Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:24]=1[Cl:25]>>[Br:19][C:20]1[CH:21]=[C:22]([S:26]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:28])=[O:27])[S:23][C:24]=1[Cl:25]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1cc(Br)c(Cl)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 4-bromo-5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.42-7.34 (m, 2H), 7.25 (br m, 3H), 7.13 (dd, J=9.0 & 17.1 Hz, 1H), 6.02 (dt, J=2.4, 6.6 & 17.4 Hz, 1H), 5.52 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:20])[CH3:19]>CCOC(C)=O>[CH2:17]([O:21][C:22]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)COc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CC(C)COc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3-Isobutoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-Isobutoxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-100% EtOAc in hexanes as eluant provided 170 mg (94%) of a pale yellow solid. MP 177-178° C., M+H=351.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[CH:5]=[C:6]([CH3:14])[C:7]=1[NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12]>CN=C=O.C1(CC#N)C=CC=CC=1.C(N(CC)CC)C>[CH3:7][NH:8][C:9](=[O:13])[O:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:13])[CH2:10][O:11][CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: COCC(=O)Nc1c(C)cc(O)cc1C
Agent: CN=C=O
Solvent: N#CCc1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cc(C)c(NC(=O)COC)c(C)c1
Reaction time: 48 h

Procedure:
3,5-Dimethyl-4-methoxyacetamidophenol (0.8g., 0.0038 mole, m.p. 169°-73° C., prepared by reaction of methoxyacetyl chloride with 3,5-dimethyl-4-aminophenol) was reacted with methyl isocyanate (0.245g., 0.004 mole) in benzeneacetonitrile using a few drops of triethylamine as a catalyst. After stirring the initially clear reaction solution for about two days, the precipitated product was filtered (0.6g., m.p. 179.5°-82° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]\[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)[CH3:36]>C1C=CC=CC=1>[CH2:35]([O:37][C:38](=[O:51])[C@@H:39]([O:48][CH2:49][CH3:50])[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:15][CH2:14]/[CH:13]=[C:12](\[C:9]2[CH:10]=[CH:11][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH:8]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:43][CH:42]=1)[CH3:36]
Reactant: OC/C=C(/c1ccccc1)c1ccc(-c2ccco2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(-c3ccco3)cc2)cc1)OCC
Yield: 48 %

Procedure:
Reaction of (Z)-3-(4-furan-2-yl-phenyl)-3-phenyl-prop-2-en-1-ol (300 mg, 1.09 mmol), tributylphosphine (0.40 ml, 1.64 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (286 mg, 1.20 mmol) and azodicarboxylic dipiperidide (413 mg, 1.64 mmol) in benzene in an identical manner to example 3 gave the title compound (260 mg, 48%).
Reaction SMILES: [O:1]([CH2:9][C@@:10]12[C@@H:27]3[C@H:18]([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C:22](=[O:28])[CH2:21][CH2:20]4)[CH2:17][C@H:16]([CH3:29])[C:15]1=[CH:14][C:13](=[O:30])[CH2:12][CH2:11]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].O(C[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2)[Si](C(C)(C)C)(C)C>>[O:1]([CH2:9][C@@:10]12[C@@H:27]3[C@H:18]([C@H:19]4[C@@:23]([CH2:25][CH2:26]3)([CH3:24])[C:22](=[O:28])[CH2:21][CH2:20]4)[CH2:17][C:16]([CH3:29])=[C:15]1[CH2:14][C:13](=[O:30])[CH2:12][CH2:11]2)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO[Si](C)(C)C(C)(C)C)CCC(=O)C=C12
Agent: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC1=C2CC(=O)CC[C@]2(CO[Si](C)(C)C(C)(C)C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@@H]2C1

