Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:31])([F:30])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[CH:25]=O)[N:18]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[O:40][CH:41]=[C:42]([C:44]([CH3:48])([CH3:47])[CH2:45][NH2:46])[N:43]=2)=[CH:35][CH:34]=1>ClCCCl>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[O:40][CH:41]=[C:42]([C:44]([CH3:48])([CH3:47])[CH2:45][NH:46][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:30])[F:15])[O:21][N:20]=4)[CH:23]=3)[N:43]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=Cc1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(CNCc1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 17.5 %

Procedure:
Sodiumtriacetoxy borohydride (197 mg, 0.9 mmol) was added to a solution of 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde (150 mg, 0.62 mmol) and 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine (150 mg, 0.64 mmol) in dry DCE (2 mL) at 0° C. under nitrogen atmosphere and stirred at room temperature for 8 h (monitored by TLC, petroleum ether/EtOAc 6:4). Reaction mixture was carefully quenched with 10% NaHCO3 solution and the organic product was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10-15% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine (50 mg, yield 18%). 1H NMR (400 MHz, MeOD) δ 8.01 (m, 2H), 7.96-7.92 (m, 3H), 7.67 (s, 1H), 7.54-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.20-7.15 (m, 1H), 3.82 (s, 2H), 2.76 (s, 2H), 1.32 (s, 6H). MS (ESI) m/z: Calculated for C23H20F4N4O2: 460.15. found: 461.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:53])[CH:3]1[CH2:6][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:8])[CH2:4]1.[H][H]>O1CCCC1.O.[Pd]>[CH3:53][N:2]([CH3:1])[CH:3]1[CH2:4][N:5]([C:7]([C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:16]([CH3:39])[C@@H:17]4[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:18]4[C:19]=3[C:20]([OH:22])=[O:21])[CH2:11][NH:10]2)=[O:8])[CH2:6]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(N(C)C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N(C)C)C4)C3)[C@H](C)[C@H]12

Procedure:
0.75 g of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(3-dimethylaminoazetidin-1-ylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 129(1)] was dissolved in a mixture of 21 ml of tetrahydrofuran and 14 ml of water, and 0.75 g of a 10% w/w palladium-on-carbon catalyst was added to the resulting solution, after which the mixture was hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration and the filtrate was washed with diethyl ether. The resulting aqueous solution was then concentrated by evaporation under reduced pressure, after which the residue was subjected to reverse phase column chromatography [Cosmosil 75C18 -prep, 25 g, manufactured by Nacalai Tesque). Of the fractions obtained by elution with 7% by volume aqueous acetonitrile, the fraction containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to obtain 171 mg of the title compound as a powder.
Reaction SMILES: [CH:1]12[C:13](=O)[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13.[BH4-].[Na+].[NH3:21]>CO>[CH:1]12[CH:13]([NH2:21])[CH:5]3[C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[CH:8]1[CH:2]2[C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=13
Reactant: N
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC1C2c3ccccc3C3C(c4ccccc42)C13
Reaction time: 48 h

Procedure:
An amount of 464 mb (2mMoles) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one is dissolved in 15 ml of a 15% solution of ammonia in methanol, and the solution allowed to stand in a closed flask for 48 hours at 20°. An addition is then made at ca. 20°, with stirring, of 152 mg of sodium borohydride. After 30 minutes, the reaction mixture is briefly refluxed and again cooled. Processing is carried out analogously to Example 1 to obtain 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cycloheptene-11-amine; M.P. 126°-127°.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH:6]([N:16]([CH3:27])[S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:7][C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3]1=[O:4]
Reactant: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(=O)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 82 %

Procedure:
To a cooled (with ice water) and stirred solution of 256 g of 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)-butyryl chloride in 1500 ml of dry benzene 195 g of aluminium chloride is added rather rapidly. The mixture is stirred at room temperature for an additional 25 minutes and then poured on to a mixture of ice and 950 ml of concentrated hydrochloric acid. After stirring the mixture at room temperature for 30 minutes the organic layer is separated whereas the aqueous layer is shaken twice with benzene. The combined organic solutions are washed twice with water and again twice with an aqueous solution of potassium carbonate whereupon, after drying, the whole is concentrated in vacuo. The residue is taken up in ether which brings about the crystallization of the title product. White crystals melting at 119°-120° C. Yield 82%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H]1CCCN[C@H]1c1ccccc1)OCc1ccccc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br. d, J=9 Hz, 1H), 1.6-1.9 (m, 2H), 2.02 (br. d, J=9 Hz, 1H), 2.79 (dd, J=9 and 10 Hz, 1H), 3.22 (dd, J=1 and 10 Hz, 1H), 3.91 (br. s, 1H), 4.01 (dd, J=1 and 8 Hz, 1H), 4.89 (s, 2H), 5.65 and 5.88 (2br. s, 1H), 7.1-7.4 (m, 10H).
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([C:28](OC)=[O:29])([C:24]([F:27])([F:26])[F:25])[F:23])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[BH4-].[Na+]>CC(O)C>[C:1]([C:5]([C:8]([O:11][C:12]([C:18]([O:21][C:22]([CH2:28][OH:29])([C:24]([F:25])([F:26])[F:27])[F:23])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: COC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F

