Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([OH:15])=O.[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=1[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:13]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[NH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[C:11]3[CH3:12])=[O:15])=[CH:21][C:20]=1[C:26]1[CH:31]=[N:30][CH:29]=[N:28][CH:27]=1
Reactant: Cc1ccc(N)cc1-c1cncnc1
Reactant: Cc1c(C(F)(F)F)[nH]c2c(C(=O)O)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cccc3c(C)c(C(F)(F)F)[nH]c23)cc1-c1cncnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.3 %

Procedure:
To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid (122 mg) and 4-methyl-3-(pyrimidin-5-yl)aniline (93 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 24 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[4-methyl-3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide (155 mg, 75.6%).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH:5]1[CH2:10][CH:9]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:7]([CH3:20])([CH3:19])[O:6]1>[OH-].[Na+].CO>[CH3:19][C:7]1([CH3:20])[O:6][C@@H:5]([CH2:4][C:3]([OH:21])=[O:2])[CH2:10][C@@H:9]([CH:11]=[CH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8]1
Reactant: COC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)O[C@@H](CC(=O)O)C[C@@H](C=Cc2ccccc2)O1
Yield: 89 %

Procedure:
A solution of 2,2-dimethyl-6-(2-phenylethenyl)-1,3-dioxane-4-acetic acid methyl ester (8.5 g, 29.3, mmol) in 1N NaOH (32 mL) and methanol (64 mL) was heated to reflux for 45 minutes. After evaporation under reduced pressure, the aqueous solution was washed once with diethyl ether and acidified with 1N HCl (33 mL). The precipitate was collected and recrystallized from ethyl acetate/isopropyl ether to afford 7.2 g (90%) of the title compound as a colorless solid; m.p.=153°-155° C.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH:25]1[C:33]2[C:28](=[CH:29][C:30]([Br:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)[C:7]([NH:9][CH:10]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:11]([O:13]C)=[O:12])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[Br:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH:25]([CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:15][C:16]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=1)=[O:8])[CH2:26][CH2:27]2
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)C(CSC(C)=O)C1CCc2cc(Br)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained in Example 1 is dissolved in 2 ml of degassed methanol. After 10 minutes' stirring at room temperature, 6 eq. of a degassed 1M sodium hydroxide solution are added to the solution. The resulting solution is stirred at room temperature under argon. The progress of the reaction is monitored by HPLC. When the reaction is complete, the solution is rendered acidic to pH═I with 1N hydrochloric acid. The methanol is removed in vacuo, 10 ml of water are added to the residue and extraction is carried out with 10 ml of chloroform. The organic phase is dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:13][C:14]([N:16]2[CH:21]=[CH:20][C:19](=[O:22])[CH2:18][C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:31](C)C=O.C(Cl)(=O)C(Cl)=O.N>ClCCl.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:13][C:14]([N:16]2[CH:21]=[CH:20][C:19](=[O:22])[CH2:18][C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:15])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:31])=[O:8]
Reactant: CN(C)C=O
Reactant: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)O
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(N)=O
Reaction time: 3 h

Procedure:
(S)-5-Bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid (72 mg) was dissolved in 2 ml dichloromethane and 0.001 ml dimethylformamide under argon. To this solution was added 0.02 ml oxalyl chloride and the solution was stirred for three hours. The solution was then slowly added at 0° C. to 0.5M NH3 in dioxane. After stirring for 10 minutes, the mixture was concentrated in vacuo and chromatographed (dichloromethane) to yield 26 mg (S)-5-bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzamide. MS (M+H) 463.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:12]=[N:11]2)[C:7](O)=[O:8])[CH2:4][CH2:3][CH2:2]1.[C:26]([Si:30]([CH3:41])([CH3:40])[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([Si:30]([CH3:41])([CH3:40])[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][C:36]([NH:39][C:7](=[O:8])[CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[CH:12]=[N:11]2)[CH2:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:35]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)C(CC1CCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)C(CC2CCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 40 %

Procedure:
Using the method described in Example 49, 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 29) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (342.2 mg, 40%); ES+-HRMS m/e calcd for C28H37N5O4SiF2 [M+H+] 574.2656 found 574.2656. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.07 (s, 6H) 0.80 (s, 9H) 1.49-1.67 (m, 1H) 1.68-2.02 (m, 5H) 2.03-2.30 (m, 3H) 3.86 (t, J=5.2 Hz, 2H) 4.06 (t, J=5.2 Hz, 2H) 5.28-5.38 (m, 1H) 6.01 (d, J=2.7 Hz, 1H) 6.36 (d, J=2.1 Hz, 1H) 7.33-7.43 (m, 2H) 7.43-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.26 (d, J=2.7 Hz, 1H) 10.78 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH:24]([CH3:26])[CH3:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH:24]([CH3:26])[CH3:25])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 25.2 %

