Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:31])=[O:30])[NH:25][C:24]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([NH:45][CH2:46][CH2:47]Br)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].[OH-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.C1(C)C=CC=CC=1.C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[S:29]([CH3:32])(=[O:30])=[O:31])[N:25]([CH2:47][CH2:46][NH:45][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:24]([C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])=[CH:23]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
To a stirred solution of 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one (780 mg, 1.27 mmol) in THF/methanol (15 mL/15 mL) was added Cs2CO3 (1.25 g, 3.83 mmol) in one portion. The mixture was allowed to stir at rt for 4 h and concentrated in vacuo to afford the crude product 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one. It was used for the next step reaction without further purification. To a solution of crude 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-6-(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-one, 2-(Boc-amino)ethyl bromide (2.8 g, 12 mmol), tetrabutylammonium iodide (235 mg, 0.63 mmol) in CH2Cl2/toluene (2 mL/4 mL) was added 40% NaOH aqueous solution (20 mL). The mixture was allowed to stir at rt for 20 h. The reaction mixture was diluted with CH2Cl2 (40 mL) and washed with H2O (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2/Methanol (95/5) to provide tert-butyl (2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate (300 mg, 35% yield for two steps).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH:15]=[C:16]2[NH:25][CH:24]3[CH2:26][CH:19]4[CH:20]([CH2:21][CH2:22][CH2:23]3)[CH:18]4[C:17]2=[O:27])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C)C>CCOCC.C1(C)C=CC=CC=1>[C:1]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]2[NH:25][CH:24]3[CH2:26][CH:19]4[CH:20]([CH2:21][CH2:22][CH2:23]3)[CH:18]4[C:17]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1C(=Cc2ccccc2)NC2CCCC3C(C2)C13
Solvent: CCOCC
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C1C(C(c2ccccc2)c2ccccc2)NC2CCCC3C(C2)C13
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 100 mL three-neck round-bottomed flask equipped with a condenser and nitrogen inlet was added 0.71 mL (4.21 mmol) of a 3M solution of phenyl magnesium bromide in ether. The solution was cooled to 0° C. and a solution of 818 mg (3.24 mmol) 9-phenylmethylene-10-azatricyclo[4.4.1.05,7 ]undecan-8-one in 16 mL toluene was added. The reaction was warmed to room temperature, stirred for 2 hours, and then quenched with aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluent to afford an oil, 196 mg (18%). This material gave a solid from isopropanol, mp 178-181° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[O:25]([C:32]1[N:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:38]([C:35]1[CH:36]=[N:37][C:32]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1)(=[O:39])=[O:40])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate (32 mg, 0.086 mmol), triethylamine (50 μL, 0.36 mmol) and DMAP (1 mg, 0.008 mmol) in anhydrous CH2Cl2 (1 mL) was added 6-phenoxypyridine-3-sulfonyl chloride is reacted with R-aminocarnitine benzyl ester (67 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was purified by preparatory HPLC. The residue was dissolved into CH2Cl2 (50 mL) and washed with 0.1 N NaOH (5 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (18 mg, 37%). MS ESI 470.2 [M+H]+, calcd for [C24H27N3O5S+H]+ 470.17.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[C:9]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[O:10])=[CH:5][CH:4]=1)=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][N:30]1[CH2:34][CH2:33][C:32]2([CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:31]1>>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:16][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:1][N:36]2[CH2:37][CH2:38][C:32]3([CH2:33][CH2:34][N:30]([CH2:29][C:25]4[S:24][CH:28]=[CH:27][CH:26]=4)[CH2:31]3)[CH2:35]2)=[CH:4][CH:5]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)=[O:10]
Reactant: c1csc(CN2CCC3(CCNC3)C2)c1
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)C(=O)c2ncc[nH]2)cc1
Product: O=C(c1ncc[nH]1)N(Cc1ccc(CN2CCC3(CCN(Cc4cccs4)C3)C2)cc1)Cc1ncc[nH]1
Yield: 54.4 %

Procedure:
The same operation as in Example 2 was performed, except for using the compound (107 mg) obtained in Example 38 in place of 2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide, and 2-(2-thienylmethyl)-2,7-diazaspiro[4.4]nonane (86 mg) in place of benzylamine, to obtain the title compound (97 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:12][S:13](O)(=[O:15])=[O:14].O=S(=O)=O.[OH-].[Na+:22]>>[F:1][C:2]([F:10])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:13]([O-:15])(=[O:14])=[O:12])=[CH:6][CH:5]=1.[Na+:22]
Reactant: O=S(=O)(O)O
Reactant: FC(F)(F)Oc1ccccc1
Agent: O=S(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
A 100 mL flask equipped with a stir-bar and a nitrogen bubbler was charged with (trifluoromethoxy)-benzene (5.015 g) at room temperature. Oleum (15% SO3, 9.30 g) was added to the above flask at 10° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 15 h. A sodium hydroxide solution (7.75 g, in 23 mL water) was slowly added to the reaction mixture while the reaction mixture was cooled with an ice-water bath. The resulting solid was collected by filtration, dried under vacuum, and then extracted with refluxing ethanol. The ethanol solution was dried to give sodium 4-(trifluoromethoxy)benzenesulfonate (3FMBSNa) 2.0 g (yield 24%): 1H NMR (D2O) 7.45 (d, J=9 Hz, 2H), 7.89 (m, 2H) ppm; 19F NMR (D2O)-58.1 (s) ppm.
