Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:24](=[O:26])[CH3:25])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1c(OC(C)=O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 79 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxy-benzofuran (1.2 gm, 3.87 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-acetoxybenzofuran, mp. 39°-41° C.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8](=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25]C)[O:15][N:14]=1)[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8](=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[OH:25])[O:15][N:14]=1)[CH3:6]
Reactant: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2OC)on1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Add boron tribromide (39 mL, 39 mmol, 1.0 M solution in CH2Cl2) dropwise to a stirred −78° C. solution of 5-[5-(5-chloro-2-methoxy-phenyl)-isoxazol-3-yl]-pentanoic acid ethyl ester (4.39 g, 13 mmol) in CH2Cl2 (40 mL). Allow to warm to room temperature. After 2 hours, cool to −78° C. and add boron tribromide (13 mL, 13 mmol, 1.0 M solution in CH2Cl2) dropwise and allow to warm to room temperature overnight. Quench via dropwise addition of ethanol (60 mL, absolute). Concentrate, dissolve residue in CHCl3, wash with saturated NaHCO3 solution (×2), dry over MgSO4 and concentrate to get 3.7 g of a tan solid. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-60% EtOAc/hexanes to afford the title compound (3.3 g, 78%). MS (IS) 324 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24][O:25][CH2:26]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[N:6]([CH2:24][O:25][CH3:26])[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccncc2)[nH]c(-c2ccncc2)c1C
Reactant: COCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCn1c(-c2ccncc2)c(C)c(C(C)=O)c1-c1ccncc1
Temperature: 75 °C
Reaction time: 15 h
Yield: 8.6 %

Procedure:
To a stirred solution of 3-acetyl-4-methyl-2,5-di(4-pyridyl)-1H-pyrrole (1.0 g, 3.6 mmol) in DMF (5 mL) was added NaH (60% oil dispersion; 0.29 g, 7.2 mmol) at room temperature. The mixture was heated at 70-80° C. for 30 minutes, and after cooling to 0° C., chloromethyl methyl ether (0.41 mL, 5.4 mmol) was added. The mixture was stirred for 15 hours, and saturated aqueous NaHCO3 (30 mL) was added to the reaction mixture. The whole was extracted with ethyl acetate (50 mL×3). Combined organic layers were washed with water (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vactio. The residual oil was purified by preparative TLC (1 mm×3) to give the title compound (0.1 g, 9% yield) as a light brown powder.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[SH:31]>CC(C)=O>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([S:31][C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)=[C:3]([CH:18]=[O:19])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: Sc1cccs1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)c(C=O)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccs3)c(C=O)sc21
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-thieno[2,3-d]pyrimidine-6-carboxaldehyde in acetone (30 ml) was added potassium carbonate (0.402 g) followed by 2-thiophene thiol (0.337 g). The reaction was stirred for 24 hours under nitrogen. The acetone was evaporated and the resulting residue was partitioned between ethyl acetate and water (1:1, 50 ml in total). The aqueous phase was extracted twice with ethyl acetate (25 ml) The organic extracts were washed with brine, then dried over magnesium sulfate, filtered and evaporated to leave a brown oil. This oil was triturated with diethyl ether to give the subtitle compound as a pale brown solid (0.528 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]2[C:14](=O)[O:13][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[NH4+:23].[K+].[Br-]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]([C:14]([NH2:23])=[O:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NN=C2N=C(c3ccccc3)OC2=O)c1
Reactant: [NH4+]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(-n2nc(C(N)=O)nc2-c2ccccc2)c1
Yield: 63 %

Procedure:
Three grams (0.01 mole) of 4-(3-methylphenyl-hydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =R3 =H in the formula II) was suspended in 93 ml of methanol. To the resulting suspension, 66.2 ml of 29% solution of ammonium hydroxide (0.549 mole) was added and refluxed for 5 minutes. Methanol and ammonia were then distilled off under a reduced pressure, and the resulting crystals were filtered out and washed with water. The crystals were recrystallized from a mixed solvent of 5.8 ml of methanol and 4.5 ml of water to obtain 1.8 g of almost colorless crystal, m.p. 142°-143° C., with a yield of 63%. I.R. (KBr, cm-1, refer to FIG. 2); 3500-3240 (broad and strong), 1700, 1670, 1610, 1458, 1400, 1302, 789 and 700.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:10]([CH2:20][CH2:21][CH:22]([OH:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:9]2=[O:31])=[CH:4][CH:3]=1.[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:29][C:26]2[CH:25]=[CH:24][C:23]([CH:22]([OH:30])[CH2:21][CH2:20][CH:10]3[CH:11]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:31])=[CH:28][CH:27]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(O)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2C(CCC(O)c3ccc(OCc4ccc(CBr)cc4)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
1-(4-Fluorophenyl)-3-[3-hydroxy-3-(4-hydroxyphenyl)-propyl]-4-(4-methoxyphenyl)-azetidin-2-one was reacted with 1,4-bisbromomethylbenzene and potassium carbonate analogously to Example IV, giving a colorless solid (29) of molecular weight 604.52 (C33H31BrFNO4); MS (ESI): 605.2 (MH+).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:20][C:19]=1[C:33]1[O:34][C:35]2[C:40]([N:41]=1)=[CH:39][CH:38]=[CH:37][N:36]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:61]1([CH2:66][CH2:67]O)[CH2:65][CH2:64][CH2:63][CH2:62]1>ClCCl>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[C:19]([C:33]3[O:34][C:35]4[C:40]([N:41]=3)=[CH:39][CH:38]=[CH:37][N:36]=4)[C:18]([NH2:17])=[N:23][CH:22]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:67][CH2:66][N:61]1[CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: COc1cc(-c2cnc(N)c(-c3nc4cccnc4o3)c2)ccc1O
Reactant: OCCN1CCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cnc(N)c(-c3nc4cccnc4o3)c2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
[C1] A solution of di-tert-butyl azodicarboxylate (37.9 mg) in dichloromethane (1 ml) was added to a stirred suspension of 4-(6-amino-5-(oxazolo[5,4-b]pyridin-2-yl)pyridin-3-yl)-2-methoxyphenol (50 mg), triphenylphosphine (43 mg) and 2-(pyrrolidin-1-yl)ethanol (19 mg) dissolved in dichloromethane (4 ml) under nitrogen. The resulting suspension was stirred at room temperature for 1 hour. Triphenylphosphine (43 mg) and a solution of DTAD (37.9 mg) in dichloromethane (1 ml) were added. The resulting mixture was stirred at room temperature for 20 minutes. After evaporation of the solvents, the residue was purified by flash chromatography on silica gel eluting with 5% methanol in dichloromethane and methanolic ammonia (7 N) in dichloromethane. After collection of the desired fractions and evaporation of the solvents, the resulting solid was triturated with acetonitrile to give 5-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3-oxazolo[5,4-b]pyridin-2-yl-pyridin-2-amine (20 mg) as a solid. NMR Spectrum: (DMSOd6) 1.66-1.73 (m, 4H), 2.51-2.58 (m, 4H), 2.81 (t, 2H), 3.88 (s, 3H), 4.09 (t, 2H), 7.07 (d, 1H), 7.21 (dd, 1H), 7.28 (d, 1H), 7.53 (dd, 1H), 7.78 (bs, 2H), 8.30 (dd, 1H), 8.40 (dd, 1H), 8.47 (d, 1H), 8.60 (d, 1H)
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[F:21]NS(C1C=CC=CC=1)(=O)=O>C1COCC1.CCOC(C)=O>[F:21][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3][C:2](=[CH2:1])[CH2:7][CH2:6]1
Reactant: O=S(=O)(NF)c1ccccc1
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CCC(F)(C(=O)OCC)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of ethyl 4-methylenecyclohexanecarboxylate (2 g, 11.89 mmol) in THF (5 mL) was cooled at −78° C. and then added over a period of 5 min to the LDA solution. The resulted reaction mixture was stirred at −78° C. for 0.5 h. Then a solution of N-fluorobenzenesulfonamide (4.2 g, 13.32 mmol) in THF (25 mL) was added dropwise over a period of 5 min. The reaction mixture was stirred in the cool bath and allowed to slowly reach rt. After 18 h, it was diluted with EtOAc, washed with a saturated aqueous solution of NH4Cl (2×), water and brine. The organic layer was dried over MgSO4, concentrated and purified on a 25 g silica gel cartridge to afford the product as a liquid (1.97 g, 81% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.74 (t, J=1.6 Hz, 2H), 4.25 (q, J=7.2 Hz, 2H), 2.51-2.35 (m, 2H), 2.31-2.22 (m, 2H), 2.18-2.06 (m, 2H), 2.05-1.80 (m, 2H), 1.37-1.24 (m, 3H).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[CH:11][C:9](N)=[C:8]([F:13])[C:7]=1[C:14]([F:17])([F:16])[F:15].[CH3:18][S:19]SC.O>S(=O)(=O)(O)O.C(O)(=O)C.[Cu]>[Br:5][C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[C:8]([F:13])[C:9]([S:19][CH3:18])=[CH:11][CH:12]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1F