Procedure:
CF3CF2CF2OCF(CF3)CF2OCF(CF3)COF obtained in Example 2-6 is reacted with methanol in an equimolar amount in the presence of sodium fluoride to obtain CF3CF2CF2OCF(CF3)CF2OCF(CF3)COOCH3. The obtained CF3CF2CF2OCF(CF3)CF2OCF(CF3)COOCH3 is reacted with sodium borohydride in 2-propanol to obtain CF3CF2CF2OCF(CF3)CF2OCF(CF3)CH2OH. The obtained CF3CF2CF2OCF(CF3)CF2OCF(CF3)CH2OH is employed as the compound in Example 2-1 to carry out the same reaction. Further, the same reactions as in Examples 2-2 to 2-6 are carried out to obtain FSO2CF2CF2COF and CF3CF2CF2OCF(CF3)CF2OCF(CF3)COF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH:15]([C:17](=[O:19])[CH3:18])[CH3:16])[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[N:12]([CH:15]([C:17]([OH:19])([CH3:24])[CH3:18])[CH3:16])[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(C(C)C(C)=O)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(=O)n(C(C)C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 5-(4-fluorophenyl)-6-oxo-1-(3-oxobutan-2-yl)-1,6-dihydropyridine-3-carboxylate (11.1 g, 35.0 mmol) in tetrahydrofuran (175 mL) at 0° C. was added methylmagnesium bromide (3.0 M in THF; 14.0 mL, 42.0 mmol). After 20 min, the mixture was quenched with saturated aqueous sodium bicarbonate. The mixture was cooled to ambient temperature and extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→80% dichloromethane/ethyl acetate) gave the title compound. MS 334.2 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH2:27][CH2:28][O:29][CH2:30][CH:31]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:26]5[CH2:27][CH2:28][O:29][CH2:30][CH:31]=5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)[CH:36]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ncc(C3=CCOCC3)cc12
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cc(Cl)ccc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A vial was charged with (S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.050 g, 0.103 mmol), 5-chloro-2-fluorophenylboronic acid (0.054 g, 0.310 mmol), and Pd(PPh3)4 (5.97 mg, 5.17 μmol). The vial was purged with Ar (g). Then, DMF (0.517 mL) and potassium carbonate (0.259 mL, 0.517 mmol) (as a 2.0 M aq. solution) were added in sequence. The vial was sealed and stirred at 70° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-7% MeOH in DCM) to afford (S)-7-(5-chloro-2-fluorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid. Found MS: MH+=464.
Reaction SMILES: [CH3:1][Mg:2][Br:3].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH2:11][C:12](=[O:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH2:22](OCC)C>>[CH3:1][Mg:2][Br:3].[CH3:22][C:12]([OH:21])([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:11][O:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][O:4]1
Reactant: CCOCC
Reactant: O=C(COC1CCCCO1)COC1CCCCO1
Agent: C[Mg]Br
Product: CC(O)(COC1CCCCO1)COC1CCCCO1
Reaction time: 16 h

Procedure:
A solution of 0.14 moles of methylmagnesium bromide in diethyl ether was prepared by dissolving 15.5 g of 3M methylmagnesium bromide solution (in diethyl ether) in 100 ml of specially dried diethyl ether. While stirring at 25°-30° , a solution of 25.8 g of 1,3-bis(2-tetrahydropyranyloxy)-2-propanone, prepared as above, in 100 ml of diethyl ether was added dropwise. A white solid separated and refluxing occurred. The mixture was warmed to maintain reflux for 1 hour, then allowed to stand for 16 hours. Saturated ammonium chloride solution (100 ml) was added very slowly and when addition was completed, the layers were separated. The aqueous layer was extracted (2 × 100 ml) with diethyl ether. The ether solutions were combined, washed (2 × 100 ml) with water and dried over magnesium sulfate. The dried solution was concentrated and distilled to give 16.2 g of 2-methyl-1,3-bis(2-tetrahydropyranyloxy)-2-propanol, b.p. 121°-136°/2--3 × 10- 4 mm.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[O:4].[H-].[Na+].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>CS(C)=O.C(Cl)(Cl)Cl>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=[C:5]1[C:3]([N:2]([CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:4]
Reactant: CN(C)CCCl
Reactant: CN(C(=O)c1nc2ccccc2[nH]1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCn1c(C(=O)N(C)c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Methyl-N-(2-pyridyl)benzimidazole-2-carboxamide (1.0 g) prepared in Example 5 was dissolved in dry DMSO (20 ml), 60% sodium hydride (0.17 g) was added and stirred at room temperature for 1 hr in an argon atmosphere. Excess β-dimethylaminoethyl chloride was added to the mixture and reacted at room temperature under agitation for 20 hrs. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous Na2SO4 and the solvent was distilled off. Purification of the residue by column chromatography on silica gel (using silica gel manufactured by Merck Co., Ltd.) gave the title compound (0.88 g) as an oily product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH3:40])[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2C)n1