Reaction SMILES: [C:1]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:20](O)C>>[CH3:20][N:13]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12]1
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(C(=O)O)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire batch of methyl 1-5-benzoylpyrrole-3-carboxylate from Example 84 was combined with 200 ml. of ethanol and 100 ml. of 1 N sodium hydroxide and refluxed for 2 hours. The ethanol was boiled away, the aqueous residue was cooled to room temperature, extracted with 25 ml. of ether and acidified with conc. hydrochloric acid to yield crystalline product (4 g., m.p. 210°-212° C.). A portion (1.5 g.) was recrystallized from acetone to yield purified 1-methyl-5-benzoylpyrrole-3-carboxylic acid (925 mg., m.p. 215°-216.5° C., m/e 229).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([O:11][CH2:12][CH2:13][O:14][C:15]([F:18])([F:17])[F:16])=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.O=P(Cl)(Cl)Cl.N1C=CC=CC=1>CC#N.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([O:11][CH2:12][CH2:13][O:14][C:15]([F:18])([F:16])[F:17])=[C:6]([CH:10]=1)[C:7]#[N:9]
Reactant: NC(=O)c1cc(Cl)c(Cl)nc1OCCOC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cc(Cl)c(Cl)nc1OCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of 5,6-dichloro-2-(2-(trifluoromethoxy)ethoxy)nicotinamide (240 mg, 0.75 mmol) in MeCN (10 mL) were added POCl3 (350 mg, 2.3 mmol) and pyridine (360 mg, 4.5 mmol) at room temperature. After being stirred for 2 hours at room temperature, the mixture was diluted with 10 mL of sodium hydroxide solution, then extracted with ethyl acetate (2×50 mL), the combined organic layers were washed with brine twice, dried over Na2SO4 and concentrated to give 5,6-dichloro-2-(2-(trifluoromethoxy)ethoxy)nicotinonitrile (0.20 g, 88%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]([OH:17])([CH3:16])[CH3:15].CC([O-])(C)C.[K+]>C1COCC1>[CH:14]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 1.5 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (154 g, 814 mmol) in THF (1.5 L) was added isopropanol (73.4 g, 1.22 mol). The reaction flask was purged with N2 and cooled in an ice bath (1.5° C. internal temperature). t-BuOK (1.0 M in THF, 847 mL, 847 mmol) was added slowly over 10 minutes via addition funnel (slight exotherm to 31° C. was observed) and let stir at that temperature for 30 min (temp decreased to 18° C. during this time). The ice bath was removed and allowed to stir at room temperature until starting material was consumed as observed by LC/MS (˜20 min). The resulting mixture was quenched with water (500 mL) and the layers were separated. The organic layer was concentrated and the aqueous layer was extracted with MTBE (1 L). The organics were combined and washed with H2O (750 mL) and brine (750 mL). Dried organics over MgSO4, filtered, and concentrated to give 4-isopropoxy-3-(trifluoromethyl)benzonitrile (183 g, 798 mmol, 98% yield) as a yellow solid. Exact mass calculated for C11H10F3N0: 229.1, found: LCMS m/z=230.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.1 Hz, 6 H), 4.73 (sep, J=6.1 Hz, 1 H), 7.06 (d, J=8.7 Hz, 1 H), 7.75 (dd, J1=8.7, J2=2.1 Hz, 1 H), 7.85 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][CH2:8][C:9]1[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:11]=2[N:10]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:22][C:19]1[CH:20]=[CH:21][C:11]2[N:10]=[C:9]([CH2:8][O:7][C:6]3[CH:23]=[CH:24][CH:25]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:12]=2[CH:18]=1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cccc(OCc2nc3ccc(O)cc3n2CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2nc(COc3cccc(OCC)c3)n(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 66b (3.00 g, 8.81 mmol) and DMF (35 mL). To the resultant solution was added K2CO3 (1.83 g, 13.2 mmol) followed by ethyl bromoacetate (1.62 g, 1.07 mL, 9.69 mmol). The mixture was stirred at rt overnight. The solids were then filtered off and rinsed with EtOAc (2×50 mL). The filtrate was washed with saturated NH4Cl (2×75 mL), H2O (2×75 mL), and brine (75 mL) and filtered through phase separation paper. The organic phase was filtered through a plug of silica gel, rinsed with EtOAc (3×100 mL), and concentrated in vacuo to 4.0 g of a brown oil. 1 g of the crude oil was chromatographed on a Biotage MPLC 25+M silica gel column with the product eluting with 30-36% EtOAc in hexanes. The product fractions were concentrated to give 975 mg of Compound #13 as a yellow oil (100%). 