of imidazole, 1.80 g of pyridine and 10 ml of DMSO, 0.41 g (59%) of N-[4-fluoro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[C:20]1([N:26]2[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:51]CCCl>>[ClH:51].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:31][C:29]4[CH:28]=[N:27][N:26]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:30]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cl
Product: Fc1ccc(-c2nccnc2N2CCN(Cc3cnn(-c4ccccc4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
Form the free base of 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride by SCX-2® chromatography washing with methanol then eluting with 2M ammonia in methanol. Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.200 g, 0.774 mmol) in DCE (5 mL). Add 1-phenyl-1H-pyrazole-4-carbaldehyde (0.200 g, 1.16 mmol, 1.5 eq.). Stir at room temperature for 20-30 min. Add sodium triacetoxyborohydride (0.33 g, 1.55 mmol, 2 eq.) followed by acetic acid (0.048 g, 0.81 mmol, 1.05 eq.). Stir the reaction mixture at room temperature for 48 hr. Purify by SCX cartridge, followed by reverse phase chromatography to obtain the freebase of the title compound (0.360 g, 0.87 mmol, 100% yield). MS (ES): m/z=415.3[M+H]. Dissolve in methanol (5 mL). Add ammonium chloride (0.047 g, 0.87 mmol, 1 eq.). Stir the reaction mixture at room temperature for 2 hr. and concentrate to give the title compound (0.327 g, 83% yield for salt formation). MS (ES): m/z=415.3[M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1.[OH-].[Na+]>O>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:15]1[C:14]1[CH:18]=[CH:19][C:11]([NH:10][CH3:9])=[CH:12][CH:13]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 80 °C

Procedure:
5.00 g (46.2 mmol) o-Phenylene diamine and 6.99 g (46.2 mmol) 4-(methylamino)benzoic acid are stirred in 40.0 g polyphosphoric acid at 210° C. for 4 hours. The mixture is cooled to 80° C., poured into water and stirred over night at RT. The mixture is alkalinized with sodium hydroxide solution. The precipitate is filtered off and washed with water. The product is dried in vacuo at 70° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[OH-].[NH4+:15]>C1COCC1>[CH3:1][C:2]1[S:6][C:5]([S:7]([NH2:15])(=[O:9])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1sc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a stirred solution of 5-methyl-4-nitrothiophene-2-sulfonyl chloride [CAS No. 61714-77-0] (1.0 g, 4.14 mmol) in THF (20 ml) was added at 0° C. (ice water bath) ammonium hydroxide solution (25%, 5 ml). The reaction mixture was stirred at room temperature for 1 h, evaporated, poured into water (30 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (2×30 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization from ethyl acetate/hexane to yield 5-methyl-4-nitro-thiophene-2-sulfonamide (0.75 g, 82%) as a brown solid. MS (ISP) 221.0 [(M−H)−], mp 120° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=[N:20][NH:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COCCOc1ccnc(NN=Cc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-((2-(4-(2-methoxyethoxy)pyridin-2-yl)hydrazono)methyl)quinoline (0.101 g, 0.223 mmol) in DCM (1.0 mL) was added iodosobenzene diacetate (0.0719 g, 0.223 mmol). After stirring at ambient temperature for 5 hours the reaction mixture was