Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[N:3]=1.C[Si](C)(C)N[Si](C)(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(O[C@@H:32]1[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:43]([O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:33]1[O:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=O)C>ClCCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]2[N:11]([C@@H:32]3[O:54][C@H:53]([CH2:55][O:56][C:57](=[O:64])[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C@@H:43]([O:44][C:45](=[O:52])[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C@H:33]3[O:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:10]=[CH:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Nc1nc2nccn2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Nc1nc(=O)n2ccn([C@@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of dry 2-aminoimidazo[1,2-a]-s-triazin-4-one (V) 3.02 g, 0.020 mol), freshly distilled hexamethyldisilazane (15.0 mL), and a few crystals of ammonium sulfate (25 mg) was heated at reflux temperature for 15 h. with the exclusion of moisture. The clear, slightly brown solution was fractionated by distillation to remove excess of hexamethyldisilazane and the residual gum was presumed to be the bis(trimethylsilyl) derivative which was used without further prification. To a solution of the above trimethylsilyl derivative in anhydrous 1,2-dichloroethane (100 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (10.09 g, 0.02 mol) followed by stannic chloride (7.0 g, 0.027 mol). The reaction mixture was protected from moisture and stirred for 30 h. at ambient temperature. The brown reaction solution was then poured into 200 mL of chloroform, with efficient stirring and keeping the mixture basic at all times. The resulting emulsion was filtered through a Celite pad which was washed with chloroform (3×25 mL). The combined organic layer was washed with water (2×100 mL) before it was dried over anhydrous sodium sulfate. The solvent was evaporated to a light brown foam which was chromatographed on an open-bed, silica gel column (5×75 cm) prepacked in ethyl acetate and eluted with ethyl acetate-water-1-propanol (4:2:1, v/v, upper phase). The band containing the requisite product was collected and the solvent evaporated to leave 6.8 g (56.30%) of a light yellow, chromatographically homogeneous foam: [α]25D -32.0° (cl.O.Me2SO); UVλmax (pH 1) 233 nm (ε=45800), 268 (18800); UVλmax (pH 7) 235 nm (ε=39400), 263 sh (24700); UVλmax (pH 11) 234 nm (ε=42300), 260 sh (20600). Anal. (C31H25N5O8.0.5H2O, 604.57) C, H, N.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH2:5]([O:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=2)[N:16]=[C:15]([NH:32][NH2:33])[C:14]1=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1.CN(C)C=O>[CH2:5]([O:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[N:16]2[C:1](=[S:2])[NH:33][N:32]=[C:15]2[C:14]1=[O:34])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: NNc1nc2cc(-n3ccnc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2n[nH]c(=S)n2c2cc(-n3ccnc3)c(C(F)(F)F)cc2n1OCc1ccccc1
Yield: 51.1 %

Procedure:
A solution of thiophosgene (1.1 ml, 14 mmol) in 10 ml of dry tetrahydrofuran was added dropwise to a stirred solution of 2.91 g (7 mmol) of 1-benzyloxy-3-hydrazino-6-(1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one in a mixture of 100 ml of dry tetrahydrofuran and 25 ml of dry N,N-dimethylformamide at 0° C. The mixture was stirred for 2h at 0° C. and evaporated to dryness. The solid residue was suspended in 100 ml of water, neutralized with solid sodium hydrogen carbonate and filtered. Recrystallization from ethanol afforded 1.64 g (51%) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=C(C2C=CC(OCCCCCCCC)=C(F)C=2)C=C[C:7]=1O.[CH2:25]([C@@H:30]1[CH2:33][C@H:32]([C:34]([Cl:36])=[O:35])[CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:25]([CH:30]1[CH2:31][CH:32]([C:34]([Cl:36])=[O:35])[CH2:33]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:7][CH2:2][CH3:3]
Reactant: CCCCC[C@H]1C[C@@H](C(=O)Cl)C1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Product: CCCCCCCCC1CC(C(=O)Cl)C1
Yield: 120.8 %

Procedure:
Except that 0.60 g of the crude 3,3'-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.4 g of cis-3-pentylcyclobutanecarboxylic acid chloride obtained in (b) above in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.58 g (yield 63.3%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl cis-3-pentylcyclobutanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[C:3]([NH:8][C:9]([C@@H:11]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product of 1-benzyl 4-tert-butyl {(1S)-1-[(5-amino-1-methyl-1H-pyrazol-4-yl)carbamoyl]tetramethylene}biscarbamate and triethylamine (1.01 g) in chloroform (50 ml) was added triphenylmethyl chloride (2.78 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 1-benzyl 4-tert-butyl ((1S)-1-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamoyl}tetramethylene)biscarbamate (720 mg) as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>[Cu].CS(C)=O>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-iodonitrobenzene (Compound 1b; 249.0 mg, 1.0 mmol), bromodifluoroacetic acid ethyl ester (203 mg, 1.0 mmol), copper powder (128 mg, 2.0 mmol) and DMSO (2.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 15 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b) was obtained with a yield of 58%.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([CH3:46])[C:41]=1[C:47]1[C:56]2[N:55]=[CH:54][CH:53]=[N:52][C:51]=2[C:50]([C:57](O)=[O:58])=[CH:49][CH:48]=1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:57]([C:50]3[C:51]4[N:52]=[CH:53][CH:54]=[N:55][C:56]=4[C:47]([C:41]4[C:42]([CH3:46])=[CH:43][CH:44]=[CH:45][C:40]=4[CH3:39])=[CH:48][CH:49]=3)=[O:58])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cn2)c2nccnc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 2 days at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 467.1 [M+H]+; tR=3.55 min (System 1); TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:14][C@@H:15]([CH2:23][CH2:24][CH3:25])[CH:16]([CH2:19][C:20](=O)[CH3:21])[CH:17]=O.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]1[CH:14]=[C:15]([C@@H:16]([CH3:17])[CH2:19][CH2:20][CH3:21])[CH:23]=[C:24]1[CH3:25])=[O:5]
Reactant: CSc1ccc(C(=O)NN)c(Cl)c1
Reactant: CCC[C@H](C)C(C=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H](C)c1cc(C)n(NC(=O)c2ccc(SC)cc2Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
The compound prepared in Example 76 (1.65 g) and (3S)-3-methyl-2-(2-oxopropyl)hexanal (1.86 g) were dissolved with tetrahydrofuran (10 mL), and 5N hydrochloric acid (0.2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed by water and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=85/15→65/35) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[C:26]([C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: C=Cc1ccc(C(=O)O)nc1
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, 5-vinylpyridine-2-carboxylic acid and a KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][OH:17])[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:9][CH:10]=[C:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:18])[CH2:16][O:17][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CC=C(C)CCCC(C)CO)C(C)=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC(CC=C(C)CCCC(C)COC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
324 mg (1.20 mmol) of a raw product of 3-acetoxy-11-hydroxy-6,10-dimethyl-5-undecen-2-one and 219 μl (202 mg, 2.40 mmol) dihydropyrane was dissolved in 8.5 ml DCM. After addition of 30 mg (0.12 mmol) pyridinium paratoluene sulfonate, the reaction mixture was stirred for 18 hrs at ambient temperature. Then, 25 ml diethylether was added, the resulting organic phase was washed once with 25 ml semiconcentrated NaCl solution, and dried over Na2SO4. After filtration and removal of the solvent in vacuo, the remaining product was purified by flash chromatography (parameters of the chromatography column: 2.0×20.0 cm, ethylacetate/petroleum ether=1:4) on silica gel.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH2:29]([O:32][NH2:33])[CH:30]=[CH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:29]([O:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[CH:30]=[CH2:31]
Reactant: C=CCON