1H NMR (300 MHz, CDCl3): δ 7.69 (d, 1H), 7.20 (t, 1H), 6.93 (dd, 1H), 6.88 (d, 1H), 6.67 (dd, 1H), 6.63 (t, 1H), 6.54 (dd, 1H), 5.32 (s, 2H), 4.70 (s, 2H), 4.29 (qt, 2H), 4.05 (qt, 2H), 4.04 (d, 2H), 2.34 (nonet, 1H), 1.41 (t, 3H), 1.32 (t, 3H), 0.97 (d, 6H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 99% with a retention time of 3.9 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1ccc2ccccc2c1
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: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccccc3c2)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 243 g (1.41 mol) of 2-naphthalene boronic acid, 400 g (1.41 mol) of 3-bromoiodobenzene, 3.27 g (28.2 mmol) of tetrakis(triphenylphosphine)palladium(0), 6.4 L of toluene and 3.2 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 303 g of 2(3-bromophenyl)naphthalene was obtained with an yield of 76%.
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[Na].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10].C(S(O)(=O)=O)=C>O.O1CCOCC1>[C:9]([NH:13][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(=O)(O)CCBr
Reactant: CC(C)(C)N
Agent: C=CS(=O)(=O)O
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)NCCS(=O)(=O)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A solution of 2-bromoethanesulfonic acid, sodium salt (4.2 g, 20 mmol) in water (total 12 mL) was added over 6 hours to a 420C solution of t-butylamine (10 mL, 94 mmol) in a mixture of water (10 mL) and 1,4-dioxane (10 mL). The mixture was stirred at 42° for 18 hours. The mixture was then heated to 60° C. for 24 h. By proton NMR, 30% of elimination product (vinylsulfonic acid) was observed. The mixture was concentrated to dryness and treated with ethanol at refluxing temperature. The solid material was collected (crop 1). The mother liquor was concentrated to dryness and the solid was again treated with ethanol at refluxing temperature, and the solid material was collected (crop 2). Both crops of the solid material were dissolved in water, and the resultant aqueous solutions passed in sequence through a Dowex 50 W X 8 ion-exchange column (100 g resin). The fractions containing the title compound were collected and concentrated to dryness. The solid material obtained was recrystallized from a mixture of ethanol (20 mL) and water (2 mL). The crystals were collected by filtration, dried in a vacuum oven at 60° C. for 18 hours. Compound DU was obtained as fine white needles (860 mg, 24% yield). 1H NMR (500 MHz, D2O) δ 1.16 (s, 9H), 3.02 (t, J=6.8 Hz, 2H), 3.19 (t, J=6.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 24.8, 37.3, 47.0, 57.8. ES-MS 182 (M+1)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26]([N:29]2[CH2:44][CH2:43][C:31]3([N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][CH2:32]3)[C:30]2=[O:45])=[CH:25][CH:24]=1>>[CH3:14][N:13]([CH3:15])[C:11]([C:9]1[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)[C:6]2[N:7]=[C:2]([NH:22][C:23]3[N:28]=[CH:27][C:26]([N:29]4[CH2:44][CH2:43][C:31]5([N:35]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:33][CH2:32]5)[C:30]4=[O:45])=[CH:25][CH:24]=3)[N:3]=[CH:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCOC1
Reactant: CC(C)(C)OC(=O)N1CCCC12CCN(c1ccc(N)nc1)C2=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC5(CCCN5C(=O)OC(C)(C)C)C4=O)cn3)nc2n1C1CCCOC1