partitioned between DCM and aqueous saturated Na2S2O3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40:1 DCM/MeOH) to provide 70 mg (70%) of desired product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH2:7]([O:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[CH:18][NH:19]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][NH:26][CH3:27]>CCOCC.CCOC(C)=O>[CH2:7]([O:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([C:1](=[O:5])[C:2]([N:26]([CH3:27])[CH3:25])=[O:3])=[CH:18][NH:19]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CNC
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc2[nH]ccc2c1OCc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C(=O)c1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of oxalyl chloride (0.78 mL, 8.963 mmol) in anhydrous ether (20 mL) was added dropwise over 20 min to a 0° C. solution of 1-5a (1.44 g, 5.975 mmol) in anhydrous ether (20 mL). The reaction mixture was stirred at room temperature for 5 h, cooled to −20° C., and treated with a stream of dimethyl amine gas. The reaction was diluted with EtOAc, washed with water and brine, and dried over Na2SO4. After concentration, the resulting residue was recrystallized from EtOAc to provide the product (1-6a) as white crystals in 87% yield, 1.58 g. 1H NMR (300 MHz, CDCl3-d) δ (ppm) 2.92 (s, 3H), 2.94 (s, 3H), 5.17 (s, 2H), 6.91-7.00 (m, 2H), 7.29-7.37 (m, 3H), 7.58-7.61 (m, 2H), 7.70-7.72 (m, 1H), 10.02 (br, 1H). APCI [M+1]: 341.2.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=O.[CH2:14]([CH:17](C(=O)C)[C:18](=O)[CH3:19])[CH2:15][CH3:16]>O.C(O)(=O)C.[Zn]>[CH3:9][C:7]1[C:17]([CH2:14][CH2:15][CH3:16])=[C:18]([CH3:19])[NH:1][C:6]=1[C:5]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: CCCC(C(C)=O)C(C)=O
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCCc1c(C)[nH]c(C(=O)OCC)c1C
Reaction time: 8 h

Procedure:
A solution of sodiumnitrite (28.2 g, 0.41 mol) in water (100 ml) was added to a stirred cold solution of ethyl acetoacetate (49.4 g, 0.38 mol) in acetic acid as the temperature was held below 15° C. After the solution was stirred and stored overnight at 25° C., 3-n-propyl-2,4-pentanedione (53.7 g, 0.38 mol) and zinc (53 g) were sequentially added and the mixture was stored at 60° C. for 1 h. Dilution with water brought about the precipitation of ethyl 3,5-dimethyl-4-n-propylpyrrole-2-carboxylate 4d as a yellow solid, 22.4 g (29%), mp 98°-99° C. (lit. mp 99°-99.5° C.) after recrystallization from ethanol; 1HNMR (CDCl3): δ 9.3 (s, 1H), 4.25 (q, 2H), 2.25 (t, 2H), 2.24 (s,3H), 2.1s (s, 3H), 1.41 (m, 2H), 1.30 (t, 3H), 0.90 (t, 3H). The procedure was extended to the conversions of (a) 3-n-butyl-2,4-pentanedione to ethyl3,5-dimethyl-4-n-butylpyrrole-2-carboxylate 4e, a yellow solid, 32%, mp 99°-100° C. (lit. mp 99° C.), 1H NMR (CDCl3): δ 9.35 (S, 1H), 4.27 (q, 2H), 2.50 (t, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 1.40 (m, 4H), 1.31 (t, 3H), and 0.91 (t, 3H); (b) 3-isopropyl-2,4-pentanedione to ethyl 3,5-dimethyl -4-isopropylpyrrole-2-carboxylate 4f , 20%, mp 104°-106° C. (lit. mp 105°-106.5° C.); and (c) 2-acetylcyclohexanone to ethyl 3-methyl-4,5,6,7-tetrahydroinadole-2-carboxylate 4i, 50%, mp 111°-113° C. (lit. 110° C.), 1H NMR (CDCl3): δ 9.03 (s, 1H), 4.25 (q, 2H), 2.41 (m, 4H), 2.21 (s, 3H), 1.65 (m, 4H), 1.30 (t, 3H).
