Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[C:14](=[O:17])([O-])O.[Na+].[CH3:19][OH:20]>C1COCC1>[OH:20][C@H:19]1[C@H:5]([CH3:4])[N:6]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:10]=2)[C:14](=[O:17])[C:3]1([CH3:10])[CH3:2]
Reactant: O=C([O-])O
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a mixed solution of 4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl)]-2-(trifluoromethyl)benzonitrile (391.7 mg) in THF (12 mL) and methanol (12 mL) was added 6 mol/L hydrochloric acid (12.0 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless oil (yield: 203.6 mg, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=Cc1cc(Br)cc2c1OCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2,3-dihydrobenzo[b]furan-7-carbaldehyde (11.42 g), was dissolved in 50 ml of tetrahydrofuran and 50 ml of ethanol, then 2 g of sodium borohydride was added thereto, and the mixture was stirred overnight at room temperature. 1 N hydrochloric acid was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed, to give (5-bromo-2,3-dihydrobenzo[b]furan-7-yl)methanol. This product was treated in the same way as Production Example 90b) to give 12.6 g of the title compound.
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[C:5]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([N:20]([CH3:29])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:13][C:12]=2[O:30][CH3:31])=[N:8][CH:9]=1>O.C(O)C.[Fe]>[Cl:3][C:4]1[C:5]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N:20]([CH3:29])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:13][C:12]=2[O:30][CH3:31])=[N:8][CH:9]=1
Reactant: COc1cc(N(C)CCN2CCOCC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N(C)CCN2CCOCC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 79.6 %

Procedure:
A solution of NH4Cl (28.1 mg, 0.53 mmol) in water (13.00 mL) was added in one portion to a stirred mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-(2-morpholin-4-ylethyl)-5-nitrobenzene-1,4-diamine (Intermediate 106, 426 mg, 0.75 mmol) and iron (251 mg, 4.50 mmol) in ethanol (39 mL). The resulting mixture was stirred at reflux for 2 h. Further iron (251 mg, 4.50 mmol) and NH4Cl (28.1 mg, 0.53 mmol) was added and the mixture was stirred at reflux for a further 0.5 h. The mixture was concentrated in vacuo and the residue was mixed with DMF (5 mL) and then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia in CH2Cl2 and appropriate fractions were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 2M methanolic ammonia in CH2Cl2 gave the title compound (304 mg, 80%) as a yellow foam; 1H NMR: 2.43 (4H, m), 2.45 (2H, t), 2.68 (3H, s), 2.93 (2H, t), 3.51-3.61 (4H, m), 3.66 (3H, s), 4.73 (2H, s), 6.77 (1H, s), 6.90 (1H, s), 7.12 (1H, m), 7.34 (1H, m), 8.37 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=2[C:25]2[O:26][C:27](=[O:35])[C:28]3[CH:34]=[CH:33][N:32]=[CH:31][C:29]=3[N:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-]#N.[K+].[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([NH2:46])=[N:44][CH:45]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:18]=[CH:17][C:16]=2[C:25]([NH:30][C:29]2[CH:31]=[N:32][CH:33]=[CH:34][C:28]=2[C:27]([NH:46][C:43]2[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][N:44]=2)=[O:35])=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2-c2nc3cnccc3c(=O)o2)CC1
Reactant: Nc1ccc(Cl)cn1
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2cnccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C
Yield: 23.5 %

Procedure:
A mixture of 2-[2-(1-tert-butoxycarbonylpiperidin-4-yl-oxy)-4-tert-butylphenyl]-4H-pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.21 mmol), KCN (100 mg), 5-chloro-2-aminopyridine (53 mg, 0.42 mmol), and dry DMF (2 mL) was heated at 70° C. for 4 h, then quenched with brine (25 mL). The mixture was extracted with 10% MQOH in EtOAc (2×20 mL), and the combined extracts were washed with brine (3×100 mL) then dried over MgSO4. After filtering, the filtrate was concentrated to an oil which was purified by chromatography using 60% EtOAc in hexanes to give 30 mg of an oil which crystallized.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[CH2:10][CH:9]1[CH2:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(C(C)(C)C)(C)C.C([O:30]O)(C)(C)C>C(O)(=O)C.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[O:30]=[C:14]([CH2:13][CH:9]1[CH2:10][C:11](=[O:12])[NH:8]1)[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OO
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Temperature: 55 °C
Reaction time: 11 h

Procedure:
To a solution of benzyl 4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate (50 mg) in 60% aqueous acetic acid (1.5 ml) were added tert-butyl-hydroperoxide (40 μl) and sodium tetrachloropalladate (18 mg). The solution was heated at 55° C. for 5.5 hours. Additional tert-butyl-hydroperoxide (100 μl) and sodium tetrachloropalladate (18 mg) were added and stirring at 50° C. was continued for further 11 hours. After evaporation of the solvent in vacuo, the residue was taken up into ethyl acetate and washed in turn with water (twice) and brine. Drying over magnesium sulfate and removal of the solvent left an oil (30 mg) which was chromatographed on a silica gel plate (developing solvent: 25% acetone in benzene) afforded benzyl 3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (13 mg).
