Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-].O>C1COCC1>[CH3:15][C:12]1[N:11]=[CH:10][C:9]([C:6]2([C:7]#[N:8])[CH2:2][CH2:3][CH2:4][O:5]2)=[CH:14][N:13]=1
Reactant: Cc1ncc(C(C#N)OCCCBr)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(C2(C#N)CCCO2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (24 mg, 0.089 mmol) in THF (3 mL) was cooled at −78° C. Lithium bis(trimethylsilyl)amide in THF (141 μl, 0, 141 mmol, 1 molar) was added slowly and the mixture was stirred for 1 hour at −78° C. To the reaction mixture was added sat. aq. NH4Cl (10 mL) and the mixture was allowed to warm to room temperature. The reaction mixture was dilluted with H2O (10 mL) and extracted with AcOEt (3×15 mL). The combined org. phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was used directly for next step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:1](=[O:3])[CH3:2])[CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccccc2O)nc2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1cc(C(=O)OCc2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Acetic anhydride (1 mL) was added to a pyridine (10 mL)) solution of 2-(2-hydroxyphenyl)-4-quinolinecarboxylic acid benzyl ester (1.09 g, 3.07 mmol) obtained above, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated, and then, the residue was purified by silica gel column chromatography to obtain 2-(2-acetoxyphenyl)-4-quinolinecarboxylic acid benzyl ester (940 mg, 2.34 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:15]=[CH:14][C:13]=2[N+:26]([O-])=O)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5])[CH3:2].Cl>[Zn].O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])nc1-c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.066 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VI.1c), 0.5 mL of 1M hydrochloric acid, 2 mL of tetrahydrofuran was added 0.060 g of zinc powder. The suspension was stirred at ambient temperature for 2 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with 2 mL of saturated sodium bicarbonate, 10 mL of water and extracted three times with 5 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2-[2-amino-5-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-4-phenyl-thiazole-5-carboxylic acid ethyl ester (VII.1a) as a yellow oil. This material was carried to next step of reaction without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([CH3:17])[C:11]=3[N:10]=[CH:9]2)=N[CH:7]=1.[CH3:18]O>[Pd].[Pt].CC(O)=O>[CH3:17][C@H:12]1[C:11]2[N:10]=[CH:9][N:8]([C:5]3[CH:18]=[CH:7][CH:2]=[CH:3][N:4]=3)[C:16]=2[CH2:15][CH2:14][NH:13]1
Reactant: Cc1nccc2c1ncn2-c1ncc(F)cn1
Reactant: CO
Agent: [Pd]
Agent: [Pt]
Solvent: CC(=O)O
Product: C[C@@H]1NCCc2c1ncn2-c1ccccn1

Procedure:
The title compound was prepared in a manner analogous to Example 153, Step D substituting the product from Example 191, Step 2 for 1-(5-fluoropyrimidin-2-yl)-4-methyl-1H-imidazo[4,5-c]pyridine, Pd/C for Pt/C and MeOH for AcOH. MS (ESI) mass calcd. C12H14N4, 214.1. m/z found, 215.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])[C:7]2=[O:12].[CH2:26](OCC)C.[N+](=C)=[N-]>CO>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[CH:5]=[C:6]([C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[CH:18][C:14]=1[C:15]([O:17][CH3:26])=[O:16])[C:7]2=[O:12]
Reactant: CCOCC
Reactant: COc1cc(C)cc(C(=O)O)c1C1=CC(=O)c2c(O)cccc2C1=O
Agent: C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1cc(C)cc(OC)c1C1=CC(=O)c2c(O)cccc2C1=O

