Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]([OH:28])=[O:27])=[CH:18]2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]>ClCCl>[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]([O:28][C:1]([C:2]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:17]([C:14]4[CH:15]=[CH:16][C:11]([S:8]([CH3:7])(=[O:10])=[O:9])=[CH:12][CH:13]=4)[CH:18]=3)=[O:5])=[O:27])=[CH:18]2)=[CH:13][CH:12]=1)(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(=O)O)c3cccnc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2cc(C(=O)OC(=O)c3cn(-c4ccc(S(C)(=O)=O)cc4)c4ncccc34)c3cccnc32)cc1
Temperature: 20 °C
Reaction time: 300 h

Procedure:
0.52 cm3 (6 mmol) of oxalyl chloride was added, under an argon atmosphere, to 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in 15 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 300 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was triturated with 20 cm3 of dichloromethane, filtered and pulled dry, and then the solid was washed with 50 cm3 of distilled water to give, after drying, 0.13 g of bis[1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic]anhydride in the form of a powder which was used directly in the following stage. IR spectrum (KBr): 3116, 2926, 1767, 1705, 1592, 1537, 1421, 1294, 1177, 1151, 1083, 999, 962, 775, 551 and 532 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: CCOC(=O)CN(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: CN(C)CC1CC(c2ccc(C(F)(F)F)cc2)c2ccccc2O1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using 4-bromobenzotrifluoride in place of 4-bromochlorobenzene in part (c) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[C:17](Cl)(=O)[C:18](Cl)=O>C(Cl)Cl.CN(C=O)C>[CH2:17]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1)[NH2:1])=[O:8])[CH3:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(N)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 3-nitro-5-trifluoromethylbenzoic acid (0.36 g, 1.53 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.58 g, 4.60 mmol) followed by DMF (3 drops). An immediate evolution of gas occurred and the reaction was stirred for 18 h. The solvent was removed under reduced pressure, the resulting oil was dissolved in THF (80 mL) and cooled to 0° C. To the cooled solution was added EtOH (5 mL) in THF (15 mL) and the mixture was stirred for 18 h at room temperature. The mixture was concentrated to remove the THF and the resulting precipitate was filtered and dried. The solid was dissolved in EtOH (25 mL) and 10% Pd/C (0.12 g) was added and the suspension was stirred for 15 h under a blanket of H2. The reaction was filtered through celite and the filtrate evaporated to dryness to provide 3-ethoxycarbonyl-5-trifluoromethylaniline as a yellow oil. This compound was then coupled to 2-chloro-4-trifluoromethyl pyrimidine-5-carbonyl chloride as described above to provide the title compound in a 12% yield; m.p. 67°-71° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)C(C)(C)CCC(=O)N2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)NC(=O)CCC3(C)C)ncc1Cl
Yield: 27.5 %

Procedure:
7-Amino-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (59 mg, 0.25 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (75 mg, 0.25 mmol), and 10-Camphorsulfonic acid (58 mg, 0.25 mmol), in Isopropyl alcohol (4 mL) were irradiated at 120° C. for 40 min in a CEM microwave. The sample was cooled, treated with MP-carbonate resin, filtered and conc. in vacuo. Silica gel chromatography afforded the product as a yellow solid (34 mg, 27%). MP: 197-199° C.; LCMS 495 (M+H); 1H-NMR, CDCl3: 11.1 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.16 (s, 1H), 7.50 (d, 1H, J=7.9 Hz), 7.43 (dd, 1H, J=7.7, 7.7 Hz), 7.30 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 3.90 (s, 3H), 3.07 (d, 3H, J=4.9 Hz), 2.40 (t, 2H, J=7.0 Hz), 2.08 (t, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:26]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:26]=2[S:34]([N:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CN(C)c1ccc(Nc2nc(Cl)ncc2Cl)c(S(=O)(=O)N(C)C)c1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4S(=O)(=O)N(C)C)n3)cc2CC1