Reactant: CSSC
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(Br)c(C(F)(F)F)c1F
Temperature: 5 °C

Procedure:
A solution of sodium nitrite (11.2 g) in concentrated sulphuric acid was added to a stirred cooled suspension of 4-bromo-2-fluoro-3-trifluoromethylaniline (40 g) in glacial acetic acid while maintaining the temperature below 5° C. The mixture was stirred at 5° C. for one and a half hours. The resultant mixture was added gradually to a mixture of dimethyl disulphide (20 ml) and copper power (0.224 g) in glacial acetic acid at 45° C. It was stirred and heated at 70° C. for 3 hours. It was cooled, poured into water, extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and purified by column chromatography eluted with petroleum spirit (b.p. 60°-80° C.) to give 6-bromo-2-fluoro-3-(methylsulphenyl)benzotrifluoride (30.6 g) as an orange oil NMR (CDCl3) 2.45(s,3H), 7.25(t,1H), 7.5(d,1H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][N:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: Cc1noc(N)c1Cl
Product: Cc1noc(NS(=O)(=O)c2nccs2)c1Cl
Yield: 33 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-chloro-3-methylisoxazole and thiazole-2-sulfonyl chloride in 33% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 171-173° C.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(Nc1ccc(C2=CCNCC2)nc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2=CCN(C(=O)c3ccccc3)CC2)nc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, J=2.5 Hz, 1H), 8.61 (s, 1H), 8.01 (dd, J=8.6, 2.2 Hz, 1H), 7.42-7.54 (m, 6H), 7.35-7.39 (m, 2H), 7.29-7.35 (m, 2H), 6.46-6.67 (m, 1H), 4.79 (s, 4H), 4.05-4.32 (m, 2H), 3.77-3.94 (m, 1H), 3.47-3.58 (m, 1H), 2.61-2.65 (m, 2H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:14]([C:12]3[S:13][C:9]([S:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)=[O:15])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and benzo[d][1,3]dioxol-5-ylamine (53 mg, 0.39 mmol). The title compound was obtained as a solid (28 mg, 44% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.43 (1H, m), 9.00 (2H, s), 8.67 (1H, s), 7.29 (1H, m), 7.06 (1H, m), 6.91 (1H, m), 6.04 (2H, s). MS m/z: 468.04, 470.04 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH3:22].CO>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: N
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)NCc2cccnc2)ccc1Cl
Solvent: CO
Product: Nc1ccc(S(=O)(=O)NCc2cccnc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a saturated ammonia-methanol solution (60 ml) was added 4-chloro-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.77 g), followed by about 2 days of heating at 100° C. in a sealed tube. After the reaction, the solvent was evaporated under reduced pressure and the formed yellow crystals were collected by filtration and dried to obtain 4-amino-3-nitro-N-(pyridin-3-ylmethyl)benzenesulfonamide (2.51 g). Hereinafter, the compound of Reference Examples 26 was obtained similarly.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:42][C:39]3([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=4)[CH2:41][CH2:40]3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: NC1(c2cccc(C(F)(F)F)c2)CC1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)NC3(c4cccc(C(F)(F)F)c4)CC3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 6.7 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 1-[3-(trifluoromethyl)phenyl]cyclopropanamine (Intermediate-44, 0.078 g, 0.388 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.17-1.37 (m, 4H), 1.51 (s, 6H), 3.06 (s, 2H), 7.34-7.51 (m, 8H), 8.39 (s, 1H), 11.00 (2H); MS [M+H]+: 559.16.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].C(N(CC)CC)C.[C:59](OC(=O)C)(=[O:61])[CH3:60]>C(Cl)Cl>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[O:44][C:59]([CH3:60])=[O:61])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2OC(C)=O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