Procedure:
In methanol (50 ml) was dissolved 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoic acid (1 g) as obtained in Example 15, followed by addition of a diethyl ether solution of diazomethane (20 ml). The mixture was allowed to stand at room temperature for an hour, after which the diethyl ether and methanol were distilled off. The residue was subjected to silical gel chromatography and recrystallized from diethyl ether-n-hexane. The procedure yielded yellow crystals (500 mg) of methyl 2-(5-hydroxy-1,4-naphthoquinon-2-yl)-3-methoxy-5-methylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cnc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 3-methyl-5-nitro-2-(4-(trifluoromethyl)phenyl)pyridine (223 mg, 0.79 mmol) in ethanol (30 mL) was added 10 wt % palladium on carbon (100 mg). The reaction was pressurized to 50 psi hydrogen and was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and concentrated to give 5-methyl-6-(4-(trifluoromethyl)phenyl)pyridin-3-amine (198 mg, 99%). 1H NMR (400 MHz, CDCl3, δ): 8.04 (s, 1 H), 7.67 (m, 2 H), 7.60 (m, 2 H), 6.91 (s, 1 H), 3.72 (br s, 2 H), 2.30 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[O:12]([CH2:11][C@H:10]([OH:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccccc1C[C@@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
Under ice-cooling, to a solution of (R)-3-(2-methoxyphenyl)propane-1,2-diol (1.62 g) and imidazole (0.92 g)in dimethylformamide was added t-butyldimethylsilyl chloride (1.36 g),and stirred for 15minutes successively. The reaction solutionwas poured into water, extracted with ethyl acetate, and dried oversodium sulfate. After the solvent was evaporated in vacuo, thegained crude product was purified by silica gel columnchromatography, and it was eluted with a mixed solvent of hexaneand ethyl acetate (7:1, v/v). The fractions containing the desiredproduct were combined and evaporated in vacuo to obtain (R)-1-t-butyldimethylsiloxy-3-(2-methoxyphenyl)-2-propanol(2.22 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1.Cl[C:15]1[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=1>C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: COc1cc(N)nc(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C#N)s2)nc(OC)n1
Temperature: 40 °C

Procedure:
A flame dried flask under Ar was charged with sodium hydride (110 mg, 60% dispersion, 2.77 mmol) and 3 mL anhydrous THF. 2,6-Dimethoxy-pyrimidin-4-ylamine (118 mg, 0.76 mmol) was added slowly. After the resulting bubbling ceased, 2-chloro-thiazole-5-carbonitrile (100 mg, 0.69 mmol) was added and the reaction was heated to 40° C. After several hours the reaction was cooled to room temperature, the ThF was removed in vacuo, and the mixture was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid was purified by flash column chromatography (eluted with 3:1 hexane/EtOAc) followed by purification by reverse phase HPLC. The product was free based with sat NaHCO3 (aq) and filtered to give a pure sample of the title compound. 1H-NMR (300 MHz, DMSO-d6) 12.36 (s, 1H), 8.29 (1H, s), 6.02 (1H, s), 4.02 (s, 3H), 3.87 (s, 3H). mp>250.
Reaction SMILES: Cl[C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[Cl:9][C:10]1=[C:11](Cl)[C:12](O[C:15]1=O)=O.C=CC(Cl)=C.Cl>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.ClC1C=CC=CC=1.O>[Cl:9][C:10]1[CH2:15][C:7]2[C:6](=[O:8])[O:5][C:3](=[O:4])[C:2]=2[CH2:12][CH:11]=1
Reactant: O=C1C=C(Cl)C(=O)O1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: C=CC(=C)Cl
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1OC(=O)C2=C1CC=C(Cl)C2
Temperature: 92 °C
Reaction time: 16 h
Yield: 498.4 %

Procedure:
A 3-necked 50 mL flask was equipped with a pressure equalizing additional funnel, a thermocouple well with a thermocouple, a water cooled condensor and a magnetic stir bar. The flask was charged with 6.62 g (0.05 mol) of monochloromaleic anhydride contaminated with approximately 0.005 mol of dichloromaleic anhydride, 6.1 g of monochlorobenzene and 100 mg of phenothiazine. The contents of the flask were heated to 92° C. and 4.42 g (0.05 mol) of chloroprene was added over 15 to 30 minutes. HCl gas was observed evolving from the reactor. After 16 hours at 92° C., the solvent was removed in-vacuo and triturated with 10 mL of diethyl ether to yield 4.6 g (50% of theoretical) of 4-chloro-3,6-dihydrophthalic anhydride. High resolution mass spectrometry (MS) of the solid resulted in the following analysis: Calculated mass=183.99271; observed mass=183.9924. 13C and 1H nuclear magnetic resonance (NMR) spectra were consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[N:17]=[CH:18][N:19]([CH3:30])[C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:31].CO.[OH-].[Na+]>O1CCCC1>[C:24]1([S:21]([C:20]2[N:19]([CH3:30])[CH:18]=[N:17][C:16]=2[CH2:15][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=2[CH3:31])(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)Cn1c(C)c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ncn(C)c2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A mixture of [3-(5-benzenesulfonyl-1-methyl-1H-imidazol-4-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.027 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.12 mL) was stirred at room temperature for 1 hour. The mixture was treated with tetrahydrofuran (1.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.24 mL), and stirred at room temperature for 4 hours and then at 40° C. for 30 minutes. The mixture was concentrated under reduced pressure and acidified by the addition of 1.0 M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.024 g).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC=CC=2N=1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25]C)=O.[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[NH:17]1[C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23](=[O:25])[NH:29][C:28]1=[O:27]
Reactant: N#C[O-]
Reactant: COC(=O)c1sccc1N
Agent: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2sccc2[nH]1

