Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1>C(O)C.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>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:2]2[CH:14]=[CH:13][C:5]3[O:6][C:7]([CH3:12])([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: COc1ccc(S)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1

Procedure:
6-Bromo-2,2,3-trimethyl-2H-benzo[b]pyran (9.637 g) (see Preparation 4) was dissolved in absolute ethanol (200 ml), then sodium tert -butoxide (11.029 g), 4-methoxybenzenethiol (4.9 ml) and tetrakis(triphenylphosphine)palladium(0) (0.454 g) were added and the mixture was heated under reflux under a nitrogen atmosphere for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using 1:1, hexane:dichloromethane as the eluent to yield 6-(4-methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.823 g) as a yellow oil.
Reaction SMILES: Br[C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][Cl:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C[Si]([C:21]#[N:22])(C)C.[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[Cl:15][CH2:14][CH2:13][CH2:12][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:4])([CH3:3])[C:21]#[N:22])=[CH:10][CH:9]=1)=[O:16]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(C(=O)CCCCl)cc1

Procedure:
Dissolve 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.00 g, 6.59 mmol) in anhydrous methylene chloride (20 mL) and place under an argon atmosphere. Add trimethylsilyl cyanide (1.10 mL, 8.25 mmol) followed by tin (IV) chloride (0.20 mL, 1.7 mmol) via syringe. Stir at reflux for 1 hour, add water (20 mL) and stir for an additional ½ hour. Separate the layers and extract the aqueous layer with methylene chloride. Combine the organic layers, wash with brine, dry (MgSO4), filter and evaporate the solvent in vacuo. Purify by silica gel chromatography (15% ethyl acetate/hexane) to give the title compound as a white solid; mp 79-80° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[C:10]([O:12][CH3:13])[CH:11]=1)[C:7]([OH:9])=[O:8].Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.O>O1CCCC1>[CH3:13][O:12][C:10]1[C:6]2[C:7](=[O:9])[O:8][C:16](=[O:18])[NH:14][C:5]=2[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)c2c(=O)oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 262.9 %

