Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH:34]=O)=[CH:6][N:7]2[CH2:32][CH3:33].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl>ClCCCl>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:36])[C:5]([CH2:34][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C=O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydro quinoline-3-carbaldehyde (21.3 g, 34.4 mmol) in 1,2-Dichloroethane (DCE) (200 mL) was added pyrrolidine (3.13 mL, 37.8 mmol) and sodium triacetoxyborohydride (10.93 g, 51.6 mmol). The mixture was stirred at r.t. for 3 h. Then reaction mixture was concentrated, partitioned between DCM and brine, and extracted with DCM twice. The combined organic extracts were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was then purified through normal phase chromatography (CombiFlash Rf), eluting with [DCM/MeOH/NH4OH (v:v:v=80:20:2)]:DCM (0% to 60%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (17 g, 30.2 mmol, 88% yield) as a light yellow solid. LCMS: (M+H)+: 563.2.
Reaction SMILES: C([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[N:13]([CH3:29])[NH:14][CH:15]([C:24]([O:26]CC)=[O:25])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)(C)C>FC(F)(F)C(O)=O>[C:24]([CH:15]([NH:14][N:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:31])=[O:5])=[O:30])[CH3:29])[CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([OH:26])=[O:25]
Reactant: CCOC(=O)C(CCc1ccccc1)NN(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
A soluion of azapeptide 16S (more mobile diastereomer; (0.335 g; 0.774 mmol) in trifluoroacetic acid (5 ml) was allowed to stand for 3 hours. The reside after evaporation wa combined with sodium hydroxide (1 N; 3 ml) and THF (0.5 ml) and the resulting solution was stirred under nitrogen for 18 hrs. After neutralization with dilute hydrochloric acid, the solution was placed onto a column of DOWEX 50W-X4 ion-exchange resin (5 g). The product wa eluted with 20:1 H2O-pyr and freeze-dried to a white foam (0.215 g; 0.1=616 mmol; 80%). A portion of this material (0.052 g) was purified by chromatography on silica gel (85:30:5:1 CHCl3 -CH3OH-H2O:HOAc), affording pure product (0.031 g). The disodium salt (0.025 g) precipitated from CH2Cl2 ; m.p. 220-225 (dec). TLC (silica gel; 10:5:1:3 EPAW) Rf=0.45. Analysis: Calculated for C17H23N3O 5 . 2Na: C, 51.65; H, 5.82; N, 10.63. Found: C, 51.54; H, 5.79; N, 10.28. MS (for diacid): m/e 403 (monotrimethylsilyl of M+ -H2O). NMR (CDCl3). 1.7-2.3 (6H, m); 2.6-2.8 (2H, m); 3.00 (3H, s); 3.5-3.6 (3H, m); 4.3-4.5 (1H, m); 7.1-7.3 (5H, m); 7.4-8.0 (2H, broad).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[CH:14]1.S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH2:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:27]
Reactant: Nc1c(SC(F)(F)F)ncn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Nc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 120 h
Yield: 29.1 %

Procedure:
To a solution of 6.0 g (15.15 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-4-trifluoromethylsulfenylimidazole in 100 ml of methylene chloride was added 1.70 ml (18.18 mmole) of sulfuryl chloride at 0° C. The resulting mixture was stirred at RT for 5 days under a nitrogen atmosphere. The mixture was quenched with water, then partitioned between methylene chloride and aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography using 20% ethyl acetate in hexane to give 1.9 g (31.62% yield) of the desired product, mp 172.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][C:12](=O)[C:11]=2[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([CH3:18])=[C:9]1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(Cl)cc1)CCNC2=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(Cl)cc1)CCNC2
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(4-chlorophenyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.84 g, 7.64 mmol, prepared as in Scheme 2 and in a similar manner to Example 22) in tetrahydrofuran (38 mL) was added borane-tetrahydrofuran complex (1 M, 76 mL) at 0° C. over 20 minutes. The mixture was heated at reflux for 3 h. The mixture was cooled to rt, methanol was added, and then the solvent was evaporated off. The residue was purified by silica gel chromatography. Elution first with ethyl acetate, followed by 10% methanol in methylene chloride, gave a colorless gum (950 mg, 34.8%). LC-MS m/z (MH+) 357.1, retention time 2.78 min (method 2).
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][C:8]=2[CH:18]=1)(=O)C.ClC1C=CC=[C:22]([C:26]([O:28]O)=[O:27])C=1>C(Cl)Cl>[C:26]([O:28][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][C:8]=2[CH:18]=1)(=[O:27])[CH3:22]
Reactant: CCOC(=O)C1COc2ccc(C(C)=O)cc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1COc2ccc(OC(C)=O)cc2O1
Yield: 75 %