Procedure:
The title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a yellow foam (0.053 g, 45%). MP: 72-82° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.75 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.04 (s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.20 (dd, 1H, J=8.1 Hz and J=2.0 Hz, 1H), 7.15 (d, J=2.8 Hz, 1H), 6.97 (d, J=8.1 Hz, 1H), 6.91 (dd, J=9.1 Hz and J=3.0 Hz, 1H), 6.88 (s, 1H), 3.53 (t, J=5.7 Hz, 2H), 3.36 (s, 3H), 3.02 (s, 6H), 2.91-2.80 (m, 4H), 2.76-2.66 (m, 12H). MS: 574.17 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (388 mg, 2.0 mmol) in dimethylformamide (5 mL) was added triethylamine, Et3N, (0.556 mL, 4.0 mmol) followed by trityl chloride (557.5 mg, 2.0 mmol) and 4-dimethylaminopyridine (DMAP) (20 mg). The reaction mixture was kept on stirring at room temperature overnight, poured into a mixture of ice-water, the white precipitate was collected by filtration. This precipitate was subjected to silica gel flash chromatography (0-5% ethyl acetate in petroleum ether) to give the subtitled compound (350 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH2:24]O)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[Cl-].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH2:24][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:11](=[O:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Reactant: C1COCCN1
Agent: [Cl-]
Product: COc1ccc(-c2cc(=O)n(CCN3CCOCC3)nc2-c2ccc(OC)cc2)cc1
Yield: 42.6 %

Procedure:
After 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one was reacted with paratoluenesulfonyl chloride in a similar manner as in Example 116-(2), a further reaction was conducted with morpholine, whereby the title compound was obtained in a yield of 42.6%.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Reaction time: 0.17 h
Yield: 29.8 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 6.9 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.5 mg (0.1 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCCl>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([CH2:47][C:43]5[S:42][CH:46]=[CH:45][N:44]=5)[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: O=Cc1nccs1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(Cc2nccs2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in 1,2-dichloroethane (1 mL) was added triethylamine (14 μL, 0.1 mmol), 2-thiazole-carboxaldehyde (6.6 mg, 0.05 mmol) and sodium triacetoxylborohydride (10.6 mg, 0.05 mmol). The resulting mixture was stirred for 4 hours at ambient temperature before it was quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvents, the residue was brought to a flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-methyl-1-(8-{2-[4-phenyl-1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]ethyl}-8-azabicyclo-[3.2.1]oct-3-yl)-1H-benzimidazole (23 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.65 (m, 2H), 7.46-7.37 (m, 2H), 7.34-7.15 (m, 7H), 5.32 (br, 1H), 3.68 (s, 2H), 3.54 (br, 2H), 2.82-2.80 (m, 2H), 2.67 (s, 3H), 2.63-2.47 (m, 4H), 2.25 (br, 4H), 2.08-1.96 (m, 8H), 1.86 (br, 2H). HRMS m/z (M+H)+ calcd: 526.3004, obsd: 526.3008.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][O:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1C[O:18]CC1>>[OH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:1]([OH:14])=[O:18]
Reactant: O=C1OCCc2c1[nH]c1ccccc21
Reactant: C1CCOC1
Product: O=C(O)c1[nH]c2ccccc2c1CCO
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 4,9-dihydro-3H-pyrano[3,4-b]indol-1-one (Arch. Pharm., 1987, 320, 1202–1209, 5.225 g, 27.9 mmol) in THF (25 mL) was added deoxygenated 3 N KOH (25 mL). The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was washed with EtOAc, acidified with 1 N HCl, and extracted with EtOAc. The organic extract was dried over MgSO4 and concentrated to give 5.589 g of 3-(2-hydroxyethyl)-1H-indole-2-carboxylic acid as a solid. This material was used for the next reaction without further purification: 1H NMR (DMSO-d6) δ 3.26 (t, J=7.5 Hz, 2H), 3.63 (t, J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H). Anal. Calcd. for C11H11NO3.0.1 EtOAc: C., 63.98; H, 5.56; N, 6.54. Found: C, 63.90; H, 5.57; N, 6.46.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[C:21]([CH3:22])[N+:18]([O-:20])=[O:19]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C(C)[N+](=O)[O-])c(OC)c1
Reaction time: 12 h

Procedure:
A solution consisting of 25 g of 2,4-dimethoxybenzaldehyde (Aldrich) in 200 ml of nitroethane was treated with 0.5 g anhydrous ammonium acetate and held on a steam bath for 12 hours. The solvent was removed in vacuo from the mixture yielding 22.3 g of yellow crystals, m.p. 80°-81° C., upon cooling in 50 ml of methanol.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)[CH:8]=[C:7]([CH:22]([CH3:24])[CH3:23])[N:6]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CCOCC>[CH3:25][S:26]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([F:21])=[CH:13][CH:12]=2)[CH:8]=[C:7]([CH:22]([CH3:24])[CH3:23])[N:6]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NCCN)n1
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(NCCNS(C)(=O)=O)n1