Reaction SMILES: [F:1][C:2](=[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[CH:15]=[C:14]2C(C)C)[CH2:9][CH3:10])[C:3]([O:5]CC)=O.F/[C:29](=[C:35](/C1C=C2C(=CC=1OC)OC(C)(C)C=C2C(C)C)\CC)/[C:30](OCC)=O.[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[C:8](/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[C:15]([CH:29]([CH3:35])[CH3:30])=[CH:14]2)\[CH2:9][CH3:10])/[CH2:3][OH:5]
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc2c(cc1OC)OC(C)(C)C(C(C)C)=C2

Procedure:
Following General Procedure L, ethyl 2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-pent-2-enoate (Compound 78, 128 mg, 0.34 mmol) and a diisobutylaluminum hydride (1 M in dichloromethane, 1.0 mL, 1.0 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[NH:23]C(OCC[Si](C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[NH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a solution of tert-butyl (6R,7S)-7-(3,4-dichlorophenyl)-6-({[2-(trimethylsilyl)ethoxy]carbonyl}amino)-1,4-oxazepane-4-carboxylate (0.67 g) in THF (5 mL) was added tetra-n-butylammonium fluoride (5.2 mL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][C:13]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:14]([O:16]C)=O)=[O:11].C[C:23]([O-:26])(C)C.[K+].O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:26][CH3:23])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:16])[C:13]([CH:18]([CH3:20])[CH3:19])([CH3:21])[NH:12][C:10]1=[O:11]
Reactant: COC(=O)C(C)(NC(=O)Cc1ccc(F)cc1Cl)C(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(=O)NC(C)(C(C)C)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
71.4 g (0.226 mol) of methyl N-(2-chloro-4-fluorophenyl-acetyl)-2-amino-2,3-dimethyl-butyrate, dissolved in 450 ml of absolute toluene, are added dropwise to a suspension of 56 g (0.498 mol) of potassium tert-butylate in 150 ml of absolute tetrahydrofuran at the boil, and stirring is continued for 90 minutes at reflux temperature. After the reaction mixture has cooled to room temperature, 700 ml of water are added, the organic phase is separated off and washed again using 340 ml of water. The combined aqueous phases are acidified at 15-20° C. using separately 80 ml of concentrated hydrochloric acid, and the product is filtered off with suction. After drying, 57.1 g (85% of theory) of 3-(2-chloro-4-methoxyphenyl)-5-isopropyl-5-methyl-pyrrolidine-2,4-dione of m.p. 130-140° C. are obtained.