Procedure:
Heat a solution of 2 g (8 mmol) of ethyl 7-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate and 3.05 g (17.7 mmol) of meta-chloro-perbenzoic acid in 30 cm3 of methylene chloride at 50° C. for 18 hours under a nitrogen atmosphere. After cooling, removing by filtration the benzoic acid formed, and washings with aqueous solutions of sodium hydrogen carbonate and then sodium chloride, the reaction mixture is concentrated to dryness under reduced pressure and the crude product obtained is purified by chromatography on a silica column (eluant:petroleum ether/diethyl ether, 70:30). Ethyl 7-acetoxy-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 75%. ##STR34##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:12])SCC.[NH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[S:12]
Reactant: CCSC(=S)Nc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCCN
Product: CC(C)(C)OC(=O)NCCCNC(=S)Nc1ccccn1
Yield: 89.7 %

Procedure:
In a similar manner to in Reference Example 58, ethyl 2-pyridyldithiocarbamate (1.98 g) and t-butyl 3-aminopropylcarbamate (1.74 g) were reacted and crystallized from n-hexane-diethyl ether to give the title compound (2.78 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[Cl:11][CH2:12][C:13](Cl)=[O:14]>C(Cl)Cl>[Cl:11][CH2:12][C:13]([NH:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10])=[O:14]
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 4-aminoresorcinol hydrochloride (30 g, 0.1857 mol) in CH2Cl2, (460 mL) TEA (77.6 mL, 0.557 mol) was added at 0° C. To the resulting mixture, chloroacetyl chloride (14.78 mL, 0.1857 mol) was added drop wise and the solution was stirred for 60 h at RT. The crude product was washed through a plug of silica gel with CH2Cl2 and purified through column chromatography using 100% CH2Cl2→25%→50%→75% 90:10:1 CH2Cl2:MeOH:NH4OH. The solution was concentrated in vacuo to give the title compound. MS (ESI, pos. ion) m/z: 202 (M+1). Mass calc'd for C8H8ClNO3: 201.02.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([N+:6]([O-:21])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[N:9]2[CH2:12][CH2:13][N:14]=3)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:11]=[C:10]3[C:5]([N+:6]([O-:21])=[C:7]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:8]4[N:9]3[CH2:12][CH2:13][N:14]=4)=[CH:4][CH:3]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(F)ccc21
Solvent: CC(C)O
Product: CN1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Yield: 17.3 %