Procedure:
To a cooled (0° C.) brown solution of 4,6-dimethoxy anthranilic acid (76.0 g, 0.385 mol), prepared as in Example 2, in tetrahydrofuran (1.3 L) was added triphosgene (40.0 g, 0.135 mol) in portions over a 20 min period. After 30 min, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The reaction mixture was poured into an Erlenmeyer flask containing water and cooled to 0° C. with an ice bath. Additional water was added to facilitate the stirring of the thick solid formed. After stirring for 30 min, the reaction mixture was filtered to give a beige solid. The solid was washed with water, air-dried, and then dried under high vacuum to give 79.2 g (92%) of the isatoic anhydride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([N+]([O-])=O)[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:36])=[O:35])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.C(=N/[OH:53])/C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[C:29]([OH:53])[CH:28]=[CH:27][C:26]=4[S:34]([CH3:37])(=[O:35])=[O:36])[C:15]=3[CH3:38])=[CH:11][C:10]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: O/N=C\c1ccccc1
Reactant: Cc1c(-c2cc([N+](=O)[O-])ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(-c2cc(O)ccc2S(C)(=O)=O)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-5-nitrophenyl)quinolin-4-amine (3.0 mg, 4.8 μmol), (Z)-benzaldehyde oxime (1.0 μL, 9.6 μmol), 325 mesh potassium carbonate (2.7 mg, 0.019 mmol) and DMSO (9.6 μL) was heated in a microwave reactor for 45 min at 100° C. The reaction was cooled and diluted with water. The mixture was extracted with EtOAc (2×35 mL). The combined organic layers were washed with brine (1×20 mL) and dried over magnesium sulfate. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 20 min to provide 3-(4-(2,5-dimorpholinopyridin-3-ylamino)-7-fluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenol after extracting with satd sodium bicarbonate solution. 1H NMR (CDCl3) δ ppm 8.00 (1H, br. s.), 7.94 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.65 (1H, br. s.), 7.43 (1H, t, J=8.2 Hz), 6.91 (1H, d, J=8.4 Hz), 6.85 (1H, br. s.), 6.52 (1H, br. s.), 3.83-4.05 (4H, m), 3.76 (4H, t, J=4.7 Hz), 3.42 (2H, br. s.), 2.93-3.20 (9H, m), 1.99 (3H, br. s.). Mass Spectrum (ESI) m/e=594.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C.Cl>C(O)C.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH2:11]
Reactant: CC(C)(C)OC(=O)NCCSSc1ccccn1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: NCCSSc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
tert-Butyl 2-(pyridin-2-yldisulfanyl)ethylcarbamate (1.06 g, 3.70 mmol) in 16 ml of EtAc was added 4.0 ml of HCl (conc.) at RT. The mixture was stirred at RT for 0.5 h, diluted with ethanol/toluene (6 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried over a vaccum to afford 135 mg (88%) of the title compound. 1H NMR (CD3OD) 7.58 (m, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.83 (m, 1H), 3.34 (m, 2H), 3.02 (m, 2H); 13C NMR 158.69, 149.07, 137.81, 122.48, 120.98, 39.52, 36.94; MS m/z+ 187.10 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:44]=[CH:43][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=2)[O:30][CH2:31][CH:32]2[CH2:34][CH:33]2[C:35]([O:37]CC)=[O:36])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCCC1>O>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=2)[O:30][CH2:31][CH:32]2[CH2:34][CH:33]2[C:35]([OH:37])=[O:36])=[CH:43][CH:44]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC1COc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCC3CC3C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product from Example 284A was added 2N hydrochloric acid (1 mL), tetrahydrofuran (0.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature overnight. Water (2 mL) was added. The solution was neutralized with 1N hydrochloric aid until pH=2˜3. The product was extracted with ethyl acetate (2 mL), dried in vaccuo, and purified by HPLC to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.01-12.29 (br.s, 1 H), 8.95 (s, 1 H), 7.23 (m, 8 H), 7.03 (m, 1 H), 6.94 (m, 4 H), 6.69 (m, 1 H), 6.50 (m, 2 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (m, 1 H), 3.80 (m, 1 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 1.67 (m, 1 H), 1.57 (m, 1 H), 1.05 (m, 1 H), 0.92 (m, 1 H); MS (APCI+) m/z 587.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6](F)[CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:21](#[N:25])[CH:22]([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:22]([CH3:24])([CH3:23])[C:21]#[N:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(F)c1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cccc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
2-(3-Ethoxy-phenyl)-2-methyl-propionitrile was prepared using a procedure adapted from literature (Organic Syntheses, Vol. 79, pp. 209-215). To a solution of 1-ethoxy-3-fluoro benzene (3.0 g, 19.4 mmol) in 25 mL of toluene was added solid potassium bis(trimethylsilyl)amide (5.84 g, 29.2 mmol, 1.5 eq) followed by isobutyronitrile (7.08 mL, 77.8 mmol, 4 eq). The reaction mixture was stirred at 100° C. for 12 hr. It was diluted with 75 mL of ethyl acetate and 75 mL of 1N aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (1×50 mL), brine (1×50 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of methylene chloride and applied to a 40 g silica gel cartridge. The product was eluted using a gradient of ethyl acetate in hexanes to yield 2.96 g (15.6 mmol, 80%) of pure 2-(3-ethoxy-phenyl)-2-methyl-propionitrile. LR-MS: 190.12 [(M+H)+]
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+].C(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[S:10][CH:12]=1)[CH3:19]
Reactant: NC(=S)c1ccccc1O
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Yield: 92.6 %