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-allyl-hydroxylamine hydrochloride (18.3 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 25.5 mg (74%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.28 (1H, s), 8.67 (2H, d, J=3.4), 8.05 (4H, m), 7.48 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=7.6 Hz), 6.91 (1H, m), 3.69 (3H, s). ESIMS (M+H+): 386.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:24]3[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ccc(S)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(Sc2ccc(N)cc2)c2c(Cl)ncnc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 0.98 mmol) was treated with 4-aminobenzenethiol (130 mg, 1.04 mmol), copper(I) iodide (400 mg, 2.1 mmol), potassium carbonate (300 mg, 2.17 mmol) in N,N-dimethylformamide (8 ml) according to Preparation 86 but stirring at 100° C. for 2 h. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 350 mg (75% yield) of the title compound. Purity 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:24])=[O:33])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(SC)cc3Cl)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(S(C)=O)cc3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (148 mg) in dichloromethane (2.8 ml) was added m-chloroperbenzoic acid (81 mg) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with chloroform, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and acetonitrile was added to the residue for crystallization, whereby the objective compound (118 mg) was obtained as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][O:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CO[C@@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(C(F)(F)F)cc4s2)n3C)C1
Yield: 30.8 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]amide (30 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (80 mg), (R)-3-methoxy-piperidine (100 mg), HBTU (200 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 546.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.54-8.53 (m, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 7.83-7.81 (d, 1H), 7.71 (m, 2H), 7.56-7.54 (d, 1H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 3.73-3.71 (m, 1H), 3.70 (s, 3H), 3.52-3.47 (m, 1H), 3.38-3.34 (m, 2H), 3.31-3.25 (m, 4H), 1.88-1.81 (m, 1H), 1.71-1.62 (m, 1H), 1.45-1.36 (m, 1H), —NH proton signal was not observed.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)c(F)cc4F)ncnc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1cc(F)c(Oc2ncnc3c2cnn3C2CCNCC2)cc1F
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 35; 66 mg, 0.15 mmol) and 4M HCl in 1,4-dioxane (10 mL) was stirred at 40° C. for 1 h. The solvent was evaporated under vacuum to provide 1-piperidin-4-yl-4-(2,4,5-trifluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride as a solid which was used directly in the next step without purification. Dichloromethane (5 mL) was added, and the mixture was cooled to about 0° C. using an ice-water bath. Isopropyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 0.22 mL, 1.0 M in toluene, 0.22 mmol) was added, followed by triethylamine (0.13 mL, 0.96 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 2 h. Water and dichloromethane were added and the aqueous phase was extracted twice with each of the following solvents: dichloromethane, ether and hexane. The combined organic phases were evaporated and the resulting residue was purified by C18 reversed phase HPLC using a gradient of 20-100% acetonitrile/water to give 4-[4-(2,4,5-trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (47 mg, 73%) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 1.28 (d, 6H, J=6.2 Hz), 1.98-2.05 (m, 4H), 2.18-2.25 (m, 2H), 3.00-3.10 (m, 2H), 4.08-4.15 (m, 2H), 4.80-4.82 (m, 1H), 5.00-5.05 (m, 1H), 7.88-7.94 (m, 2H), 8.47 (s, 1H), 8.59 (s, 1H). Mass spectrum MH+=436. HRMS Calcd. For C20H21F3N5O3 (MH+): 436.1591. Found: 436.1589.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[I-].[Na+]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[C:11]([F:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c(F)c1

Procedure:
In analogy to the procedure described in example 101A], 2-(3-fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-fluoro-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as white crystals of mp. 177.5–178.0° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:11]=1[C:12]#[N:13]
Reactant: OB(O)c1ccsc1
Reactant: N#Cc1c(N)cccc1Br
Product: N#Cc1c(N)cccc1-c1ccsc1
Yield: 94 %

Procedure:
Prepared as in Example 129c from thiophen-3-ylboronic acid and 2-amino-6-bromobenzonitrile in 94% yield as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 6.08 (br s, 2H), 6.70 (dd, J=1.2, 7.6 Hz, 1H), 6.77 (dd, J=1.2, 8.4 Hz, 1H), 7.31 (dd, J=7.6, 8.4 Hz, 1H), 7.38 (dd, J=1.2, 4.8 Hz, 1H), 7.66 (dd, J=2.8, 4.8 Hz, 1H), 7.78 (dd, J=1.2, 2.8 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25].O>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 2,4-dichlorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 ml), extracted with EtOAc (2×50 mL), washed with H2O (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used for further transformation .