Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:12](O)(=[O:23])[CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])(=[O:23])[CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: CC(C)CCCCCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COc1cc(CC(=O)OCCCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 81.8 %

Procedure:
8-Methyl-1-nonanol (752 mg, 4.74 mmol), homovanillic acid (907 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl homovanillate (1.25 g, yield 81.5%) as a colorless oil.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[NH:26]1[CH:30]=[N:29][C:28](S)=[N:27]1.N1C=NC=N1>>[N:26]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: Sc1nc[nH]n1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: N#Cc1cccc(OCCCl)c1
Agent: c1nc[nH]n1
Product: N#Cc1cccc(OCCCn2cncn2)c1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 1H-1,2,4-triazole, the title compound was obtained as a colorless oil (750.0 mg, 32%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]1(=[O:16])[N:10]([CH2:2][CH2:3][CH2:4][OH:5])[C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCO
Temperature: 70 °C
Reaction time: 4 h

Procedure:
3-Bromopropanol (4.0 g, 28.78 mmol), potassium phthalimide (8.0 g, 43.17 mmol) and potassium carbonate (4.0 g, 28.78 mmol) were added to 20 mL DMF. The reaction mixture was stirred at 70° C. for 4 hours, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, saturated NaCl solution and evaporated in vacuo to a solid which was crystallized in ethyl acetate (3.5 g, 67%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)C.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl.Cl[C:29]1C(Cl)=C(Cl)C=CC=1>C1(C)C=CC=CC=1>[CH3:29][CH:9]1[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][C:15]3[C:16]2=[C:7]([CH2:6][N:4]=[CH:3][CH:2]=3)[CH2:8]1
Reactant: Clc1cccc(Cl)c1Cl
Reactant: CN(CCO)CC1CCCc2ccccc21
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CC1CC2=C3C(=CC=NC2)CCCC3C1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 27.0 g (0.126M) of 1-[N-(2-hydroxyethyl)-N-methylaminomethyl]-1,2,3,4-tetrahydronaphthalene, a compound of Formula 12 prepared, for example, as described in Preparation 12, dissolved in 170 ml of trichlorobenzene, at ambient temperature, was added 10.0 g (0.048M) of phosphorous pentachloride. The mixture was then heated to 110° C., and 34.0 g (0.255M) of aluminum chloride was added in portions over a period of 30 minutes. The temperature was increased 200° C. and the mixture stirred for an additional 3 hours. The reaction mixture was allowed to cool 80° C., and was then carefully combined with 900 ml of approximately 12% HCl. Toluene was added and the organic layers were removed in a separatory funnel. The remaining aqueous phase was made alkaline by the addition of 50% NaOH, and the product was extracted with ethyl acetate. The ethylacetate was evaporated and the remaining crude product purified, first by column chromatography (silica gel; 5% methanol in ethyl acetate) and finally by distillation; to yield 2-methyl-1,2,3,4,8,9,10,10a-octahydronaphth[1,8-cd]azepine (bp 105°-110° C. at 0.1 mm); (HCl salt, from ethanol-hydrogen chloride, mp 185°-186° C.).
Reaction SMILES: [ClH:1].Cl.CN1CCN(CC(C2(O)CCCCC2)C2C=CC=C(OC3C=CC=CC=3)C=2)CC1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39](=O)[CH:40]([C:54]2([OH:60])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:43][CH:42]=2)[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH:40]([C:54]2([OH:60])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)[C:41]2[CH:42]=[CH:43][C:44]([O:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[CH:45][CH:46]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(C(=O)C(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1
Agent: CN1CCN(CC(c2cccc(Oc3ccccc3)c2)C2(O)CCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(Oc3ccccc3)cc2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(4-methylpiperazin-1-yl)-1-(3-phenoxyphenyl)ethy]cyclohexanol dihydrochloride was prepared from 1-[2-(4-methylpiperazin-1-yl)-1-(4-phenoxyphenyl)-2-oxoethy]cyclohexanol. MS (ESI) m/z 395 ([M+H]+). Anal Calcd for C25H34N2O22HCl 0.9H2O: C, 62.08; H, 7.88: N, 5.79. Found: C, 62.26; H, 8.11; N, 5.70.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzoic acid (500 g) was added to a mixed solvent of dimethylformamide (500 ml) and toluene (1.5 Liters). Thionyl chloride (217 ml) was added thereto at room temperature with stirring and the mixture was stirred at a refluxing temperature for 3 h. The reaction mixture was then ice-cooled and added dropwise to 28% aqueous amonia (750 ml). The mixture was stirred further for 1 h. The precipitated crystals were collected by filtration, and the crystals were recrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzamide (346 g), melting point: 177–179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1[C:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]=2[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([Si:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:38]3[CH:39]=[CH:40][C:34]4[S:33][C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:36]=5[C:35]=4[CH:37]=3)[CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Reactant: OB(O)c1ccc2sc3ccccc3c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3ccc4sc5ccccc5c4c3)c2)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture solution of bis(3-bromophenyl)diphenylsilane (10.84 g, 21.92 mmol), dibenzo[b,d]thiophen-2-yl boronic acid (2.000 g, 8.77 mmol), Pd(PPh3)4 (0.101 g, 0.088 mmol) and K2CO3 (2.424 g, 17.54 mmol) in toluene (200 mL) and water (50 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9:1, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]thiophen-2-yl)phenyl)diphenylsilane (3.16 g, 60% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].[CH:19]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH2:20]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:19][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: C=CS(C)(=O)=O
Solvent: C1COCCO1
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 79.4 %