Reaction SMILES: S(O)([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:40][O:41][CH3:42])[C:13]([NH:15][CH:16]2[C:38](=[O:39])[N:18]3[C:19]([C:35]([OH:37])=[O:36])=[C:20]([CH2:23][N+:24]45[CH2:31][CH2:30][C:27]([C:32](=[O:34])[NH2:33])([CH2:28][CH2:29]4)[CH2:26][CH2:25]5)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.[C:43](=O)([O-:45])[OH:44].[Na+:47]>CC(C)=O>[C:43]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:40][O:41][CH3:42])[C:13]([NH:15][CH:16]2[C:38](=[O:39])[N:18]3[C:19]([C:35]([O-:37])=[O:36])=[C:20]([CH2:23][N+:24]45[CH2:31][CH2:30][C:27]([C:32](=[O:34])[NH2:33])([CH2:26][CH2:25]4)[CH2:28][CH2:29]5)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:45])=[O:44].[Na+:47]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@H]12)c1nsc(N)n1
Reactant: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@H]12)c1nsc(NC(=O)[O-])n1
Yield: 50.4 %

Procedure:
To a suspension of crystals of 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (500 mg) in 50% aqueous acetone (4 ml) was added sodium hydrogencarbonate (323 mg) at ambient temperature. Carbonic acid gas was bubbled into the mixture for four hours and diluted with water. The resulting mixture was chromatographed on non-ionic adsorption resin "Diaion HP-20" (50 ml) eluting with water. The desired fractions were collected and lyophilized to give sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate (syn isomer) (239.6 mg).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19]>>[CH3:3][C@H:2]([C@@H:18]([OH:19])[CH2:17][CH:16]([CH3:20])[CH3:15])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CC(C)CC=O
Product: CC(C)C[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 3-methylbutanal. 1H-NMR (CDCl3, 400 MHz): δ 8.06 (m,1H); 7.25 (m,3H); 4.17 (m,1H); 3.91 (dq,1H,J=3,7); 2.52 (br s,1H); 1.82 (m,1H); 1.56 (ddd,1H,J=5,9,13); 1.31 (d,3H,J=7); 1.25 (ddd,1H,J=4,6,13); 0.95 (d,3H,J=7); 0.94 (d,3H,J=7).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1.ClCCl.[Br:19]Br>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[C:10]([Br:19])[C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1
Reactant: CCn1c(=O)ccc2c(C)nc(N)nc21
Reactant: BrBr
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2 mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL, 1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 h at room temperature. After that, the solvent was evaporated nearly 80% volume of reaction mixture under vacuum, and then acetone was added to give 3.54 g 2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid. LC/MS: Calculated for C10H11BrN4O (283.12). Found: 285.15 (M+2). HPLC analytical purity: 97.7%.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([CH:7]([C:10]1[CH:14]=[CH:13][NH:12][N:11]=1)[CH2:8][CH3:9])[CH3:6].C(N(CC)C(C)C)(C)C.O[CH:25]1[O:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:26]1=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:5]([CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH:25]2[O:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=3)[C:26]2=[O:40])[N:11]=1)[CH2:8][CH3:9])[CH3:6]
Reactant: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Reactant: CCC(CC)c1cc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)c1ccn(C2OCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of thionyl chloride (5 mL, 68.55 mmol) in methylene chloride (100 mL) at ˜10° C. was slowly added 3-(1-ethylpropyl)-1H-pyrazole (11.74 g, 84.94 mmol). The resulting solution was stirred for ˜20 minutes and was then cooled to ˜0° C. To this solution was added N,N-diisopropylethylamine (24.7 mL, 141.8 mmol) dropwise and then 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-oxazolidinone (14 g, 56.64 mmol), portionwise at temperatures between 0° C. and 15° C. After the addition, the reaction mixture was allowed to warm to room temperature, and then stirred at room temperature for 2 days. To the reaction mixture was then added concentrated aqueous sodium bicarbonate solution (100 mL). The methylene chloride layer was separated, and the aqueous layer was extracted twice with methylene chloride (˜100 mL each). The methylene chloride layers were combined, dried over MgSO4 and then concentrated. The residue was loaded on silica gel in a column and eluted with methylene chloride to give a crude product. The crude product was further purified by trituration in hexanes followed by filtration to give the title compound, a compound of this invention, as a white solid (10.67 g) melting at 83–85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:17][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])[CH:5]=[C:6]([O:15][CH3:16])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COc1cc(O)cc(Cl)c1CN1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(OS(=O)(=O)C(F)(F)F)cc(Cl)c1CN1CCCCC1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a stirred solution of 3-chloro-5-methoxy-4-piperidin-1-ylmethylphenol (223 mg, 0.87 mmol) and pyridine (0.28 mL, 3.5 mmol) in DCM (10 mL) at −20° C. was added trifluoromethanesulfonyl chloride (0.29 mL, 1.7 mmol). After the addition was complete the reaction mixture was allowed to warm to ambient temperature then diluted with DCM (20 mL) then washed with water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford an oil that was purified by flash chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a red oil (341 mg, 73%). 1H NMR (CDCl3, 300 MHz): 7.06 (d, J=2.3 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 4.40 (s, 2H), 4.05 (s, 3H), 3.72-3.42 (m, 1H), 3.06-2.72 (m, 1H), 2.23-1.75 (m, 4H), 1.73-1.36 (m, 4H).
