Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[C:17](Cl)=[O:18].Cl.[CH3:21]OCN>CN(C=O)C>[C:17]([C:11]1[C:12]2[C:7](=[C:6]([Br:5])[CH:15]=[C:14]([Br:16])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:18])[CH3:21]
Reactant: O=C(Cl)c1cccc2c(Br)cc(Br)cc12
Reactant: COCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(=O)c1cccc2c(Br)cc(Br)cc12

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]indol-2-(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 28 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of tirethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Yield: 100.3 %

Procedure:
A solution of 1.19 g of 2-amino-5-(4-chlorophenyl)-3-nitro-pyridine in 17 ml of ethanol is treated with 5.5 g of SnCl2.2H2O at 90° C. for 17 h under a nitrogen atmosphere. Thereafter, the solution is concentrated in vacuo to dryness. The residue is dissolved in 300 ml of water and adjusted to pH 8 using a 1.0 M solution of aqueous sodium hydroxide. Subsequently, the aqueous layer is extracted four times each with 50 ml of ethyl acetate. The combined organic phases are extracted once with 50 ml of brine, dried using MgSO4, filtered with suction, and evaporated to dryness to yield 1.05 g of the pure title compound of m.p. 178° C. MS: 220.3 (MH+). MS: 220.3/222.3 (MH+, 100%/20%/200%). TLC: Rf=0.30 (dichloromethane/methanol 5:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:23][CH2:24][CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: COC(=O)c1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCNC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 1.0 g, 3.44 mmol), methyl 4-(2-aminoethyl)benzoate hydrochloride (0.83 g, 4.13 mmol), triethylamine (0.72 mL, 5.16 mmol), EDCI (0.64 g, 4.13 mmol) and HOBt (0.63 g, 4.13 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 34:66) to give the title compound (1.11 g, 71%) as a white amorphous.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]2[NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:20][C:9]=12.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])#[CH:29]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[NH:18][C:10]3=[N:11][CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]([C:29]#[C:28][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[C:9]3[CH:20]=2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(-c2cc3c(Cl)c(C(F)(F)F)cnc3[nH]2)cc1
Reactant: C#Cc1ccccc1N(C)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(c1ccccc1C#Cc1c(C(F)(F)F)cnc2[nH]c(-c3ccc(F)cc3)cc12)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
Cul (19 mg), Pd(OAc)2 (22 mg) and Cs2CO3 (1.27 g) are added to a degassed solution of 4-chloro-2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]-pyridine (628 mg), N-(2-ethynylphenyl)-N-methylmethanesulfonamide (450 mg) in 1,4-dioxane (10 ml), and the mixture is stirred at 100° C. for 5 h. Conventional work-up and purification gives the title compound in 70% yield (663 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=1)[CH3:2].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][CH:15]=[O:17])=[C:7]([Cl:13])[CH:6]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Solvent: O=CO
Product: CCOC(=O)c1cc(Cl)c(NC=O)c(Cl)c1
Yield: 78.9 %