Procedure:
To 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (0.5 g, 1.99 mmol) in 10 mL of dioxane was added, methyl vinyl sulfone (0.53 g, 4.97 mmol). The mixture was heated to 120° C. for 2 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step B (0.565 g, 1.58 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (d, J=9.34 Hz, 1H), 6.57 (dd, J=9.43, 2.47 Hz, 1H), 6.51 (d, J=2.38 Hz, 1H), 4.16 (q, J=6.96 Hz, 2H), 3.36-3.41 (m, 4H), 3.30-3.34 (m, 2H), 3.01 (s, 3H), 2.73 (t, J=6.87 Hz, 2H), 2.49-2.55 (m, 4H), 1.32 (t, J=6.96 Hz, 3H).
Reaction SMILES: [C:1]1(=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CC2C=CC=CC=2[N+]([O-])=O)CCCC=1.C1(CC2C=CC=CC=2N)CCCC=1>>[C:1]1(=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccccc1C=C1CCCC1
Agent: Nc1ccccc1CC1=CCCC1
Agent: O=[N+]([O-])c1ccccc1CC1=CCCC1
Product: Nc1ccccc1C=C1CCCC1

Procedure:
In the preparation of 1-(cyclopentylidenemethyl)-2-nitrobenzene, its isomer, 1-[(cyclopent-1-enyl)methyl]-2-nitrobenzene, was also isolated and then converted to 2-[(cyclopent-1-enyl)methyl]aniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[CH:31][C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[C:34]([F:35])[C:29]=1[F:28])(=[O:39])=[O:38]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(F)c2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (3.0 g, 12 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.5 mL, 15.5 mmol). The reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was cooled to −78° C. and 2,3,4-trifluorobenzene-1-sulfonyl chloride (1.8 mL, 12 mmol) was added. After 2 further lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 2.4 mL, 2.4 mmol) and 2,3,4-trifluorobenzene-1-sulfonyl chloride (0.3 mL, 2.4 mmol) were added. After 1 h, the reaction mixture was allowed to warm to ambient temperature, diluted with ethyl acetate (150 mL), washed with saturated ammonium chloride (2×125 mL) and brine (2×125 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with methanol to afford N-(2,4-dimethoxybenzyl)-2,3,4-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a pale yellow solid in 67% yield (3.5 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=O)[CH3:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O>>[CH3:10][C:9]1[C:2]2[N:1]([CH:5]=[CH:4][CH:3]=2)[CH2:6][CH2:7][N:8]=1
Reactant: CC(=O)NCCn1cccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2cccc21
Yield: 95 %