Procedure:
To a solution of 2-(2-aminoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.170 g) dissolved diethyl ether was added dropwise a solution of methansulfonyl chloride (0.060 g) in ether. The reaction was carried out at room temperature, and after 1 hour the solvent was removed under reduced pressure. The crude material was taken up in methylene chloride and the free base was liberated by the addition of sodium carbonate solution. The organic layer was dried over magnesium sulfate and the reaction product isolated by evaporation, purified by column chromatography on silica gel, eluting with ethyl acetate/hexane to give 2-(2-methanesulfonamidoethyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine. The hydrochloride salt of the product was made (0.180 g), m.p. 85-91° C. (C 54.67%, H 5.59%, N 12.48%).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].OO.C([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=3[CH:30]=2)=[CH:15][CH:14]=1)(=O)C>C(O)(=O)C>[C:3]([O:5][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][C:23]=3[CH:30]=2)=[CH:15][CH:14]=1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)c1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1

Procedure:
2 ml of trifluoroacetic acid and 92 ml of 30% hydrogen peroxide solution were added to a mixture of 13 g of 10 in 300 ml of acetic acid. The mixture was heated at 70°-75° C. for 10 hours, then was cooled in a refrigerator. The solid that formed was collected and dried. The acetic acid solution was poured into 3.6 liters of ice water. The solid that formed was collected and dried (P2O5). The two solids were combined and dissolved in 150 ml of tetrahydrofuran. The solution was filtered, concentrated to 20 ml and chilled. The solid that formed was collected, dried under reduced pressure, and recrystallized from tetrahydrofuran to give 11, mp: 251°-254° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])#[N:2].[NH2:20][OH:21]>C(O)C>[NH2:2][C:1](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:8]
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C#N)c1
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl [(3-cyanobenzyl)(methyl)amino]acetate (9 g, 34.6 mmol) in ethanol (60 mL) under N2, was added hydroxylamine (6 g, 178.8 mmol) in one portion. After being stirred at RT for 12 h, the reaction mixture was concentrated under reduced pressure to afford a colorless oil. It was triturated in diisopropyl ether, affording the title product as a white solid that was filtrated and dried under vacuo (8.5 g, 84%). 1H NMR (DMSO-d6, 300 MHz) δ 9.57 (1H, s), 7.59 (1H, s), 7.52-7.53 (1H, m), 7.29-7.31 (2H, m), 5.75 (2H, s), 3.61 (2H, s), 3.15 (2H, s), 2.23 (3H, s), 1.41 (9H, s). LC/MS (Method A): 294.0 (M+H)+. HPLC (Method B) Rt 3.31 min (Purity: 97.5%).
Reaction SMILES: [N:1](OCC(C)C)=[O:2].[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:9][CH:10]([CH3:12])[CH3:11].O1CCCC1.Cl>C(O)C>[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:1]=[O:2])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CON=O
Reactant: CC(C)CCN(C(=O)NCCCl)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CCN(C(=O)N(CCCl)N=O)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Yield: 67.3 %

Procedure:
Isobutyl nitrite (3.5 ml) was dropped into a solution of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.48 g, 8.47 mmol) in a mixture of ethanol (50 ml), tetrahydrofuran (150 ml), and 2N hydrochloric acid (30 ml) with well stirring at 0° to 5° C. Thereafter, 2.51 g of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained by the same operations of Example 63(2); yield 67.3%, m.p. 69°-71° C., [α]D20 +45.8° (C 1.0, methanol).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:15]([OH:31])=[C:16]([NH:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]([C:22]#[N:23])=[C:18]([CH3:21])[C:19]=1[I:20].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:19]([I:20])=[C:18]([CH3:21])[C:17]([C:22]#[N:23])=[C:16]2[C:15]=1[O:31][C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])=[N:24]2
Reactant: Cc1c(I)c(Br)c(O)c(NC(=O)C(C)(C)C)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(I)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Yield: 93.9 %

Procedure:
Toluene (25 ml), p-toluenesulfonic acid monohydrate (10.9 mg, 57.2 μmol) were added to N-(3-bromo-6-cyano-2-hydroxy-4-iodo-5-methylphenyl)-2,2-dimethylpropionamide (I-7) (250 mg, 572 μmol), followed by refluxing with a Dean-Stark condenser for 3 hours. After cooling, saturated sodium bicarbonate water (30 ml) was added to the reaction liquid, the product was extracted with ethyl acetate (50 ml×2). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the entitled compound (225 mg, 94%) as a pale yellow solid.