Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[C:16]([F:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Rh]>[F:18][CH:16]1[CH2:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[NH:13][CH:14]1[OH:15].[F:18][CH:16]1[CH2:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[NH:13][CH2:14]1
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@H](O)[C@@H]2O)cc1F
Agent: [Rh]
Solvent: O
Product: O=C1NC(O)C(F)CN1[C@@H]1O[C@H](CO)[C@H](O)[C@@H]1O
Product: O=C1NCC(F)CN1[C@@H]1O[C@H](CO)[C@H](O)[C@@H]1O

Procedure:
In the manner given in Example 2D, 1-β-D-lyxofuranosyl-5-fluorouracil, [C. N. Yung et al., J. Am. Chem. Soc. 83, 4060 (1961)] was catalytically hydrogenated in ammoniacal water in the presence of a rhodium on alumina catalyst to give 5-fluoro-4-hydroxy-1-β-D-lyxofuranosyl-tetrahydro-2(1H)-pyrimidinone and 5-fluoro-1-β-D-lyxofuranosyl-tetrahydro-2(1H)-pyrimidinone which were separated by extraction in a Craig apparatus.
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]2[C:18](=[O:19])[C:17](=[O:20])[C:16]=2OCC)C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[CH3:29][C:28]([O:27][C:25](=[O:26])[CH2:24][N:14]1[CH2:13][CH2:12][CH2:11][NH:10][C:16]2[C:17](=[O:20])[C:18](=[O:19])[C:15]1=2)([CH3:31])[CH3:30]
Reactant: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CC(=O)OC(C)(C)C)c(=O)c1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CC(C)(C)OC(=O)CN1CCCNc2c1c(=O)c2=O
Temperature: 20 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
To a cooled (20° C.) flask containing 10% palladium on carbon (5.25 g) under nitrogen was added [3-[[(1,1-dimethylethyloxycarbonyl)methyl]-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester (5.25 g, 11.8 mmol) in ethanol (500 mL), followed by 1,4-cyclohexadiene (11 mL, 0.12 mol) over 5 min. After 5 hours, the suspension was filtered through Celite® with generous ethanol washing (1 L). The ethanol was evaporated and the residue was dissolved in dichloromethane and purified by flash chromatography (7.5 cm diameter, gradient elution with 2.5-3% methanol in dichloromethane) to yield (8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)acetic acid 1,1-dimethylethyl ester as a white solid (2.59 g, 82%, mp 167°-168° C.); IR (KBr, cm-1): 3200, 1800, 1720; MS (EI): 266 (M+, 42), 210 (33), 166 (37), 165 (100), 154 (58), 138 (37), 70 (58); 1H NMR (DMSO, 400 MHz): δ 8.62 (br s, NH), 4.38 (s, 2H), 3.36-3.27 (m, 4H), 1.91 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH3:57]O>>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH3:57])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: CO
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Product: COCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Reference Example 21 were performed except for using methanol instead of ethanol, and from 72 mg (0.092 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, 48 mg of the title compound was obtained as a foam (yield: 66%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C>>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[N:33]=[CH:34][CH:35]=[CH:36][N:37]=4)[CH:27]=3)[CH2:24][C:23](=[O:39])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ncccn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (81 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[F:46])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2ccccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2F)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.23 g), sodium hydrogen carbonate (1.75 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.50 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.82 g, 78%).
Reaction SMILES: C([O-])(O)=O.[Na+].S(O)(O)(=O)=O.[NH2:11][CH2:12][C:13]#[N:14].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.O1CCOCC1.C(Cl)Cl>[CH2:15]([O:22][C:23](=[O:24])[NH:14][CH2:13][C:12]#[N:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CCNC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 56.8 %

