Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH2:54])[S:52][CH:53]=1)[CH3:45].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([NH:54][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:52][CH:53]=1)[CH3:45]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (prepared as in Example 22A, 263.0 mg, 1.0 mmol) in N,N-dimethylformamide (10 mL) was treated with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (379 mg, 1.0 mmol), (2-amino-thiazol-4-yl)-acetic acid ethyl ester (279 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). The reaction mixture was stirred at 25° C. for 5 h. The reaction mixture was then poured into a 2N aqueous hydrochloric acid solution (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (1×75 mL), a saturated aqueous sodium bicarbonate solution (1×75 mL), and a saturated aqueous sodium chloride solution (3×75 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (70.0 mg, 39.4%) as a pale yellow oil: FAB-HRMS m/e calcd for C21H25N3O5S (M+H)+ 432.1593, found 432.1595.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(CCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of {3-[(5-chloro-4-{[2-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (2.3 mL, 2.3 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Both aqueous layer (no product in it) and organic layer (containing small amounts of product, plus byproducts) were checked and discarded. The remaining solid residue was triturated with cold EtOAc and then filtered. The cake was washed with cold EtOAc and then H2O to give the desired product as a white powder (0.30 g, 89%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0, 437.0. 1H NMR (400 MHz, CD3OD): δ 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (m, 2H), 7.32 (m, 1H), 7.05 (m, 1H), 6.60 (m, 3H), 4.54 (s, 2H), 3.76 (t, J=6.4 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(CCCc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-Methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and phenylpropylbromide (0.183 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.015 g (4.0%); MS m/z: 372.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.84-1.90 (m, 2H); 2.62 (t, 2H, 3J=7.6 Hz); 3.39 (t, 2H, 3J=7.6 Hz); 3.39 (s, 3H); 4.45 (s, 2H); 6.71 (br s, 1H); 6.73 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.83-6.85 (m, 2H); 7.12-7.14 (m, 2H); 7.16-7.19 (m, 3H); 7.24-7.27 (m, 2H); 7.36 (d, 1H, 3J=8.9 Hz); 8.08 (s, 1H); HPLC (METHOD [A]): rt 16.97 min (93.2%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH2:13]([N:15]([CH2:30]C)[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])C>>[CH3:30][N:15]([CH3:13])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Product: COc1ccc2c(c1)C(=Cc1cc(C)c(C(=O)NCCCN(C)C)[nH]1)C(=O)N2
Yield: 39 %

Procedure:
5-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 80 mg (39%) of the title compound.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@H:13]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C@@H:13]4[CH2:14][NH:15][CH2:16][CH2:17][C@@H:12]4[N:10]([C:9]=23)[CH2:11][CH2:2]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CCCCI
Product: CCCCN1CCN2c3c(cccc31)[C@@H]1CNCC[C@@H]12

Procedure:
Utilizing the material from Example 255 Step A, the title compound was prepared in analogous fashion using n-butyl iodide as the alkyl halide and following the procedure of Step B-D of Example 255, as a viscous brown liquid. 1H NMR (CDCl3, 300 Mhz) δ 0.95 (t, 3H), 1.30–1.45 (m, 2H), 1.50–1.65 (m, 2H), 1.95–2.15 (m, 2H), 2.65–2.80 (m, 2H), 2.65–2.80 (m, 2H), 2.85–3.08 (m, 1H), 3.08–3.22 (m, 3H), 3.22–3.40 (m, 6H), 3.68–3.78 (m, 1H), 6.38 (d, J=7.1 Hz), 6.46 (d, J=7.1 Hz, 1H), 6.66 (t, J=7.7 Hz, 1H) ppm. MS (CI): 436 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:20][O:14][C:13]([C:3]1[C:2]([OH:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([OH:12])=[CH:8][CH:9]=2)[CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc2cc(O)ccc2cc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cc(O)ccc2cc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,7-dihydroxynaphthalene-2-carboxylic acid (4.0 g, 19.6 mmol) in MeOH (80 mL) is added thionyl chloride (10 mL, 136 mmol) and it is stirred at RT for 48 h. The solvent is removed and purified to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[CH:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Yield: 97.3 %