Reaction SMILES: [CH3:1][C@:2]([OH:17])([CH2:15][CH3:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].BrBr>C(Cl)Cl.[F-].[K+].CCOCC>[OH:17][C@@:2]([CH3:1])([CH2:15][CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC[C@](C)(O)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of the crude product from Step 7 (7 g) and (Bu3Sn)20 (30 mL) in 150 mL of CH2Cl2 cooled at 10° C. was added a solution of Br2 (9.3 g in 30 mL of CH2Cl2). After stirring at r.t. for 30 min. the mixture was diluted with a solution of KF (500 mL, 3N) and 500 mL of Et2O. The solid generated was removed by filtration and the filtrate was separated. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give 5 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C1COCC1.[Si:10]([O:17][CH2:18][CH:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:20]#[N:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[OH-].[Na+]>CCOCC.C(Cl)Cl>[Si:10]([O:17][CH2:18][CH:19]([C:20]1([NH2:21])[CH2:2][CH2:1]1)[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC[Mg+]
Reactant: CC(C)(C)[Si](C)(C)OCC(C#N)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(c1ccc(Cl)cc1)C1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
TBS-Cl (2.29 g, 15.2 mmol) in dry DMF (12 mL) was added to a solution of 2-(4-chlorophenyl)-3-hydroxypropanenitrile (2.30 g, 12.7 mmol) and imidazole (3.45 g, 50.7 mmol) in DMF (20 mL) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ether and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexanes:EtOAc, 30:1) to give 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.40 g, 91%) as a colorless oil. A solution of EtMgBr in THF (3.0 M, 7.0 mL, 21 mmol) was added dropwise at room temperature to a stirred solution of this 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.1 g, 10 mmol) and Ti(i-PrO)4 (3.4 mL, 11 mmol) in Et2O (60 mL). After the mixture was stirred at room temperature for 1 hour, BF3OEt (2.7 mL, 21 mmol) was added at once. The mixture was stirred for an additional 1 hour. A solution of 10% NaOH (10 mL) was added, followed by DCM (300 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (30:1 DCM:MeOH) to give 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chlorophenyl)ethyl)cyclopropanamine (2.3 g, 67%) as a colorless oil. LCMS: 326.1 [M+H+] (APCI+); Rf: 3.04 min.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=O)[CH:33](C)[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:3](=[O:5])[CH2:2][CH:33]([CH3:34])[CH3:32])[CH2:28][CH2:27]2)[N:10]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CC(C)C(=O)O
Reactant: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)CC(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt Example 11 and isobutyric acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-methyl-butan-1-one. HRMS, observed: 412.2350; Calcd for (M+H)+: 412.2343.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.O(C)[Li].CON(C)[C:32]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33]>>[CH:34]1([C:32]([C:2]2[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]3[O:9][C:8]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:7][C:6]=3[CH:22]=2)=[O:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CON(C)C(=O)C1CCCCC1
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Li]OC
Product: O=C(O)c1cc(C(=O)C2CCCCC2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (1.26 g, 3.16 mmol, 1 eq.), LiOMe (240 mg, 6.32 mmol, 2 eq.) and cyclohexanecarboxylic acid methoxy-methyl-amide (650 mg, 3.8 mmol, 1.2 eq.) as the electrophile were reacted according to GP4, Method A. The crude product was purified using flash chromatography (silica gel, hexane/Et2O/AcOH 5:1:0.1) and subsequent recrystallization from CH2Cl2/hexane to give the title compound as a yellowish solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:26]([N:28]1[C:40]2[CH:39]=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27]>>[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([NH:41][C:37]1[CH:38]=[CH:39][C:40]2[N:28]([CH2:26][CH3:27])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:12])(=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, benzoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z=424.2.