Procedure:
Following the procedure in Rouot et al., in J. Med. Chem., 19, 1049 (1976), 4-amino-3,5-dichlorobenzoic acid ethyl ester (70.2 g., 030 m) is reacted with the product from acetic anhydride (61.3 g., 0.60 m) and formic acid (34.5 g., 0.75 m) to yield the desired 3,5-dichloro-4-formamidobenzoic acid ethyl ester (62.0 g., 0.237 m) in crude yield of 79% with a melting point of 168°-170° C. Reaction of this crude (16.35 g., 0.062 m) with a mixture of thionyl chloride (55.4 g., 0.47 m) and sulfuryl chloride (3.4 g., 0.062 m) leads to the desired 3,5-dichloro-4-dichloromethaniminobenzoic acid ethyl ester (14.65 g., 46 mmol) which distills at 105° C. at 250 mm of Hg after standard workup. It should be noted that this material may solidify on standing. Finally, this distilled dichloromethamine (4.35 g., 0.0138 m) is reacted with ethylene diamine (1.66 g., 0.0276 m), and 10 mL of triethylamine in approximately 25 mL of ethyl acetate for 10 hours. An immediate white precipitate is noted, but stirring is continued overnight to ensure complete reaction. This reaction mixture then is vacuum filtered to yield 5.35 g. of white powder (which is greater than 100% yield, but is probably due to the fact that, in addition to the desired compound, triethylamine hydrochloride as well as the hydrochloride of the desired compound are present at this stage). Recrystallization of the white powder from absolute ethanol produced a white crystalline solid (2.3 g., 0.0076 m) in a yield of 55% with a melting point of 238°-240° C. This compound demonstrates the expected IR absorptions at 3380 (sharp), 3150 (broad), 1710 (sharp), 1660 (sharp and most intense), 1580 (sharp), 1275 (sharp), 1105 cm-1 (sharp).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH:12]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(CCc2cc(NC(=O)c3cccc(OC)c3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
1-Chloro-N,N,2-trimethylprop-1-en-1-amine (89 μl, 0.67 mmol, 1.05 eq) was added dropwise to 3-methoxybenzoic acid (97 mg, 0.63 mmol, 1 eq) in DCM (1.5 ml) at ambient temperature. After stirring at ambient temperature for 1.5 h, a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (199 mg, 0.57 mmol, 0.9 eq) and pyridine (142 μL, 1.74 mmol, 2.75 eq) in DCM (2 ml) was added to the reaction mixture and stirring was continued at ambient temperature for a further 3 h. A solution of TFA (386 μL, 5.2 mmol, 8.25 eq) in DCM (3.5 ml) was then added and stirring was continued at ambient temperature for 18 h. The reaction mixture was concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (129 mg, 59% yield). 1H NMR (399.902 MHz, DMSO) δ 2.89 (4H, s), 3.73 (6H, s), 3.84 (3H, s), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.48 (1H, s), 7.12-7.10 (1H, m), 7.42-7.37 (1H, m), 7.59-7.56 (2H, m), 10.65 (1H, br.s), 12.16 (1H, br.s). MS: m/z 382 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([CH:19]=1)[C:16](O)=O>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([C:16]2[NH:9][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:19]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: Cc1cnc(N)c(N)c1
Product: Cc1cnc2nc(-c3cc(Br)ccc3Cl)[nH]c2c1

Procedure:
Intermediate I-4 was synthesized in a similar fashion as described in the synthesis of I-2a using 5-methylpyridine-2,3-diamine and 5-bromo-2-chlorobenzoic acid. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.60 (dd, J=2.2, 8.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 2.39 (s, 3H). MS M/Z=322/324 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[N:19]1[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][CH:20]1[N:19]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:18]([CH3:17])[CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:21]1
Reactant: CC1CNCC(C)N1c1ncccn1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1(c2ccc(CN3CC(C)N(c4ncccn4)C(C)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 647.6 %