Procedure:
A stirred solution of 2-hydroxybenzenecarbothioamide 3a (5.36 g, 35.0 mmol), ethyl 4-chloroacetoacetate (6.34 g, 38.5 mmol) in dry THF (70 mL) was heated to reflux under nitrogen for 2.5 days. At ambient temperature, the mixture was diluted with EtOAc (200 mL), then cautiously treated with saturated aq. NaHCO3 (40 mL), and followed by adding solid NaHCO3 in small portions until CO2 evolution ceased. The organic layer was separated, washed with brine (40 mL×2), dried over MgSO4, and filtered. After concentration in vacuo, the oily residue was chromatographed on silica gel gradient EtOAc/CH2Cl2 :0-4%) to provide 4a (8.53 g, 93%) as a white solid, which was recrystallized from toluene/hexane at -30° C. mp 35.5-36.5° C.; IR (neat) 3120, 1740, 480, 1225 cm-1 ; 1H NMR (DMSO-d6) δ1.15 (3H, t, J=7.1 Hz, CH3), 3.84 (2H, t, CH2), 4.07 (2H, q, J=7.1 Hz, CH2), 6.89 (1H, S, J=7.8 Hz, Ar), 6.97 (1H, d, J=7.8 Hz, Ar), 7.26 (1H, t, J=7.8 Hz, Ar), 7.48 (1H, s, 7.93 (1H, d, J=7.8 Hz, Ar, 11.29 (1H, s, OH); FABMS m/z 263 (M30 ), 264 (M+ +1); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.16; H, 4.97; N, 5.50.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C(Cl)Cl>[C:1]12([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[C:27]3=[O:28])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1cc(CCCNCCCNCCC23CC4CC(CC(C4)C2)C3)ccn1
Solvent: ClCCl
Product: O=C1N(CCCc2ccncc2)CCCN1CCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.33 h
Yield: 9.1 %

Procedure:
A solution of the obtained N-[2-(1-adamantyl)ethyl]-N′-[3-(4-pyridyl)propyl]-1,3-propanediamine (80 mg, 0.23 mmol) in anhydrous methylene chloride (10 ml) and a solution of 1,1′-carbonyldiimidazole (40 mg, 0.26 mmol) in anhydrous methylene chloride (10 ml) were simultaneously added dropwise to anhydrous methylene chloride (60 ml) at room temperature with stirring over 20 minutes. The mixture was stirred overnight, then the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the target compound (8.0 mg, 9.4%).
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[F:38])[NH:21][C:22]1[C:31]2[C:30]([OH:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=2[N:25]=[CH:24][N:23]=1.[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59][O:32][C:30]2[CH:29]=[C:28]([O:33][CH3:34])[CH:27]=[C:26]3[C:31]=2[C:22]([NH:21][C:20]2[CH:35]=[CH:36][C:37]([F:38])=[C:18]([Cl:17])[CH:19]=2)=[N:23][CH:24]=[N:25]3)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 692 mg) was added in one portion to a mixture of 4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-ol (640 mg), tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (830 mg), and triphenylphosphine (788 mg) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (884 mg, 70%); Mass spectrum MH+ 633.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.II.[N:13]1[CH:14]=[C:15]([CH:25]=[O:26])[N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:17]=12>C1COCC1>[C:5]1([CH2:4][CH2:3][CH:25]([C:15]2[N:16]3[C:17]([S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=43)=[N:13][CH:14]=2)[OH:26])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cnc2sc3ccccc3n12
Reactant: BrCCc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCc1ccccc1)c1cnc2sc3ccccc3n12

Procedure:
Magnesium metal (0.29 g), 12 g atom) in dry THF (70 mL) was treated with (2-bromoethyl) benzene (0.44 mL) and an Iodine crystal. When the Iodine color had discharged additional (2-bromoethyl)benzene (1.2 mL) was added and the suspension was reacted for 24 hours. Solid imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula J-3) (0.606 g, 3.0 mmol) was added and the mixture was reacted for 1.25 hours. The solution was decanted into 5% NH4Cl solution (250 mL) and the mixture was extracted with ethyl acetate. Drying and evaporation of the extract gave pure α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4) (0.81 g) after trituration of residue with acetonitrile. An aliquot of the triturated product was crystallized from acetonitrile solution to provide an analytical sample of α-(2-phenylethyl)-imidazo[2,1-b]benzothiazole-3-methanol (Formula J-4) (m.p. 174-175°).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].CC(O)=O.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](C=O)=[CH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:12][N:13]([CH2:15][C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH3:32])[CH:34]=3)[CH2:14]1)[CH2:10][C:9]2=[O:26]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Reactant: Cn1cc(C=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
TEA (0.11 ml, 0.77 mmol) was added to a suspension of Intermediate 4 (240 mg, 0.77 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (148 mg, 0.93 mmol) and NaBH(OAc)3 (197 mg, 0.93 mmol) following the procedure described in Example 31, Step A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (220 mg) as a light orange oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH2:13]>C(#N)C>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:9]([NH:10]2)=[C:9]2[NH:10][C:11]4[CH:12]=[C:4]([C:1](=[O:13])[CH3:2])[CH:5]=[CH:6][C:7]=4[C:8]2=[C:9]2[NH:10][C:11]4[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[C:8]=32)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)[nH]c1c3[nH]c4cc(C(C)=O)ccc4c3c3c4ccc(C(C)=O)cc4[nH]c3c21
Yield: 70.7 %