Procedure:
The solid N-[2-(1H-pyrrol-1-yl)ethyl]acetamide (8 g, described in Example 1) is added cautiously in small portions into phosphorus oxychloride (45 ml) upon stirring. The mixture is refluxed for 60 min and evaporated under reduced pressure (1 mm Hg). The residue is partitioned between 10% sodium hydroxide and diethyl ether, and the organic phase is separated and evaporated. The residue is filtered through a column of neutral alumina packed in chloroform and the eluates are evaporated to obtain 6.7 g of the title compound which solidified: mp 25°-27° C. and nmr(CDCl3) δ 2.28(s), 3.84(s), 6.12(t), 6.36(d) and 6.64.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10]([OH:19])(=[O:18])[CH:11]([CH:13]([C:15]([OH:17])=[O:16])[OH:14])[OH:12]>C(O)C.O>[C:15]([CH:13]([CH:11]([C:10]([OH:19])=[O:18])[OH:12])[OH:14])([OH:17])=[O:16].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1CCCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CCCCN1
Temperature: 80 °C

Procedure:
2-Piperidinecarboxylic acid (26 g, 0.201 mol) and (+)-tartaric acid (31.2 g, 0.208 mol) were suspended in a mixture of ethanol (400 ml) and water (25 ml). The mixture was heated to 80° C., and the solution was allowed to cool to room temperature. The precipitated solid was filtered off, washed with ethanol and dried to give 25.4 g (45%) (R)-(+)-2-piperidinecarboxylic acid (+)-tartrate. The mother liquor was evaporated in vacuo, and the residue was dissolved in water (120 ml). A solution of potassium hydroxide (6.5 g, 116 mmol) in water (13 ml) was added, and the precipitated mono potassium tartrate was removed by filtration. Evaporation of the filtrate in vacuo afforded 19.5 g crude (S)-(-)-2-piperidinecarboxylic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]([CH3:20])[CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[S:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:41]2[C:42]([C:48]([F:51])([F:50])[F:49])=[N:43][C:44]([NH2:47])=[N:45][CH:46]=2)O1>CC#N.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:20][N:12]([CH2:11][C:9]1[S:8][C:6]2[N:7]=[C:2]([C:41]3[C:42]([C:48]([F:51])([F:50])[F:49])=[N:43][C:44]([NH2:47])=[N:45][CH:46]=3)[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]=2[CH:10]=1)[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2cnc(N)nc2C(F)(F)F)OC1(C)C
Reactant: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(N(C)Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4C(F)(F)F)nc3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-methyl-(1-methyl-piperidin-4-yl)-amine (100 mg), 1M Na2CO3 (0.7 mL), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-pyrimidin-2-ylamin (1.5 eq.) [WO 2007/084786] and bis(triphenylphosphine)palladium (II) chloride (0.05 eq.) in MeCN (15 mL) was heated at 140° C. for 25 min. in microwave. The resulting mixture was diluted with water then extracted with ethyl acetate. Combined extracts were dried (Na2SO4), filtered and concentrated then purified by preparative HPLC to give 321 (45 mg). NMR: (CDCl3): 1.2 (s, 2H, CH2), 1.57-1.65 (m, 2H, CH2), 1.72-1.74 (m, 2H, CH2), 1.87-1.92 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.54 (m, H, CH), 2.85-2.87 (m, 2H, CH2), 3.76-3.78 (m, 4H, 2×CH2), 3.84-3.86 (m, 4H, 2×CH2), 5.34 (sbr, 2H, NH2), 7.06 (s, H, ArH), 8.91 (s, H, ArH). MS: (ESI+): MH+=523.35
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:5]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[C:6]([C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.[C:35]1([S:57](Cl)(=[O:59])=[O:58])[C:44]2[CH:43]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[C:40]([S:49](Cl)(=[O:51])=[O:50])[C:39]=2[CH:38]=[C:37]([S:53](Cl)(=[O:55])=[O:54])[CH:36]=1>N1C=CC=CC=1>[C:35]1([S:57]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:3]=2)(=[O:59])=[O:58])[C:44]2[C:39](=[C:40]([S:49]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[C:5]([C:17]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[C:4]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[CH:3]=3)(=[O:51])=[O:50])[CH:41]=[C:42]([S:45]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[C:5]([C:17]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[C:4]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[CH:3]=3)(=[O:47])=[O:46])[CH:43]=2)[CH:38]=[C:37]([S:53]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH:3]=2)(=[O:55])=[O:54])[CH:36]=1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)c2cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c2c1
Reactant: Nc1cc(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cc(NS(=O)(=O)c2cc(S(=O)(=O)Nc3cc(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c3)c3cc(S(=O)(=O)Nc4cc(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c4)cc(S(=O)(=O)Nc4cc(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c4)c3c2)cc(C(=O)Oc2ccccc2)c1C(=O)Oc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 36.27 g. of 5-amino-1,2,3-benzenetricarboxylic acid, triphenyl ester in 150 ml. of dry pyridine is added 12.0 g. of 1,3,5,7-naphthalenetetrasulfonyl chloride and the mixture is stirred at room temperature for one hour and then at 55°-75° C. for 2 hours. The solution is poured into 840 ml. of 2 N hydrochloric acid and the resulting mixture is extracted with methylene chloride. The aqueous phase is filtered to remove the suspended solid which is washed with water and methylene chloride to provide 32.4 g. of a cream powder. The product is crystallized from acetone-methylene chloride and is then refluxed in acetonitrile:methanol (2:1) solution. The product is filtered and the filtrate cooled to 5° C. to provide additional product. The combined fractions are dried overnight in an Abderhalden apparatus at 110° C. to give 21.45 g. of beige powder, mp. >300° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH2:19])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:9]=[CH:8][C:7]=1[NH:19][C:21](=[O:23])[CH3:22])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ccc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [2-Amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetic acid ethyl ester (438 mg, 1.58 mmol) in CHCl3 (8.0 mL) is added acetic acid anhydride (322 mg, 3.16 mmol) and triethyl amine (240 mg, 2.37 mmol) under argon. The resulting reaction mixture is stirred for 1 h at RT and 1 h at reflux. The reaction mixture is partitioned between CH2Cl2 (25 mL) and water (20 mL) and the layers are separated. The aqueous phase is extracted with CH2Cl2 (2×25 mL) and the combined organic layers are washed with water (2×25 mL), brine (25 mL), dried over Na2SO4 and concentrated at reduced pressure to afford a pale red solid. ES+-MS: 320 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH2:7][CH2:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C1(C)COC(=O)N1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1(C2CCc3cc(O)ccc3C2)COC(=O)N1
Temperature: 20 °C
Yield: 84.5 %