Procedure:
N-[1-(4-Chloromethylphenyl)cyclopropyl]acetamide (22.3 mg) and 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride (265 mg) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (415 mg) was added and the mixture was stirred at 80° C. for 8 hr. Water (20 mL) was added and the mixture was stirred, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (245 mg).
Reaction SMILES: ClC(Cl)(Cl)C(=N)OC.F[C:10](F)(F)[C:11]([OH:13])=[O:12].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1)([O-:18])=[O:17]>ClCCl.C(OCC)C>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]2[NH:25][C:10]([C:11]([OH:13])=[O:12])=[N:26][C:21]=2[CH:20]=1)([O-:18])=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: COC(=N)C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
Methyl 2,2,2-trichloroacetimidate (0.73 g, 4.09 mmol) and trifluoroacetic acid (0.63 mL, 8.17 mmol) were added to a suspension of 4-nitrophenylenediamine (0.50 g, 3.27 mmol) in a 2:3 mixture of dichloromethane/diethyl ether (40 mL). After stirring at RT for 3 h, the reaction mixture was filtered. The residue in the filter was washed with a 1:1 mixture of dichloromethane:ether. The filtrates were combined and shaken with 1.5N aqueous sodium hydroxide (40 mL). The organic layer was removed. A 1:1 mixture of methanol/ether (40 mL) was added, and the mixture was stirred at RT overnight. The precipitated yellow solid was collected by filtration, suspended in water and the mixture acidified with 6N aqueous HCl. The precipitate was collected by filtration and dried under vacuum overnight to give the title compound (0.331 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.20 (d, 1H), 7.79 (d, 1H). MS: m/z 208 (M+H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2[C:19]3[S:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:20]=3[NH:21][N:22]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([C:18]2[C:19]3[S:25](=[O:6])[C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[C:20]=3[NH:21][N:22]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2n[nH]c3c2sc2ccccc23)cc1
Solvent: ClCCl
Product: O=S1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A solution of 3-chloroperoxybenzoic acid (450 mg, 60% pure) in dichloromethane (30 ml) was added dropwise with stirring over 15 minutes to a solution of 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole (400 mg) in dichloromethane (50 ml) at 0-5° C. The mixture was stirred at 5-15° C. for 4 hours, then washed with water, dried and evaporated to give a solid which was purified by chromatography on silica using petroleum ether/ethyl acetate (1:3) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether, and filtered to give 3-phenyl-1H-[1]benzothieno[3,2-c]pyrazole 4-oxide, m.p. 222-224° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)([CH3:9])([CH3:8])[CH3:7].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=[O:19])[C:13]=1[SH:20]>>[C:6]([S:20][C:13]1[C:14](=[O:19])[O:15][C:16]([CH3:18])=[CH:17][C:12]=1[OH:11])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)O
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c(SC(C)(C)C)c(=O)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Ice (50g.) was added slowly with stirring to 175 g. of concentrated sulfuric acid, keeping the temperature below 35°C. by means of an ice-salt bath. The temperature of the diluted acid was adjusted to 5°C., and 38.6 g. (0.460 mole) of tert.-butyl alcohol was slowly added with stirring, keeping the temperature between 5° and 10°C. 4-Hydroxy-3-mercapto-6-methyl-2-pyrone (36.4 g., 0.230 mole) was then added with vigorous stirring over a period of about 15 minutes, keeping the temperature of the reaction mixture at 5°C. The cooling bath was then removed from the reaction vessel, and stirring was continued for one hour, 20 minutes, while the temperature of the reaction mixture rose to 24°C. The mixture was then poured into ice water, and the gummy precipitate crystallized to a gray solid (weight 42.4 g. (86 percent), m.p. 108.5°-112.5°C.) upon standing at room temperature overnight. The crude product was suspended in 200 ml. of water and then dissolved by the addition of 100 ml. of 10% sodium hydroxide solution. The solution was stirred at room temperature for one hour with decolorizing charcoal, filtered and acidified with with dilute hydrochloric acid. The cream-colored solid precipitate (37.7 g., m.p. 116.5°C.) was collected on a filter, washed with water and dried. Recrystallization from 2-propanol gave the pure 3-tert.-butylthio-4-hydroxy-6-methyl-2-pyrone as white crystals, m.p. 117°-117.5°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[O:9][CH:8]=[C:7]([C:10]([O:12]CC)=[O:11])[C:6]=2[CH:15]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[O:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1coc2c([N+](=O)[O-])cc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1coc2c([N+](=O)[O-])cc(Br)cc12