Procedure:
Substituting 19-t-butyldimethylsiloxy-6α-methyl-4-androstene-3,17-dione, 19-(4'-tetrahydropyranyloxy)androst-4-ene-3,17-dione, 4-methyl-17β,19-di(4'-tetrahydropyranyloxy)-4-androsten-3-one and 1β-methyl-19-(4'-tetrahydropyranyloxy)-4-androsten-3,17-dione for the 19-t-butyldimethylsiloxy-4-androstene-3,17-dione above results in the preparation of 19-t-butyldimethylsiloxy-6-methyl-5-androstene-3,17-dione, 19-(4'-tetrahydropyranyloxy)androst-5-ene-3,17-dione, 4α-methyl-17β,19-di(4'-tetrahydropyranyloxy)-5-androsten-3-one and 1β-methyl-19-(4'-tetrahydropyranyloxy)-5-androsten-3,17dione, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([OH:29])=O.Cl.[CH3:31][O:32][C:33]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]2[C:34]=1[CH2:35][CH2:36][NH:37][CH2:38]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:33]=2[O:32][CH3:31])[CH2:38]1)=[O:29]
Reactant: COc1cc2c(c(OC)c1)CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3cc(OC)c(OC)cc13)C2
Yield: 45.3 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 118 (45.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.86 and 3.01 (2t, 2H), 3.45-4.05 (m, 23H), 4.23 and 4.77 (2s, 2H), 6.33-6.49 (m, 2H), 6.90 and 7.15 (2s, 1H), 7.48 and 7.50 (2s, 1H), 7.78 and 7.83 (2s, 2H); MS (ESI) m/z 576 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N-:17]=[N+:18]=[N-:19].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:17]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:4]=1)[CH3:9])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc(F)c(N2CCOCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(F)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluoro-3-morpholin-4-yl-phenyl)ethanol (3.7 g) and diphenylphosphory azide (6.765) in toluene (24 mL) at 0° C. was added a solution of DBU (3.74 g) in toluene (2 mL) and the resulting solution was stirred at 0° C. for 2 hours. The reaction mixture was warmed to room temperature and then stirred for 16 hours. The reaction was diluted with ethyl acetate and quenched with water. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (10% ethyl acetate in hexane) to give 3.71 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(CCCN2CCN(C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 30.4 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (110 mg, 0.24 mmol), 2-(methyloxy)-4-[3-(4-methyl-1-piperazinyl)propyl]aniline (56 mg, 0.21 mol), and p-toluenesulfonic acid (109 mg, 0.57 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 hours. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (50 mg, 0.073 mmol, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.39 (d, J=6.59 Hz, 1H), 8.50 (s, 1H), 8.31-8.34 (m, 1H), 8.25 (d, J=5.31 Hz, 1H), 8.02-8.06 (m, 1H), 7.79-7.82 (m, 1H), 7.73 (d, J=8.97 Hz, 1H), 7.56-7.64 (m, 2H), 7.45 (ddd, J=8.88, 6.78, 1.19 Hz, 1H), 7.35-7.41 (m, 1H), 7.20 (td, J=8.06, 5.13 Hz, 2H), 6.98 (t, J=6.87 Hz, 1H), 6.93 (d, J=1.47 Hz, 1H), 6.74 (dd, J=8.15, 1.56 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 3.80 (s, 3H), 2.56 (t, J=7.60 Hz, 2H), 2.32-2.42 (m, 2H), 2.21-2.32 (m, 8H), 2.11 (s, 3H), 1.67-1.76 (m, 2H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24].O>CCOCC>[CH3:26][S:23]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])(=[O:25])=[O:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 232 mg of alcohol 16b in 10 ml of ether was added 1 ml of triethyl amine, followed at 0° C. by 80 μl of mesyl chloride. The mixture was stirred at ambient temperature for 1 hr and then poured into water and extracted into ether. The organic extract was washed with water, dried and concentrated, to give 320 mg of 16c as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[CH3:24])=O)(=O)OC.O.[NH2:30][NH2:31]>>[C:25]([N:22]1[C:23]([CH3:24])=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:31][N:30]=2)[CH:20]=[N:21]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C)OC
Solvent: O
Product: Cc1c(-c2cc3c(nn2)C2CCC3C2)cnn1C(C)(C)C

Procedure:
light yellow crystalline solid. MS (ESI): 283.2 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])(=O)[CH3:2].Cl.[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25].CC([O-])=O.[Na+]>CCO>[CH2:23]([O:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=1[NH:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH3:2])[CH:24]=[CH2:25]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCON=C(C)c1ccc(C(F)(F)F)cc1NS(=O)(=O)C(F)(F)F
Yield: 79.4 %