Procedure:
4.92 g of 2-benzyl 3-tert-butyl (2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate in 50 ml of ethyl acetate was catalytically reduced with 500 mg of a 10% palladium-carbon catalyst at room temperature under atmospheric pressure of hydrogen for 3 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to give 3.44 g of the title compound as a white solid.
Reaction SMILES: [IH:1].CS[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1.O.[NH2:11][NH2:12]>C(O)C>[IH:1].[NH:11]([C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1)[NH2:12]
Reactant: CSC1=NCCCC1
Reactant: NN
Agent: I
Solvent: CCO
Solvent: O
Product: NNC1=NCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 6.43 g portion of 3,4,5,6-tetrahydro-2-(methylthio)-pyridine, hydroiodide was added to an ice-cold solution of 1.25 ml of hydrazine hydrate in 35 ml of ethanol. The suspension was stirred at ice bath temperature for 30 minutes, then the solid was collected, washed with ethanol and ether and dried, giving 3.5 g of 2-hydrazino-3,4,5,6-tetrahydropyridine, hydroiodide, which was converted to the monohydronitrate by treatment with silver nitrate in water.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:20]([C:28]1[CH:36]=[C:35]([Br:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:37][C:35]1[CH:36]=[C:28]2[C:29](=[CH:33][CH:34]=1)[C:30](=[O:31])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH3:19])=[C:20]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxypentylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-bromobenzoic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[SH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:52][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76]O)=[O:57])[CH3:54]>C1COCC1>[CH3:54][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76][S:39][C:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:57])[CH3:52]
Reactant: COc1ccccc1-c1cn2c(n1)C(CCO)N(C(=O)OC(C)(C)C)CC2
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 12 h
Yield: 111 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol) was dissolved in THF (25 ml), cooled to about 0° C. under N2 and Diethylazodicarboxylate (2.45 ml, 15.54 mmol) was added at a dropwise rate so that the reaction temperature was maintained at about <3° C. Stirring was continued for about 12 hour at 0° C. A mixture of the triphenylmethanethiol (4.30 g, 15.54 mmol) and the product from Step 13.e. (2.90 g, 7.77 mmol) in THF (25 ml) was added at a dropwise rate. The resulting mixture was stirred for about 1 hour at about 0° C. and then allowed to warm to room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in ether (40 ml) and allowed to stand overnight. The solid was filtered off and the filtrate was concentrated then purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc and then 4:1/hexanes:EtOAc as eluants. The product fractions were combined and concentrated under reduced pressure to obtain a pale yellow foam (5.49 g, 111%) which was used without further purification. Mass spec. 632.4 MH+.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17](O)=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[C:1]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]([NH:46][S:43]([CH:40]3[CH2:42][CH2:41]3)(=[O:45])=[O:44])=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: O=C(O)c1cnn2c(Nc3ccccc3-c3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: NS(=O)(=O)C1CC1
Product: O=C(NS(=O)(=O)C1CC1)c1cnn2c(Nc3ccccc3-c3ccccc3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 24.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(biphenyl-2-ylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (61 mg, 0.14 mmol) obtained in step 2 and cyclopropanesulfonamide (73 mg, 0.70 mmol), the title compound (21 mg, 27%) was obtained.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11](=O)[CH2:12]Cl)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[NH2:15][C:16](=[N:18][C:19]([NH2:21])=[S:20])[NH2:17]>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[N:21]=[C:19]([N:18]=[C:16]([NH2:17])[NH2:15])[S:20][CH:12]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: NC(=S)N=C(N)N
Reactant: CC(=O)NCc1ccc(C(=O)CCl)o1
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Yield: 46.6 %

Procedure:
A solution of 5-acetylaminomethyl-2-chloroacetylfuran (39.9 g) and diaminomethylenethiourea (21.9 g) in ethanol (400 ml) was refluxed for two hours with stirring. The solvent was evaporated in vacuo and the residue was dissolved in water (300 ml). The solution was basified with an aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed with water and recrystallized from a mixture of methanol, tetrahydrofuran and diisopropyl ether to afford 4-(5-acetylaminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (24.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(Cc2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
2,5-Dichlorobenzyl chloride (2.01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonylpiperazine and 3.45 g of anhydrous potassium carbonate in 20 ml of N,N-dimethylformamide stirred at room temperature in nitrogen atmosphere. After 24 h of stirring at the same temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase, which was dried on anhydrous Na2SO4, was evaporated to dryness under vacuum. The oily residue was purified via flash chromatography (petrolium ether-ethyl acetate 85:15) giving 2 g (63%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:25])[NH:18][NH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])=[C:11]([CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]([O:30][CH2:31][C@H:32]1[O:37][C@H:36](Br)[C@H:35]([O:39][C:40]([CH3:42])=[O:41])[C@@H:34]([O:43][C:44]([CH3:46])=[O:45])[C@H:33]1[O:47][C:48]([CH3:50])=[O:49])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:40]([O:39][C@@H:35]1[C@@H:34]([O:43][C:44](=[O:45])[CH3:46])[C@@H:33]([O:47][C:48](=[O:49])[CH3:50])[C@@H:32]([CH2:31][O:30][C:28](=[O:29])[CH3:27])[O:37][C@H:36]1[O:25][C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[CH3:26])=[C:20]([C:21]([F:24])([F:23])[F:22])[NH:19][N:18]=1)(=[O:41])[CH3:42]
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(F)(F)F)[nH][nH]c1=O
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)F)c2Cc2ccc(OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A suspension of 4-[(4-benzyloxy-2-methylphenyl)methyl]-5-trifluoromethyl-1,2-dihydro-3H-pyrazol-3-one (0.5 g), acetobromo-α-D-galactose (0.62 g) and potassium carbonate (0.29 g) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.66 g).
Reaction SMILES: [N:1]1([C:6]2([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=O)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[N:1]1([C:6]2([C:9](=[N:19][OH:20])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: NO
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(Cl)cc1)C1(n2cncn2)CC1
Yield: 82.6 %