Erythromycin A (50.0 g, 68.1 mmol) (commercially available from Abbott Laboratories) was dissolved in 600 mL of methylene chloride (CH2Cl2) at ambient temperature. Triethylamine (20 mL) and 10 mL (10.82 g, 106 mmol) of acetic anhydride were added to this solution. The reaction mixture was heated to reflux and 100 mL of CH2Cl2 was distilled from the reaction mixture to remove any traces of water. The reaction mixture was heated at reflux temperature for an additional five hours. After six hours, when the reaction was complete according to TLC analysis, the reaction mixture was cooled to ambient temperature and transferred to a separatory funnel. The CH2Cl2 solution was washed with 300 mL of ammonium hydroxide/sodium bicarbonate solution containing 2.9% ammonia and 1.8% sodium bicarbonate, dried over anhydrous sodium sulfate, and filtered. The CH2Cl2 was removed using a rotary evaporator with a water bath temperature of 30°-40° C. The residue was crystallized from 200 mL of acetonitrile (CH3CN) by first dissolving it in hot CH3CN and allowing the solution to stand overnight at ambient temperature, then cooling it to -25° C. and maintaining this temperature for 24 hours. The product was isolated as white crystals which were washed with cold (-25° C.) CH3CN and dried in a vacuum oven at 50° C. for approximately 64 hours. The 2'-O-acetylerythromycin A was obtained in 83% yield (43.91 g). mp. 138°-145° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)([CH3:11])[C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][CH2:6]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:54](OC(=O)C)(=[O:56])[CH3:55]>C1COCC1.ClCCl.CN(C1C=CN=CC=1)C>[C:54]([NH:1][CH2:4][CH:5]1[CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)([CH3:11])[C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][CH2:6]1)(=[O:56])[CH3:55]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1=CCC(CN=[N+]=[N-])CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1=CCC(CNC(C)=O)CC1(C)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 123.8 %

Procedure:
A solution of methyl (4RS,6RS)-4-(azidomethyl)-6-(4-chloro-3-(trifluoromethyl)phenyl)-6-methylcyclohex-1-enecarboxylate (21 mg, 0.054 mmol) in THF (0.5 mL) was treated with water (25 μL, 1.388 mmol) followed by triphenylphosphine (15.62 mg, 0.060 mmol). The resulting mixture was stirred at rt for 21.5 h and then concentrated under vacuum to yield a residue. The residue was dissolved in dichloromethane (0.5 mL) and the resulting solution was treated with triethylamine (0.030 mL, 0.217 mmol), dmap (3.31 mg, 0.027 mmol) and acetic anhydride (10.22 μL, 0.108 mmol). The resulting mixture was stirred at rt for 2 h and then concentrated under vacuum to yield a residue. This residue was purified by column chromatography on silica gel, eluting with 60-100% ethyl acetate-hexanes, to provide methyl (4RS,6RS)-4-(acetamidomethyl)-6-(4-chloro-3-(trifluoro-methyl)phenyl)-6-methylcyclohex-1-enecarboxylate (27 mg, estimated 68% yield), which was used in the next step without further purification despite being contaminated with about 45% by weight of triphenylphosphine oxide.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([O:24]CC)=O)[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH2:30][N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH2:30][N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[O:24])[C:4]1=[O:27])[CH3:2]
Reactant: CN(CCN)S(C)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NCCN(C)S(C)(=O)=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 67.2 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.103 mmol), and N-(2-aminoethyl)-N-methylmethanesulfonamide (489 mg, 3.21 mmol), was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (33 mg, 67% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.42 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.19 (m, 2 H), 4.14 (s, 2 H), 3.66 (m, 2 H), 3.41 (m, 2 H), 2.97 (s, 3 H), 2.84 (s, 3 H), 1.23 (m, 3 H); HRMS m/z calcd for C22H26FN4O5S: 477.1602. Found: 477.1610.