Procedure:
Scheme 1 shows the synthesis of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 starting by cyclization of methyl 3-amino-thiophenecarboxylate 1 and potassium cyanate in acetic acid and water at room temperature to give thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2. This is an improvement over cyclization of 1 with urea which requires high temperature and evolution of ammonia gas. Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 was converted to 2,4-dichlorothieno[3,2-d]pyrimidine 3 with phosphorous oxychloride and a catalytic amount of N,N-dimethylaniline (0.75 equiv.) in acetonitrile. Selective substitution at the 4-position with morpholine gave 4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15][C:14](=[O:23])[CH2:13][CH:12]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:31]O.Cl.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCO.O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:15][C:14](=[O:23])[NH:31][CH2:13][C@@H:12]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(Cl)c2)C1
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](c2ccccc2)[C@]2(C(=O)Nc3cc(Cl)ccc32)[C@@H](c2cccc(Cl)c2)CN1
Temperature: 90 °C
Yield: 12.6 %

Procedure:
In a manner similar to the method described in example 2 (method B), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-phenylspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (150.0 mg, 0.34 mmole) was reacted with NH2OH—HCl (119.5 mg, 1.72 mmol), NaOH (68.8 mg, 1.72 mmole) in EtOH-water (3/2, 10 mL) at refluxing for 2 hrs, followed by reacting with p-toluenesulfonyl chloride (133.1 mg, 0.70 mmol) in dichloromethane (10 mL) at room temperature for 2 hrs, and heating under microwave irradiation at 90° C. for 20 min. After diluted with AcOEt the mixture was washed with water, dried over Na2SO4 and concentrated. The residue was purified by chiral column chromatography to give (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-phenyl-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (19.4 mg): HRMS (ES+) m/z Calcd for C25H20Cl2N2O2+H [(M+H)+]: 451.0975, Found: 451.0974; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-phenyl-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (20.1 mg): HRMS (ES+) m/z Calcd for C25H20Cl2N2O2+H [(M+H)+]: 451.0975, Found: 451.0974; (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-phenyl-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (20.5 mg): HRMS (ES+) m/z Calcd for C25H20Cl2N2O2+H [(M+H)+]: 451.0975. Found: 451.0974; (3S,4R,5R)-6-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-phenyl-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (21.6 mg): HRMS (ES+) m/z Calcd for C25H20Cl2N2O2+H [(M+H)+]: 451.0975. Found: 451.0974.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-].Br[CH:23]([CH3:25])[CH3:24].Cl>CN(C=O)C.CCOC(C)=O>[OH:10][C:9]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Br
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
To a mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (1.0 g, 5.46 mmol) in dry DMF (10 mL) was added Cs2CO3 (3563 mg, 10.93 mmol), NaI (819 mg, 5.46 mmol) and 2-bromopropane (1009 mg, 8.20 mmol) and the mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature and added 1N HCl till pH=7, followed by a standard aqueous/EtOAc workup. The residue was purified by silica gel column chromatography (DCM:THF=20:1) to give Intermediate 49 as a yellow solid (230 mg, 18.7%). 1H NMR (DMSO-d6 500 MHz TMS): δ 9.86 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 4.79 (m, 1H), 1.28 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)C#CCCCCC.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48]CC2)CCCCC1>O1CCCC1>[CH3:1][N:42]([C:43]1[CH:48]=[CH:49][CH:50]=[CH:45][N:44]=1)[CH3:36]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: CCCCCC#CC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 730 mg of radicicol, 701 mg of 2-octynoic acid, 15 ml of dry tetrahydrofuran, 1.03 g of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 611 mg of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH:21]([CH3:23])[CH3:22].[CH3:24][CH2:25][O:26][C:27]([CH:29](P(OCC)(OCC)=O)[F:30])=[O:28].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:29](/[F:30])\[C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:3]=1[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-112, 262 mg, 0.69 mmol) and triethyl 2-fluoro-2-phosphonoacetate (669 mg, 2.76 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.73 mL, 2.76 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][N:12]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC[C@@H](CN)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 86A from 171 mg (0.52 mmol) of tert-butyl{(3S)-4-azido-3-[(tert-butoxycarbonyl)amino]butyl}carbamate (Example 91A) in 10 ml of ethanol with the addition of 20 mg of palladium on activated carbon (10%). The product is reacted without further purification.
Reaction SMILES: Br[CH2:2][C:3]1C2C(=CC=CC=2)NC(=O)[CH:4]=1.[Br:14][CH2:15][CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH:18]=1.BrCCCC1C2C(=CC=CC=2)NC(=O)C=1>>[Br:14][CH2:15][CH2:16][C:17]1[C:26]2[C:21](=[C:22]([CH:3]([CH3:4])[CH3:2])[CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:27])[CH:18]=1
Reactant: O=c1cc(CCBr)c2ccccc2[nH]1
Reactant: O=c1cc(CBr)c2ccccc2[nH]1
Agent: O=c1cc(CCCBr)c2ccccc2[nH]1
Product: CC(C)c1cccc2c(CCBr)cc(=O)[nH]c12