Procedure:
15 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.59 g of 6-acetylindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 16.2 g of ferric chloride anhydrate and 5.4 g of water in 100 ml of acetonitrile and agitating the resultant mixture solution for 15 minutes. Then, the prepared 6-acetyl indole solution was dripped over 60 minutes into the oxidant solution, and the resultant mixture solution was agitated for 5 hours at the temperature of 30° C. Color of the reaction solution changed from yellow to blue-green with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction liquid was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and was dried to obtain 1.11 g of 3,8,13-triacetyl-6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole (6-acetyl indole trimer) with a blue-green color (yield: 70%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.90 S/cm. The result of elemental analysis was: <C10.00H6.99N0.98O1.98Cl0.10>3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (72.2 mg, 0.2 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (38 mg, 0.24 mmol) to precipitate 5-[5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (55 mg, 55%). 1H NMR (DMSO-d6) δ2.27 (m, 1H), 2.32 (m, 1H), 2.39(m, 4H), 2.41, 2.42 (2×s, 6H, 2×CH3), 3.13 (s, 1H), 3.35 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.4 Hz, 1H, OH), 6.80 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.51 (t, J=5.6 Hz, 1H), 7.76 (s, 1H), 8.09 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 503.4 (M−1).
Reaction SMILES: [N+:1](C1C=C(S(Cl)(=O)=O)SC=1)([O-])=O.[N+:13]([C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1)([O-])=O.N>CC(C)=O>[NH2:13][C:16]1[S:20][C:19]([S:21]([NH2:1])(=[O:23])=[O:22])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)Cl)c1
Agent: N
Solvent: CC(C)=O
Product: Nc1ccc(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
A solution of 11.3 g (49.6 mmol) of a mixture that consists of 4-nitro-thiophene-2-sulfonyl chloride and 5-nitro-thiophene-2-sulfonyl chloride (ratio: 1.4/1.0) in acetone is added while being stirred to a saturated solution of ammonia in 170 ml of acetone at −35° C. After 30 minutes, the batch is filtered and concentrated by evaporation. The crude product is dissolved without further purification in 100 ml of ethanol. It is mixed with 6 g of Raney nickel and hydrogenated for 8 hours under low pressure at room temperature. The batch is filtered and concentrated by evaporation. 11.7 g of a mixture that consists of 4-amino-thiophene-2-sulfonic acid amide and 5-amino-thiophene-2-sulfonic acid amide is obtained at a ratio of 2:1, which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11](O)=[O:12])=[N:6][CH:7]=1.C[Si](C)(C)[O:21][NH2:22].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(NO)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH3:18])([S:14]([CH3:17])(=[O:16])=[O:15])[C:11]([NH:22][OH:21])=[O:12])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)ON
Reactant: CC(CCc1ccc(Br)cn1)(C(=O)O)S(C)(=O)=O
Agent: CC(CCc1ccc(Br)cc1)(C(=O)NO)S(C)(=O)=O
Product: CC(CCc1ccc(Br)cn1)(C(=O)NO)S(C)(=O)=O
Yield: 24.9 %

Procedure:
The title compound (454 mg, 25%) was prepared from 4-(5-bromopyridin-2-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (1740 mg, 5.2 mmol) and O-(trimethylsilyl)hydroxylamine (1810 mg, 15.5 mmol) by a procedure analogous to that described for the preparation of compound (IV) 4-(6-Bromophenyl-3-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide from Preparation 2, Step 5. MS (LCMS) m/z 351.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (s, 3H) 2.17-2.38 (m, 1H) 2.52-2.68 (m, 1H) 2.70-2.85 (m, 1H) 2.85-2.96 (m, 1H) 3.00 (s, 3H) 7.09 (d, J=8.20 Hz, 1H) 7.76 (dd, J=8.20, 2.34 Hz, 1H) 8.58 (d, J=2.34 Hz, 1H).