Procedure:
1,2-Dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (3.5 g, 0.012 mol) and N-methylpiperazine (15 ml, 0.13 mol) were heated at 100° C. in isopropanol (5 ml) for 16 hrs. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield a dark oil which was chromatographed on silica gel in 2% methanol/chloroform to yield a red solid. The red solid was recrystallized from ethyl acetate to yield 1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide, (0.75 g), as deep red crystals m.p. 179°-183° C., (δ(CDCl3) 2.38 (3H,s) 2.58 (4H,m) 3.37 (4H,m) 3.95-4.24 (4H,m) 6.08 (1H,d,J=3.5Hz), 6.62 (1H,dd,J=9 and 3.5Hz), 7.38-7.5 (3H,m), 7.84 (2H,m), and 8.11 (1H,d,J=9 Hz)), represented by the structural formula: ##STR17##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:8]([O:13]C)(OC)(=O)=[O:9].S(=O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:13])=[O:9])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccccc1
Agent: O=S(=O)=O
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A vertical glass tube having a length of 90 cm and a diameter of 4 cm was packed with glass balls and heated at 70° C. 225 g (2.0 moles) of chlorobenzene, 126 g (1.0 mole) of dimethyl sulfate and 160 g (2.0 moles) of sulfur trioxide were simultaneously fed, dropwise, to the top of the tube at approximately the same rates over 30 minutes. Contrary to the procedure adopted in Example 1, the effluent reaction mixture was not immediately precipitated in dilute sulfuric acid but was continuously recycled to the packed column at a pump rate of 2 l/h. Once all of the starting components had been fed to the reactor, recycling was continued at the same rate for a further half-hour, after which the effluent reaction mixture was precipitated in 1 liter of 5% sulfuric acid. Purification was carried out as described in Example 1 to give 261 g (91%) of bis(4-chlorophenyl) sulfone of 97% purity.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]2[NH:28][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:29][CH:30]=1)([O-:22])=[O:21]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate and 4-nitrobenzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2,5-bis(4-nitrophenyl)imidazole-4-carboxylate, which is dissolved in ethyl alcohol. 1 M Sodium hydroxide solution is added and the mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2,5-bis(4-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:20]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([O:28]C)=[O:27])[CH:17]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O.O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:20]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:26]([OH:28])=[O:27])[CH:17]=4)[N:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)CCCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of methyl 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (130 mg, 0.33 mmol) in water (1 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(chroman-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (80 mg, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:17]([O:20][C:21]1[C:29]([O:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][C:21]1[C:29]([O:30][C:31](=[O:33])[CH3:32])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[NH2:9])=[O:24])(=[O:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C(=O)N(N)C(=O)OC(C)(C)C)c1OC(C)=O
Reaction time: 0.5 h

Procedure:
N-[(t-Butyloxy)carbonyl]hydrazine (12 g) and 10 g of triethylamine were dissolved in 200 ml of dichloromethane and, at 0° C., 24 g of 2,3-bis(acetyloxy)benzoyl chloride in 50 ml of dichloromethane was added dropwise with stirring (30 minutes). After continuous stirring for one hour, the reaction mixture was extracted with 200 ml of ice water, 50 ml of 1% sodium bicarbonate and 100 ml of 5% citric acid. The organic phase was then washed with 100 ml of water, dried over sodium sulfate, and the solvent distilled off. The remaining oil crystallized after stirring with hexane. The result was beige crystals, 26.3 g; melting point 117° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(C=Cc1ccccc1)N1CCNCC1
Reaction time: 2 h
Yield: 30 %

Procedure:
Absolute piperazine (206 g) was dissolved in 500 ml of chloroform and 66.3 g of cinnamoyl chloride was added gradually at 0° C while mixing. The addition required 3 hours. After mixing was continued for another 2 hr., precipitates were filtered and then the filtrate (chloroform layer) was washed with 50 ml of 5% sodium hydroxide and 50 ml of water. The residues obtained after solvents were distilled away in vacuo were subjected to silica gel column chromatography (eluants were mixtures of chloroform and methanol). Thus crystalline N-cinnamoyl piperazine was obtained. Melting point of the product was 30°-40° C and the product was very hygroscopic. The yield was 30%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].C(OC(=O)C)(=O)C.[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:23]([O-:25])=[O:24])[CH:13]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of methyl 4-ethoxy-3-methoxybenzoate (7.12 g, 33.9 mmol) and acetic anhydride (40 mL) in acetic acid (40 mL) at room temperature was dropped fume nitric acid (90%, 3.15 g). After stirring at room temperature for 15 minutes, it was heated at 50° C. for 1 hour. The reaction mixture was poured into ice and a solid was formed. It was filtered, washed with water, and dried under vacuum with P2O5 to give methyl 4-ethoxy-5-methoxy-2-nitrobenzoate as white solid (8.392 g, 97%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.07 (s, 1H), 4.19 (q, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 1.52 (t, 3H); LC-MS (ESI) m/z 256 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])[CH2:2][CH2:3][CH3:4].[CH3:13][C:14]([CH3:16])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([C:5]1[CH:11]=[CH:10][C:8]2[O:9][C:14]([CH3:16])([CH3:13])[O:12][C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(O)c(O)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1ccc2c(c1)OC(C)(C)O2