Procedure:
Ethyl 5-bromo-7-nitro-1-benzofuran-3-carboxylate (5.5 g, 17.5 mmol; obtained in Step 1) was suspended in ethanol (20 mL). 2 M NaOH (20 mL) was added and the mixture was heated at reflux for 2 h. The ethanol was removed by evaporation and the remaining solution acidified with concentrated HCl (4 mL), diluted with water and the product collected by filtration, washed with water and dried in a vacuum oven. Yield: 4.65 g (93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (s, 1H) 8.26 (d, J=1.8 Hz, 1H) 8.34 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:8]1[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[CH:9]=1)([O:4][CH2:5][C:6]#[CH:7])[CH3:3].[BH4-].[Na+].O>C(O)C>[CH3:3][C:2]([C:8]1[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH:9]=1)([O:4][CH2:5][C:6]#[CH:7])[CH3:1]
Reactant: C#CCOC(C)(C)c1cc(C(=O)OCC)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C#CCOC(C)(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
0.25 g of ethyl 5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazole-3-carboxylate was dissolved in 2 ml of ethanol, and 0.1 g of sodium borohydride was then added. The mixture was stirred at room temperature for 5 hours. After 20 ml of water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of {5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazol-3-yl}methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2CC2C=CC(OC)=CC=2)=[CH:4][CH:3]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3cccnc3OC)C2c2ccc(Cl)cc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(4-methoxybenzyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.3) (2.8 g, 5.90 mmol) in CH3CN (80 mL) and H2O (20 mL) was added CAN (9.70 g, 17.69 mmol) and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was quenched with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-2.5%). The residue was triturated in CH2Cl2 to afford the title product (1.06 g, 2.93 mmol, 50% yield) as white solid. tR: 4.36 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 355 [M+H]+ (LC-MS 2); Rf=0.39 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]([OH:33])(=[O:32])[C:26]([CH2:28][C:29](O)=[O:30])=[CH2:27]>>[CH3:1][CH:2]([NH:12][C:13]([C@@H:15]1[CH2:17][C@H:16]1[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:27][CH:26]([C:25]([OH:33])=[O:32])[CH2:28][C:29]2=[O:30])=[CH:20][CH:19]=1)=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Product: CCCCCCCCCC(C)NC(=O)[C@@H]1C[C@H]1c1ccc(N2CC(C(=O)O)CC2=O)cc1

Procedure:
The title compound was prepared from trans-N-(1-methyldecyl)-2-(4-aminophenyl)cyclopropanecarboxamide and itaconic acid, substantially according to the procedure of Example 10. It was recrystallized from acetic acid to give a 21% yield of material having a melting point of 226°-228° C. The infrared spectrum (KBr disc) showed absorptions at 3280, 2900, 1695 and 1625 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12]Cl.[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: O=[N+]([O-])c1cc(CCl)c(Cl)cc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 21 h
Yield: 27 %

Procedure:
To a solution of 1,5-dichloro-2-(chloromethyl)-4-nitrobenzene (Hagmann, William K.; Dorn, Conrad P.; Frankshun, Robert A.; O'Grady, Laura A.; Bailey, Philip J.; et al.; JMCMAR; J. Med. Chem.; EN; 29; 8; 1986; 1436–1441, 10.6 g, 44 mmol) in methanol (30 ml) was added sodium methoxide (44 ml, 66 mmol) at room temperature. The mixture was stirred at 80° C. for 21 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (6:1/4:1) to afford 2.8 g (27%) of the title compound as pale yellow oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C(N(CC)CC)C>CO>[C:1]([NH:3][C:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1cccs1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.5 %

Procedure:
Methyl N-cyano-2-thiophenecarboximidate (0.32 g, 1.9 mmol) was dissolved in methanol (3 ml), and 2-nitroxyethylamine nitrate (0.34 g, 2.0 mmol) and triethylamine (0.20 g, 2.0 mmol) were added. The mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 25 g) eluting with ethyl acetate. The eluted fractions were concentrated under reduced pressure and crystallized from ethyl acetate-hexane to give the title compound (0.18 g, 0.77 mmol, yield: 40%) as colorless crystals.