Procedure:
In addition, 4-bromomethyl-2(1H)-quinolinone (II-1), 4-(2-bromoethyl)-2(1H)-quinolinone (II-2) and 4-(3-bromopropyl)-2(1H)-quinolinone (II-3) were prepared according to Chemical and Pharmaceutical Bull., 33(9), 3775-3786(1985).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:8]=1)[NH2:7].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:12]([F:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([NH:7][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCc1cccnc1F
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1cccnc1F)c1cc2ccccc2o1
Yield: 26.9 %

Procedure:
Following General Procedure B, the title compound (235 mg) was prepared from 5-chloro-2-(((2-fluoropyridin-3-yl)methyl)thio)aniline (522 mg, 1.948 mmol) and benzofuran-2-sulfonyl chloride (421 mg, 1.948 mmol) in pyridine (5 ml).
Reaction SMILES: [CH2:1]([OH:3])C.Cl[P:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>>[C:12]1([P:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:3][CH3:1])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCO
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: N
Product: COP(c1ccccc1)c1ccccc1
Yield: 72.9 %

Procedure:
210 g (6.56 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 200 g (0.907 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature with vigorous stirring. 18 g (1.06 mol) of ammonia gas are then introduced. The mixture is then stirred without cooling for 10 hours and filtered by suction. The filtrate is freed from methanol and excess ammonia in vacuo. The residue is filtered by suction through a glass frit. 143 g of crude methyl diphenylphosphinite are obtained. This corresponds to a yield of 73% of theory.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1N[N:9]=[CH:8]2.BrC1C=C2C([CH:22]=[C:23](N)[N:24]=C2)=CC=1>>[NH2:24][C:23]1[N:9]=[CH:8][C:7]2[C:11]([CH:22]=1)=[CH:3][CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=2
Reactant: Nc1cc2ccc(Br)cc2cn1
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Product: Nc1cc2ccc(C(=O)O)cc2cn1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 7-bromoisoquinolin-3-amine. +ESI (M+H) 189.2; 1H NMR (400 MHz, CD3OD, δ): 8.87 (s, 1H), 8.52 (d, J=0.78 Hz, 1H), 7.98 (dd, J=8.78, 1.76 Hz, 1H), 7.54 (d, J=8.78 Hz, 1H), 6.77 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:28]>C1COCC1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23](=[O:25])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1
Yield: 44 %

Procedure:
A solution of the 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole (470 mg, 1.36 mM) in 20 ml THF and 80 mL concentrated aqueous ammonium hydroxide was sonicated for 6 hours at 30-40° C. The precipitated solid was filtered and triturated with Et2O to afford 200 mg (44%) of 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbamoyl carbazole. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (bs, 1H), 8.4 (bs, 1H), 7.75 (m, 1H), 7.4 (m, 2H), 7.25 (m, 3H), 7.1 (m, 2H), 6.95 (s, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 2.4 (s, 3H). MS (ES) m/e 314, 331.