Procedure:
To a stirring solution of 4-[5-(2-methylthiopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (Example 1E) (4.0 g, 7.22 mmole) in toluene (80 mL) was added dimethylformamide dimethyl acetal (4.0 mL) and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated in vacuo to a foam and chromatographed on silica using 5% acetone/methylene chloride to give upon concentration of the product containing fractions the title compound 2.78 g.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](B3OCC(C)(C)CO3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:11]2[CH:10]=[CH:9][C:8]([NH:21][C:22]([C:24]3[N:25]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])[CH:26]=[C:27]([C:29]#[N:30])[N:28]=3)=[O:23])=[C:7]([C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:12]=2)=[CH:41][CH:42]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)COB(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)OC1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)nc2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-phenyl]-amide (as prepared in the previous step, 32.0 mg, 0.0600 mmol), 5-bromo-pyridin-2-ylamine (10.4 mg, 0.0660 mmol) and Pd(PPh3)4 (7.0 mg, 0.0060 mmol) in 1.0 mL of 1,4-dioxane was added 2.0 M Na2CO3 aqueous solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80. C for 6 h under Ar. After cooling to RT, the mixture was treated with 30 mL of EtOAc, washed with H2O (3×15 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to afford 24 mg (78%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C28H34N6O2Si, 515.3 (M+H), found 515.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CC#N>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCC(F)(F)F)CC1
Temperature: 0 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (200 mg, 0.45 mmol) was suspended in CH3CN (4 mL) and cooled to 0° C. 2,2,2-Trifluoroethyl trichloromethanesulphonate (66 mg, 0.23 mmol) in CH3CN (1 mL) was added dropwise to the reaction mixture and the reaction mixture was heated to 90° C. for 5 h. The reaction mixture was concentrated and the resulting residue was diluted with ethyl acetate. The solution was treated with 1M Na2CO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. Silica gel prep TLC using 98:2 CH2Cl2:MeOH, then 7:3 Hexanes:ethyl acetate afforded 74 mg of the title compound, m/z 523.0 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([O:14]CC)=[O:13])[NH:9][N:8]=2)[CH:2]=1.[OH-].[Na+]>C(O)C.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:2]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccnc2)n[nH]1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Ethyl 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (1.577 g, 7.26 mmol) in Ethanol (60 ml) and THF (60 ml) was reacted with 1M NaOH solution (40 ml, 7.26 mmol) and heated to 60° C. for 2 h. The solvents were evaporated under reduced pressure and the residue was diluted with water. The solution was made acidic by the addition of 2 N HCl solution. The resultant mixture was stirred in ice-cold bath for 4 h and the solid precipitated was filtered, dried and weighed. Yield 378 mg. 1H NMR (400 MHz; d6-DMSO): δ 7.39 (m, 2H), 8.21 (d, 1H), 8.53 (bs, 1H), 9.06 (bs, 1H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:10]([O:11][CH3:12])=[CH:9][C:7]([NH2:8])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1>CN(C=O)C>[Br:3][C:4]1[C:10]([O:11][CH3:12])=[CH:9][C:7]([NH:8][CH2:17][C:18]2[CH:28]=[CH:27][C:21]3[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=3[CH:19]=2)=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(NCc2ccc3nc(SC)sc3c2)c([N+](=O)[O-])cc1Br
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 24.7 %

Procedure:
To a stirred mixture of DMF (15 mL) and NaH (60% in mineral oil, 75 mg, 1.9 mmol) at −10° C. under argon was added 4-bromo-5-methoxy-2-nitroaniline (490 mg, 2.2 mmol) in one portion. The mixture was stirred for 5 min at −10° C. A solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole from Example 36 (500 mg, 2.2 mmol) in DMF (5 mL) was added dropwise. After stirring at −10° C. for 1 h, the mixture was allowed to warm slowly to rt. The mixture was stirred at rt for 58 h and then partitioned between EtOAc (150 mL) and 1 M aq Na2CO3 (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-5-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (239 mg, 25%) as an orange solid. 1H NMR (300 MHz, DMSO-d6) δ 9.02 (t, J=5.8 Hz, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 3.77 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 440 and 442 (M+H)+.