Procedure:
A solution of N-(2-acetyl-5-trifluoromethylphenyl)trifluoromethanesulfonamide 35 (168 mg, 0.50 mmol), O-allylhydroxylamine hydrochloride (60mg, 0.53 mmol) and anhydrous NaOAc (43 mg, 0.53 mmol) in EtOH (3 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:99) to afford N-[2-(1-allyloxyiminoethyl)-5-trifluoromethylphenyl]trifluoromethanesulfonamide 241 (155 mg, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.82, br s, 1H; 7.98, s, 1H; 7.65, d, J=8.2Hz, 1H; 7.49, d, J=8.2Hz, 1H; 6.02, m, 1H; 5.44, d, 3J=17.2 Hz, 1H; 5.37, d, 3J=10.4 Hz, 1H; 4.72, d, J=6.0 Hz, 2H; 2.38, s, 3H. HRMS (M+) 390.0465.
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=O)C1C=CC=CC=1.[H-].[Na+].CI.[C:69](=[O:72])([O-:71])O.[Na+]>CN(C)C=O>[CH2:26]([O:71][C:69]([CH2:9][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=[O:72])[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C([O-])O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNC(=O)OCc2ccccc2)C(=O)CO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNCC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reaction time: 1 h

Procedure:
The stirred solution of 0.351 g of benzyl 3-[4-(4-benzyloxycarbonylaminobutyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 8 ml of N,N-dimethylformamide is admixed at 0° C. with 0.031 g of sodium hydride (60% dispersion). After 1 hour, 0.144 ml of methyl iodide is added and the mixture is kept at 75° C. over 18 hours. The mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:1 EtOAc-heptane); Rt=6.18.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[O:24])[N:20]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: COCCN
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OCC(C)C)c1
Product: COCCNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC(C)C)n1
Yield: 62 %

Procedure:
2-{2-[3-(2-Isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-N-(2-methoxy-ethyl}-acetamide (130 mg, 62%) was prepared from {2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (181 mg, 0.5 mmol) and 2-methoxyethylamine following the general procedure K.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:37])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH:25]([CH3:26])[CH3:27])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Oc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccccc12
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(C(=O)[NH+]([O-])c2c(Cl)cncc2Cl)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide (60 mg, 0.144 mmol) (example 32) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.722 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 30% acetone-chloroform as the eluent to give 57 mg of N-(3,5dichlorpyrid-4-yl)-4-isopropyloxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 247-248° C.
Reaction SMILES: [ClH:1].[N+](C1C=CC(CCC[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=CC=1)([O-])=O.[Cl-].[CH3:21][S:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:39])[CH2:33]C2[NH2+]C=CN=2)=[CH:28][CH:27]=1)(=[O:24])=[O:23]>O.[Pd]>[Cl-:1].[OH:39][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][S:22]([CH3:21])(=[O:23])=[O:24])=[CH:31][CH:30]=1)[CH2:33][NH+:17]1[CH:18]=[CH:19][N:15]([CH3:14])[CH2:16]1
Reactant: Cl
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CC2=NC=C[NH2+]2)cc1
Reactant: O=[N+]([O-])c1ccc(CCCCn2ccnc2)cc1
Agent: [Pd]
Agent: [Cl-]
Solvent: O
Product: CN1C=C[NH+](CC(O)c2ccc(NS(C)(=O)=O)cc2)C1