Procedure:
NaHCO3 (1.09 g, 12.97 mmol) in water (5 mL) was added to a stirred solution of 2-aminoacetonitrile sulfate (1.0 g, 6.48 mmol) in 1,4-Dioxane (10 mL) at 0-5° C. followed by addition of Benzylchloroformate (1.3 g, 1.11 mL, 7.78 mmol) and stirring was continued at 20-35° C. for 15 h. Reaction mixture was diluted with DCM and washed it with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by Column chromatography (using Silica gel 60-120 and 10% MeOH in DCM as eluent) to afford 700 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([NH:19]C(=O)[O-])([CH3:18])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.[ClH:23]>C(O)C>[Cl-:23].[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C:16]([CH3:18])([NH3+:19])[CH3:17])=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1
Reactant: Cl
Reactant: CC(C)(COc1cccc2c1C(N)=NS(=O)(=O)N2)NC(=O)[O-]
Solvent: CCO
Product: CC(C)([NH3+])COc1cccc2c1C(N)=NS(=O)(=O)N2
Product: [Cl-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of tert-butyl(1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl-carbamate (114 g, 296 mmol) in ethanol (1 L), cooled to 0° C., was added HCl (4.0 M in dioxane, 370 mL, 1480 mmol). The mixture was stirred at 0° C. for 3 hours under nitrogen, and then allowed to warm to room temperature. The mixture was concentrated and the residue was suspended in diethyl ether (2 L) and refluxed for 1 hour. The mixture was cooled to room temperature and the solid was collected by vacuum filtration and dried under high vacuum to afford 1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-aminium chloride as a white solid (94 g, 100%). 1H NMR (DMSO-d6), 400 MHz: δ 1.37 (s, 6H), 4.12 (s, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.65 (s, 1H), 8.43 (br s, 3H), 10.9 (br s, 1H). MS 285 (MH+).
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[CH:8]1([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1C=CC=CC=1.O>C(Cl)Cl>[CH:8]1([C:14]2[CH:15]=[CH:16][C:17]([NH:18][C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:20]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloro(oxo)acetate (1.88 mL) was added to a stirred solution of 4-cyclohexylaniline (2980 mg) and pyridine (1.80 mL) in DCM (100 mL) at 0° C. After the addition was complete allowed to warm to ambient temperature and stirred for 16 hours. Water (50 mL) added. Extracted with DCM (2×75 mL). The organics were combined washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to give methyl [(4-cyclohexylphenyl)amino](oxo)acetate (4133 mg) as a solid; 1H NMR δ 10.66 (1H, s), 7.60 (2H, d), 7.19 (2H, d), 3.84 (3H, s), 2.50 (1H+DMSO, m), 1.84-2.65 (5H, m), 1.46-1.14 (5H, m); MS m/e M−H− 260.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([OH:29])=O)[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:66][CH2:67][CH2:68][CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:66][CH2:67][CH2:68][CH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71])=[O:29])[S:26][C:19]=23)=[CH:30][CH:31]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Reactant: CCOC(=O)CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (120 mg, 0.27 mmol) in 10 ml of anhydrous THF were added HATU (122 mg, 0.32 mmol) and N,N-diisopropylethylamine (104 mg, 0.81 mmol). The mixture was heated at 60° C. for 5 minutes, followed by addition of ethyl 4-aminobutyrate hydrochloride (67 mg, 0.40 mmol). The mixture was stirred for another 10 minutes, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate as white solid. Yield: 150 mg, 99%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)[CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:19]([O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:20][CH3:21]
Reactant: CCCOCCOc1cccc(OB(O)O)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in methylene chloride (15 ml) were added 3-(2-propoxyethoxy)phenylboric acid (0.67 g) and molecular sieves 4A (0.8 g), and the resulting mixture was stirred for 5 minutes. Thereto were added cupric acetate (0.27 g) and triethylamine (1.04 ml), and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered through celite, and the filtrate was washed with ethyl acetate. The resulting solution was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2) to obtain methyl 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.36 g).
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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:43])[CH2:40][C:41]#[CH:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:43][CH:39]([CH2:38][CH3:37])[CH2:40][C:41]#[CH:42])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C#CCC(O)CC
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCC(CC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 75.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 5-hexyn-3-ol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([F:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2)([O-])=O.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[CH3:25][O:24][C:22](=[O:23])[CH2:21][NH:1][C:4]1[CH:5]=[C:6]([F:19])[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:9]2
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cc(F)cc2cc(-c3ccccc3)[nH]c12
Product: COC(=O)CNc1cc(F)cc2cc(-c3ccccc3)[nH]c12

Procedure:
7-Nitro-5-fluoro-2-phenyl-1H-indole prepared in Preparation 27 and methyl bromoacetate were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Reaction time: 18 h
Yield: 70.6 %