Procedure:
A stirred solution of 100 grams of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one in 6 L dichloromethane was cooled to −80° C. under nitrogen. A solution of 177 g BBr3 in dichloromethane was added dropwise; during addition the reaction temperature was kept below −75° C. The reaction was stirred at 20° C. until the starting material was less than 2% by HPLC. Ice water was added to crystallize the solid, which was filtered, washed with water, and the cake was slurried in methanol and dried to afford 80 g of 4-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one, M=247.29, purity >98%.
Reaction SMILES: C([C:4]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)(=O)C.N>CO>[C:4]1([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[O:21])[CH:17]=3)[NH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)C1(c2n[nH]c3ccc(NC(=O)c4ccccn4)cc23)C=CC=CC1
Agent: N
Solvent: CO
Product: O=C(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1ccccn1
Temperature: 70 °C
Yield: 68.9 %

Procedure:
N-(1-acetyl-3-phenyl(1H-indazole-5-yl))-2-pyridylcarboxamide (364 mg, 1.02 mmol) was added to 0.3% ammonia in methanol (7 mL). The mixture was heated to 70° C. for 3 hours. The resulting precipitate was filtered and dried to give the title compound (221 mg, 71% yield). 1H NMR (DMSO-d6) δ 13.20 (br s, 1H), 10.75 (s, 1H), 8.72 (d, 2H), 8.16 (d, 1H), 8.05 (m, 1H), 7.94 (t, 3H), 7.66 (m, 1H), 7.53 (q, 3H), 7.38 (t, 1H). ES-MS (m/z) 315 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.[O-:21]Cl.[Na+].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:19]2[C:14]([C:13]([OH:12])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[N:4]=1
Reactant: [O-]Cl
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Temperature: 50 °C

Procedure:
490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)-furo[3,4-b]pyridine-7(5H)-one is dissolved in 50 ml of methanol and the mixture heated with stirring at 50° C. until a homogeneous solution is formed (ca 1/2 hr). 2.6 g of NaOCl is added dropwise and the solution heated for a further 1/2 hr at 55° C. 0.208 g of 50% NaOH is added at 55° and the mixture heated for a further 1/2 hr at this temperature and then cooled in an ice-bath and acidified with 1 ml conc. HCl. The solvent is evaporated and the residue partitioned between 50 ml of CH2Cl2 and 50 ml of water. The organic phase is concentrated to give a white solid, m.p. 71°-73°.