Procedure:
24.8 g (0.1 mol) of 4-chlorophenyl 1-(1, 2, 4-triazol-1-yl)-cyclopropyl ketone were refluxed for 4 hours with 10.4 g of hydroxylamine hydrochloride, 10.6 g of sodium acetate in 200 ml of ethanol and 100 ml of water, the solvent was removed in vacuo, and the crystal slurry obtained was triturated with water. 21.7 g (83%) of the title compound were obtained as colorless crystals of melting point 186°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][OH:16])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.Cl[C:18]1[NH:19][C:20]2[C:26]([NH:27][C:28](=[O:38])[C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=3)=[CH:25][C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][C:21]=2[N:22]=1>CCO>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:18]3[NH:19][C:20]4[C:26]([NH:27][C:28](=[O:38])[C:29]5[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=5)=[CH:25][C:24]([C:39]([F:42])([F:40])[F:41])=[CH:23][C:21]=4[N:22]=3)[C@H:10]([CH3:14])[CH2:9]2)=[N:6][CH:5]=[C:4]([CH2:15][OH:16])[CH:3]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc2nc(Cl)[nH]c12)c1cc(F)c(F)c(F)c1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1
Solvent: CCO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
A mixture of {5-chloro-6-[(3R)-3-methyl-piperazin-1-yl]-pyridin-3-yl}-methanol (530 mg, 2.2 mmol, Example 150a) and N-(2-chloro-6-trifluoromethyl-3H-benzoimidazol-4-yl)-3,4,5-trifluoro-benzamide from step (d) above (787 mg, 2.0 mmol) in EtOH (2 mL, Aldrich) reacted under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 599 (M+1).
Reaction SMILES: CS(C)=O.[CH:5]([C:7]1[O:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].C(O[K])(C)=O.I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][NH:25][C:24]2=[O:31]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[O:31]=[C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:10]3[O:11][C:7]([CH:5]=[O:6])=[CH:8][CH:9]=3)[CH:22]=2)[N:27]=[CH:26][NH:25]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Agent: [Pd+2]
Agent: CC(=O)O[K]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A 5:2 v/v mixture of DMSO and H2O (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. 5-Formylfuran-2-ylboronic acid ((VIa); 26.8 g, 193 mmol) was added dissolved in this mixture. [HP(t-Bu)3]BF4 (840 mg, 2.94 mmol) and Pd(OAc)2 (680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 20 min AcOK (18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min at ambient temperature. 6-Iodoquinazolin-4(3H)-one ((Va); 40 g, 147 mmol) was added and heated to 80±5° C. (internal temperature) in an oil bath under nitrogen. Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5° C.) was added into the filtrate. This was slowly cooled to 0-15° C. (solid started to precipitate at 70° C. (internal temperature) and was then filtered. The filter cake was washed with H2O (80 mL), then with MeCN (60 mL), and dried in vacuo at 60±5° C. for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol) with 99.7% HPLC purity in 97.6% HPLC yield. 1H NMR (300 MHz, d6-DMSO): δ 7.47 (d, J=3.8 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 110.5, 122.6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178.8; ESI-MS, Pos: [M+H]+ m/z 241; IR (cm−1): 1713, 1671, 1604,1462; m.p.: 267° C. See FIG. 2 for the DSC/TGA of the compound of formula (IX); See FIG. 3 for the X-ray powder diffraction pattern of the compound of formula (IX); Residual concentration of palladium: 230 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:15]=1[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([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[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)[C:15]=3[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ncccc1-c1nc2cc(F)ccc2c(Cl)c1C
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ncccc1-c1nc2cc(F)ccc2c(N2CC(C)(C)c3ncc(Br)cc32)c1C
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (100 mg, 0.44 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (126 mg, 0.44 mmol) and hydrochloric acid in 1,4-dioxane (0.11 mL, 0.44 mmol) in NMP (2.0 mL) and heating in the microwave at 150° C. for 2 h. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline was obtained as a yellow film. Mass Spectrum (ESI) m/e=477 [(M+1) (79Br)] and 479 [(M+1) (81Br)].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C[O:22][C:23](=O)[C:24]([CH3:26])=[CH2:25]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:23]([O:20][CH:18]([CH2:17][CH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)[CH3:19])(=[O:22])[C:24]([CH3:26])=[CH2:25]
Reactant: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: C=C(C)C(=O)OC(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A process as described in claim 2 where 4-(3,5-di-t-butyl-4-hydroxyphenyl)-butane-2-ol is esterified by reaction with methylmethacrylate in the presence of tetraisopropyl titanate to yield 4-(3,5-di-t-butyl-4-hydroxyphenyl)-2-butyl methacrylate.