Reaction SMILES: C[Si](C)(C)CCOC(=O)C1C=CC=CC=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35](Br)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)OCC[Si](C)(C)C
Reactant: CC1(C)OB(c2ccccc2C(=O)OCC[Si](C)(C)C)OC1(C)C
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCC[Si](C)(C)C

Procedure:
2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-benzoic acid-2-trimethylsilanyl-ethyl ester (2.7 g) was similarly prepared according to Step 2D from 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCl): 513.2, 459.1; tR=3.62 min. (method 1)
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:17]2=[N:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:20]=3[N:16]2[CH2:15][CH:14]([OH:30])[CH2:13][CH2:12]1.CI.[C:33](OCC)(=O)C>O1CCCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:17]2=[N:18][C:19]3[C:20](=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[N:16]2[CH2:15][CH:14]([O:30][CH3:33])[CH2:13][CH2:12]1
Reactant: CCOC(C)=O
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(O)CCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc3n(c12)CC(OC)CCN3c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60%, 5.7 mg, 0.14 mmol) in tetrahydrofuran (1 mL) was added a solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-4-ol (40.0 mg, 0.0954 mmol) in tetrahydrofuran (1 mL) at 0° C. After 30 min, methyl iodide (0.0178 mL, 0.286 mmol) was added to the reaction mixture at 0° C. and the resultant mixture was stirred at 40° C. for 2 hr. Ethyl acetate was added and the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (39.5 mg, 0.0911 mmol, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:28][C:27]3[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccc([N+](=O)[O-])cc1
Yield: 34.8 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro- 1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-nitroaniline (70 mg, 0.51 mmol) to give 80 mg of the title compound (35%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.65 (s, 1H), 8.23 (d, 2H, J=9.2 Hz), 7.30 (d, 2H, J=9.2 Hz), 7.24 (bs, 1H), 7.18 (bs, 1H), 5.20~5.29 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.68 (d, 2H, J=7.3 Hz), 2.11 (dm, 1H, J=13.5 Hz), 1.82~1.97 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]5[N:26]=[CH:25][N:24](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:23]=5)[CH:20]=4)[N:15](C4CCCCO4)[N:14]=3)[CH:8]=2)=[O:5])[CH2:3][CH2:2]1>Cl.O1CCOCC1>[NH:24]1[CH:25]=[N:26][C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3[C:9]2[CH:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[CH:12]=[CH:11][CH:10]=2)=[N:23]1
Reactant: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Cyclopropyl-N-(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the reaction mixture was evaporated to dryness and purified by preparative HPLC. (0.026 g, 30% yield over 2 steps): 1H NMR (DMSO d6) δ 8.75 (s, 1H), 8.36 (br s, 1H), 8.24 (s, 1H), 8.12 (d, 1H), 7.76-7.72 (m, 3H), 7.5 (t, 1H), 1.83 (m, 1H), 0.97-0.84 (m, 4H); ES-MS (m/z) 345.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([OH:20])[CH2:8][N:7]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:5])[CH3:2].[CH3:29][O:30][CH2:31][CH2:32][CH2:33][N:34]1[C:39]2[CH:40]=[C:41]([CH2:44]OC(=N)C(Cl)(Cl)Cl)[CH:42]=[CH:43][C:38]=2[O:37][CH2:36][C:35]1=[O:52].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:44][C:41]2[CH:42]=[CH:43][C:38]3[O:37][CH2:36][C:35](=[O:52])[N:34]([CH2:33][CH2:32][CH2:31][O:30][CH3:29])[C:39]=3[CH:40]=2)[CH2:8][N:7]1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](O)CN1c1ccc(OC)cc1
Reactant: COCCCN1C(=O)COc2ccc(COC(=N)C(Cl)(Cl)Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)C(=O)CO3)CN1c1ccc(OC)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 5.20 g of (2S,4R,5R)-5-hydroxy-1,4-bis(4-methoxy-phenyl)piperidine-2-carboxylic acid ethyl ester and 5.62 g of 2,2,2-trichloro-acetimidic acid 4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl ester in 150 ml of dichloromethane is added 1.1 ml of trifluoromethanesulfonic acid at −0° C. The reaction mixture is allowed to stir for another hour at this temperature and then allowed to warm to 0° C. within 2 hours. The mixture is quenched by addition of 2N sodium hydroxide, extracted with dichlormethane, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a brown oil. Rf=0.15 (EtOAc-heptane 1:1); Rt=4.73.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.N>O.CO>[NH2:6][C:5]1[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNc1ccccc1
Agent: Cl
Agent: N
Solvent: O
Solvent: CO
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 2.32 g (21 mmol) of phenylhydrazine with a purity of 98% by weight, 10 ml of methanol and 3.0 ml (36 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 10 ml of water was added to the mixture to cool the same up to 10° C., then, 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture, and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower for 30 minutes. Precipitated crystals were collected by filtration, and the crystals were washed with 5 ml of cold water and dried under reduced pressure to obtain 3.19 g of 5-amino-4-nitroso-1-phenylpyrazole (Isolation yield: 63.4%) as an ocherous solid with a purity of 74.9% by weight (absolute calibration curve method by high performance liquid chromatography).