Yield: 71.9 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (76 mg, 0.246 mmole) was combined with tert-butyl 7-(6-aminopyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (82 mg, 0.246 mmole) which gave tert-butyl 7-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (107 mg) in 72% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.80 (s, 1H), 8.69-8.57 (m, 2H), 8.35-8.25 (m, 1H), 6.54 (s, 1H), 4.63-4.52 (m, 1H), 4.06-3.88 (m, 2H), 3.86-3.70 (m, 2H), 3.64-3.46 (m, 2H), 3.18 (S, 6H), 3.02-2.84 (m, 1H), 2.84-2.59 (m, 1H), 2.24-1.99 (m, 6H), 1.96-1.79 (m, 3H), 1.77-1.52 (m, 1H), 1.48 (s, 4H), 1.39 (s, 5H). HR-MS m/z 605.3210 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:13][C:5]2[C:6]([CH3:12])([CH3:11])[O:7][C:8]([CH3:10])([CH3:9])[C:4]=2[C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[CH3:10][C:8]1([CH3:9])[O:7][C:6]([CH3:11])([CH3:12])[C:5]2[S:13][C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21]([F:20])([F:31])[F:32])=[C:3]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])[C:4]1=2
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Product: CCCOC(=O)c1c(NC(=O)c2ccccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 62A and commercially available 2-trifluoromethylbenzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 0.90 (t, J=7.5 Hz, 3H), 1.50 (s, 6H), 1.54 (s, 6H), 1.63-1.75 (m, 2H), 4.22 (t, J=6.8 Hz, 2H), 7.79-7.95 (m, 4H), 11.47 (br s, 1H). MS (ESI+) m/z 456 (M+H)+. Anal. calcd. for C22H24F3NO4S: C, 58.01; H, 5.31; N, 3.08. Found: C, 57.97; H, 5.37; N, 3.04.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37]C(CCN)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:35][CH:34]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: COc1ccc(CCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(4-methoxyphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.24 (1H, s) 8.14 (0H, t) 8.02 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.42 Hz) 7.46 (1H, d, J=5.37 Hz) 7.31 (1H, dd, J=3.34, 2.56 Hz) 7.13 (2H, d, J=8.69 Hz) 6.76-6.84 (3H, m) 6.44 (1H, dd, J=3.49, 1.93 Hz) 3.69 (3H, s) 3.37-3.48 (2H, m) 2.75 (2H, t, J=7.37 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[CH:5]=[CH:6][CH:7]=1.[Mg].II.[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)[CH:28]=[C:27]([CH3:38])[N:26]=1)[CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([N:31]2[CH2:36][CH2:35][C:34]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=3)([OH:37])[CH2:33][CH2:32]2)[CH:28]=[C:27]([CH3:38])[N:26]=1)[CH2:23][CH3:24]
Reactant: Clc1cccc(Br)c1
Reactant: CCN(c1nc(C)cc(N2CCC(=O)CC2)n1)c1ccc(C(C)C)cc1Br
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(N2CCC(O)(c3cccc(Cl)c3)CC2)n1)c1ccc(C(C)C)cc1Br
Yield: 58.8 %

Procedure:
3-Bromochlorobenzene (427 mg), 27 mg of magnesium, and a trace amount of iodine were heated in 5 ml of tetrahydrofuran under reflux for 1 hour. The reaction mixture was cooled with ice and added dropwise to a solution of 321 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-6-methyl-4-(4-oxopiperidin-1-yl)pyrimidine in 3 ml of tetrahydrofuran, followed by stirring under ice-cooling for 1 hour and then at room temperature for an addition 1 hour period. The reaction mixture was again cooled with ice, and a saturated ammonium chloride aqueous solution was added thereto dropwise. After stirring at room temperature for 10 minutes, the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated ammonium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to give 238 mg of 2-[N-(2-bromo-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-chlorophenyl)-4-hydroxypiperidin-1-yl]-6-methylpyrimidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][O:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
4-Chloro-3-nitropyridine (2.0 g, 12.62 mmol) prepared in Step 1 of Preparation 1 was added to a suspension of 4-fluorobenzyl alcohol (2.04 ml, 18.92 mmol), potassium carbonate (1.74 g, 12.62 mmol), and potassium hydroxide (2.38 g, 50.48 mmol) in anhydrous toluene (100 ml). A catalytic amount of tris[2-(2-methoxyethoxy)ethyl]amine was added to the reaction mixture, which was then stirred for 1 hour at room temperature. The reaction mixture was filtered and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, (v/v)) to give the titled compound as a white solid (2.5 g, 86.3%).