Procedure:
To a solution of tetrahydro-3-furanmethanol (6.2 g, 60.8 mmol) in 60 mL tetrahydrofuran was added p-toluenesulfonyl chloride (11.6 g, 60.9 mmol) in one portion, followed by the drop-wise addition of triethylamine (9.2 mL, 66.4 mol) over 10 min. The resulting mixture was stirred at reflux for 16 h and then treated with triethylamine (1.6 mL, 11.5 mmol). Heating was continued for an additional 18 h. The cooled mixture was diluted with diethyl ether, washed with water and brine, and dried over MgSO4. The mixture was then filtered and concentrated under reduced pressure. The resulting residue was placed on a column of silica gel (30 g) and eluted with 5% to 80% ethyl acetate in hexanes to give 11.0 g (72%) of the title compound as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN(C(C)C)C(C)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(C2=NNCC2)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NN(C(=O)Cc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A scintillation vial equipped with a stir bar was charged with 3-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-pyrazole (412 mg, 2 mmol), Hunigs base (1 mL, 6 mmol) and dry CH2Cl2 (10 mL). To this mixture was added phenyl-acetyl chloride, (0.27 mL, 2 mmol) and the reaction was stirred at RT for 3 h. LC-MS indicated consumption of SM. The mixture was diluted with CH2Cl2 (50 mL) and added to water (50 mL). The phases were separated and the CH2Cl2 phase was washed with saturated Na2CO3, (50 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 100% EtOAc. Amount obtained: 123 mg, 0.37 mmol, 19% yield. LC-MS (ESI) m/e 325 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.21 (t, J=10.03 Hz, 2H) 3.94 (s, 3H) 3.98 (s, 3H) 4.04 (t, J=10.03 Hz, 2H) 4.11 (s, 2H) 6.90 (d, J=8.35 Hz, 1H) 7.16 (dd, J=8.27, 1.88 Hz, 1H) 7.21-7.26 (m, 1H) 7.31 (t, J=7.42 Hz, 2H) 7.40-7.44 (m, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:22]
Reactant: Cc1ccc(NC(C)C)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)CBr)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a stirred solution of 6.07 g (40.7 mmol) Isopropyl-p-tolyl-amine, prepared as in Part A, and 4.12 g (40.7 mmol, 1 equiv) Et3N in 50 mL DCM is added 8.22 g (40.7 mmol, 1 equiv) Bromoacetyl bromide in 25 mL DCM dropwise over 30 minutes at 0° C. The reaction mixture is stirred 1 h at 0° C. followed by warming to ambient temperature and stirring 18 h. The reaction mixture is washed with 1N HCl (3×50 mL), dried (MgSO4), filtered through a pad of 20 g silica gel eluted with 400 mL DCM, and concentrated in vacuo to give 9.39 g (34.5 mmol) of 2-Bromo-N-isopropyl-N-p-tolyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.25 (d, 2H, J=8.1), 7.09 (d, 2H, J=8.3), 4.96 (m, 1H), 3.55 (s, 2H), 2.42 (s, 3H), 1.07 (d, 6H, J=6.8); TLC Rf =0.23 (EtOAc/Hexanes, 1:9).
Reaction SMILES: C[CH:2]([S:6][CH:7](S(C)=O)[CH3:8])[S:3]([CH3:5])=[O:4].C([Br:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br-:19].[CH3:5][S:3]([CH2:2][SH+:6][CH2:7][CH2:8][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: CC(SC(C)S(C)=O)S(C)=O
Reactant: BrCc1ccccc1
Product: CS(=O)C[SH+]CCc1ccccc1
Product: [Br-]
Yield: 26 %

Procedure:
6.21 g of methylmethylsulfinylmethyl sulfide and 17.10 g of benzyl bromide were mixed, and were then allowed to stand in reaction at 50° C. for five months. The compound obtained was washed with ether, dried at 40° C. under reduced pressure, affording a precursor, methylsulfinylmethylbenzylmethyl sulfonium bromide. Yield: 26%.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:15][CH3:16]>>[CH2:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCI
Product: CCn1c2ccccc2c2ccccc21

Procedure:
Carbazole (4 g, 0.024 mol) was reacted with iodoethane by working in a similar manner to Example 1a).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[CH3:29]I.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][O:25][CH3:29])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: CI
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(-c2nn(C)c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
4-(7,8-Dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (17 mg, 44 μmol) is dissolved in N,N-dimethylformamide (2.1 ml) under argon, and methyl iodide (8.2 μl, 131 μmol) and sodium hydride (95%, 2.4 mg, 96 μmol) are subsequently added. The reaction solution is stirred at 0° C. for 2 h. After addition of a little water, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution for work-up. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-methoxymethylbenzonitrile (4 mg, 10.3 μmol) as a colourless solid. MS: 389.2 (M+H+), TLC (HPTLC): Rf=0.41 (ethyl acetate/ethanol 8:1, parts by volume).