Procedure:
The same procedures as described in Example 10 were carried out by using 4.16 g (25 mM) of 4-n-butylcatechol, 15 ml of acetone, 30 mg of p-toluenesulfonic acid monohydrate and 7 ml of benzene. 5-n-Butyl-2,2-dimethyl-1,3 -benzodioxol was obtained in the yield of 4.74 g (23 mM) as colorless transparent liquid having a boiling point of 74°-75° C./1 mmHg.
Reaction SMILES: [BrH:1].C(O)(=O)C.[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14]([NH:15][C:16](=[O:39])[C:17]3[CH:22]=[CH:21][C:20]([C@H:23]([NH:25]C(OCC4C=CC=CC=4)=O)[CH3:24])=[C:19]([N:36]=[N+:37]=[N-:38])[CH:18]=3)=[C:9]2[CH:8]=[CH:7]1>>[BrH:1].[BrH:1].[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14]([NH:15][C:16](=[O:39])[C:17]3[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[C:19]([N:36]=[N+:37]=[N-:38])[CH:18]=3)=[C:9]2[CH:8]=[CH:7]1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1N=[N+]=[N-]
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccnc3[nH]ccc23)cc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (4 ml) was added to (R)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzamide (400 mg), and the mixture was stirred at room temperature for 1.5 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from ethanol-ethyl acetate to give 285 mg of (R)-(-)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-3-azidobenzamide dihydrobromide 1/2 hydrate having a melting point of 216-219° C. (dec.) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[S:36][C:35]([NH2:37])=[N:34][C:33]=1[CH3:38])(=[O:31])=[O:30])([CH3:27])[CH3:26]>>[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[S:36][C:35]([NH:37][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])=[N:34][C:33]=1[CH3:38])(=[O:31])=[O:30])([CH3:27])[CH3:26]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Pale-yellow solid. MS (ISN) 559.0 [(M−H)−]; mp 293-294° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:41]=[CH:42][C:43]=1F)[C:35]([N:37]1[CH2:40][CH2:39][CH2:38]1)=[O:36].[H-].[Na+].Cl>CS(C)=O>[N:37]1([C:35]([C:34]2[CH:41]=[CH:42][C:43]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[C:32]([F:31])[CH:33]=2)=[O:36])[CH2:40][CH2:39][CH2:38]1
Reactant: O=C(c1ccc(F)c(F)c1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (70 mg, 0.163 mmol) synthesized in Example (38d) and 1-(3,4-difluorobenzoyl)azetidine (68 mg, 0.345 mmol) synthesized in Example (41a) were dissolved in dimethyl sulfoxide (3.0 mL), and sodium hydride (60%, 25 mg, 0.63 mmol) was added, followed by stirring at 100° C. for 5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (30 mL) was added, and extraction was carried out with diethyl ether (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (54 mg, yield 65%) as a yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])=[O:30])=[C:25]([F:32])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]>C(Cl)Cl>[C:12]([NH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:31])(=[O:6])=[O:30])=[C:25]([F:32])[CH:24]=2)[CH2:18]1)(=[O:14])[CH3:13]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)(=O)=O)c(F)c2)C(=O)O1
Reaction time: 2 h
Yield: 91.7 %

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.0784 g, 0.350 mmol) was added portionwise to a solution of 5-(S)-Acetamidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.110 g, 0.350 mmol) in DCM (20 ml) at r.t. The mixture was stirred for 2 h, then washed with aq. saturated sodium bicarbonate, brine, dried (MgSO4), and evaporated to give product as a white solid (0.106 g, 92%). MS (m/z): [M+H]+=331.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[C@@H:6]([CH3:17])[CH2:5][N:4]([CH2:18][C:19](NC2C=CC=C3C=2C=CN=C3)=[O:20])[CH2:3]1.[ClH:32].[O:33]1CCOCC1>>[ClH:32].[CH3:17][C@H:6]1[N:7]([C:8]2[C:9]3[CH:16]=[CH:15][S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:18][C:19]([OH:20])=[O:33])[CH2:5]1
Reactant: C1COCCO1
Reactant: C[C@@H]1CN(CC(=O)Nc2cccc3cnccc23)C[C@H](C)N1c1ncnc2sccc12
Agent: Cl
Product: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (i) (1.0 g) in 1,4-dioxane was treated with 4M hydrogen chloride in 1,4-dioxane (40 ml). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give the subtitle compound as a white 15 solid. Yield 1.9 g.