Procedure:
A solution of 152.3 g (0.463 mole) of 3-methyl-1[2-[4-((methylsulfonyl)amino)phenyl-2-oxoethyl]-1H-imidazolium chloride in 1 L of distilled water and 7.62 g 10% Pd/C catalyst are placed in a 2 L Parr bottle and hydrogenated at 50 psi pressure for ca. 5 hours. Additional H2 is added as needed to maintain 50 psi pressure. The reaction mixture is filtered and the solvent is evaporated by azeotroping with ethanol to provide the title compound, which may be recrystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:10]2[CH:5]([C:6](=O)[CH2:7][CH2:8][CH2:9]2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.CC1(C)C2C(C(=O)C(=O)CC2)C(C)(C)C1C.[CH:47]([NH2:49])=[O:48]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH:10]2[CH2:9][CH2:8][C:7]3[O:48][CH:47]=[N:49][C:6]=3[CH:5]2[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: NC=O
Reactant: CC1C(C)(C)C2CCCC(=O)C2C1(C)C
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Agent: CC1C(C)(C)C2CCC(=O)C(=O)C2C1(C)C
Solvent: Cc1ccccc1
Product: CC1C(C)(C)C2CCc3ocnc3C2C1(C)C
Temperature: 200 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-octahydro-inden-4-one is first prepared by the hydrogenation of 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF). 1,1,2,3,3-Pentamethyl-hexahydro-indene-4,5-dione is subsequently prepared with 1,1,2,3,3-pentamethyl-octahydro-inden-4-one (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-hexahydro-indene-4,5-dione (10 g, 0.04 mol) and formamide (50 mL). The reaction mixture is heated to 200° C. and stirred for 24 hours. The crude mass is diluted with toluene (50 mL) and then washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Toluene is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product of a mixture of 6,6,7,8,8-pentamethyl-5,5a,6,7,8,8a-hexahydro-4H-1-oxa-3-aza-as-indacene and 6,6,7,8,8-pentamethyl-5,5a,6,7,8,8a-hexahydro-4H-indeno[4,5-d]oxazole (˜10 g) is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH:14]([C:21](=[O:33])[N:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH2:13][CH:14]([C:21](=[O:33])[N:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCCCN(CCCCC)C(=O)C(CCC(=O)OC)CS(=O)(=O)c1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCN(CCCCC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a solution of methyl 5-(4-acetylphenylsulfonyl)-4-(N,N-dipentylcarbamoyl)pentanoate (0.35 g) in methanol (15 ml) was added a 1N sodium hydroxide solution (1 ml). After stirring at room temperature for hours, the reaction mixture was concentrated in vacuo, acidified with a dilute hydrochloric acid, and extracted with chloroform. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was recrystallized from dichloromethane-hexane to give 0.27 g of 5-(4-acetylphenylsulfonyl)-4-(N,N-dipentylcarbamoyl)pentanoic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]Cl.[Na+].[CH3:21][OH:22]>C(O)(=O)C>[CH3:21][O:22][C:16]([CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:17]
Reactant: CO
Reactant: O=CC1CCC(COCc2ccccc2)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: COC(=O)C1CCC(COCc2ccccc2)CC1
Yield: 65 %

Procedure:
To a mixture of (4-benzyloxymethyl-cyclohexyl)-methanol (1.40 g, 6 mmol) in dichloromethane 28 mL is added Dess-Martin periodinate (2.53 g, 6 mmol) at 0° C., and the mixture is stirred for 0.5 hour while warming to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain 4-benzyloxymethyl-cyclohexanecarbaldehyde as clear oil (1.07 g, 79%) after purification. 4-Benzyloxymethyl-cyclohexanecarbaldehyde (1.70 g, 2.0 mmol) is dissolved in acetic acid (0.24 mL) and 2 mL of methanol. The reaction mixture is cooled to 0° C. to 5° C. and stirred while 10% NaOCl solution (2.5 mL, 4 mmol) is added dropwise over 20 minutes. The cooling bath is removed, and the mixture is allowed to come to room temperature. After addition of saturated aqueous NaHCO3, the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain 4-benzyloxymethyl-cyclohexanecarboxylic acid methyl ester as clear oil (343 mg, 65%) after purification.
Reaction SMILES: O[N:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][CH3:17])[CH:9]=2)=[O:4]>O>[CH3:17][O:16][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[O:15][N:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:3](=[O:4])[C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=1
Reactant: COc1ccc2c(O)c(C(=O)N(O)c3ccccc3)cnc2c1
Solvent: O
Product: COc1ccc2c(c1)ncc1c(=O)n(-c3ccccc3)oc12
Yield: 20.2 %

Procedure:
Using the procedure of Step B of Example 2, 3.68 g of N,4-dihydroxy-7-methoxy-N-phenyl-3-quinoline carboxamide were reacted and after 18 hours at ambient temperature, the reaction mixture was poured into water and the products which crystallized were extracted with dichloromethane. The organic phase was washed with water and the solvent was eliminated. The residue was chromatographed on silica and eluted with a mixture of methylene chloride-ethyl acetate (9-1) to obtain 0.7 g of 7-methoxy-2-phenylisoxazolo(4,5-c)quinolin-3-(2H)-one melting at 170° C.