Procedure:
3-(Benzyloxy)-5-bromopyridin-2(1H)-one (200 mg, 0.714 mmol), Cs2CO3 (302 mg, 0.928 mmol), and 2-iodopropane (0.086 mL, 0.857 mmol) were combined in DMF (3 mL) at RT. After stirring overnight the mixture was concentrated. The residue was taken up in CH2Cl2, filtered through a pad of Celite®, and concentrated. Flash column (Biotage-SNAP-10 g, 0-30% EtOAc/hexanes) gave the title compound as a clear oil (58 mg, 25%) which solidified under vacuum. 1H NMR (400 MHz, CDCl3): δ 7.46-7.29 (m, 5 H); 7.05 (d, J=2.4 Hz, 1 H); 6.66 (d, J=2.4 Hz, 1 H); 5.34-5.25 (m, 1 H); 5.09 (s, 2 H); 1.35 (d, J=6.8 Hz, 6 H). LC/MS (M+H)+ 322/324.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17](OC)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1.O.[CH3:27][N:28]1CCCCC1=O>>[NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([C:17]([NH:28][CH3:27])=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Reactant: CN1CCCCC1=O
Solvent: O
Product: CNC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
Compound 39b (100 mg) was dissolved in N-methylpiperidin-2-one (250 μL), and 40% methylaminemethanol solution (250 μL) was added thereto, followed by stirring at 40° C. for 16 hours. Subseuqntly, water was added to the reaction mixture, and the precipitate was filtrated, to thereby yield compound 46a (63.7 mg, yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH:28]([CH3:30])[NH2:29])[CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[S:19]([NH:29][CH:28]([CH3:30])[C:27]([O:26][CH2:24][CH3:25])=[O:31])(=[O:21])=[O:20]
Reactant: CCOC(=O)C(C)N
Reactant: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NS(=O)(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 58 %

Procedure:
4.0 g of 3-chloro-2-(4-chloro-3-chlorosulfonylphenyl)-5-trifluoromethylpyridine, 2.4 g of D,L-alanine ethyl ester hydrochloride and 5.2 g of triethylamine in 50 ml of anhydrous tetrahydrofuran were stirred at 23° C. for 18 hours, after which the mixture was concentrated. The residue was taken up in 100 ml of methylene chloride. The solution was extracted twice with 30 ml of water each time, dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel with cyclohexane/ethyl acetate (4:1) resulted in 2.8 g of a colorless oil. Yield: 58%;
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:18])=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:4]1=[O:19]>O1CCCC1.[Ni].O>[CH3:18][C:8]1[CH:7]=[C:6]2[C:11]([CH2:3][C:4](=[O:19])[NH:5]2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: CSC1C(=O)Nc2cc(C)cc(-c3ccccc3)c21
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(c(-c3ccccc3)c1)CC(=O)N2

Procedure:
To a slurry of 11.8 grams (0.044 mole) of 3-methylthio-6-methyl-4-phenylindoline-2-one in 500 milliliters of tetrahydrofuran are added 100 grams of a commercial Raney nickel/water preparation portionwise over a two-hour period. The mixture is filtered through Celite and the filtrate concentrated. A small amount of methylene chloride is added to the residue and the resulting solid is collected by filtration.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([CH3:22])[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])=[O:23]
Reactant: CC(C)C(=O)Cl
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)C(C)C)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with isobutyryl chloride.
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13](O)[CH3:14]>>[C:1]1([CH:7]([CH3:11])[C:8]([O:10][CH2:13][CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1ccccc1
Agent: Cl
Product: CCOC(=O)C(C)c1ccccc1
Reaction time: 60 h

Procedure:
Dissolve 2-phenylpropionic acid (30 g) in 2B ethanol (100 mL and add anhydrous HCl (10 g). Allow to sit for 48-72 hours, evaporate the solvent in vacuo and purify by distillation to give ethyl 2-phenylpropionate (31 g); bp 100 C. at 6 mmm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)(=[O:19])=[O:20])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(CNS(=O)(=O)c2cccc(Cl)c2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(Cl)c2)n1C
Yield: 66.33 %

Procedure:
3-Benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-05) (410.0 mg, 66.33%) was synthesized as a white solid from 3-benzyloxy-6-[(3-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-05) (600.0 mg, 1.299 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[OH-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(CCN)c1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
3-methoxyphenethylamine(50 g, 0.33 mol) was dissolved in a soultion of water(130 ml), dichloromethane(210 ml) and sodium hydroxide(17.6 g). Acetyl chloride(25.9 ml, 0.36 mol) was added dropwise at a room temperature to the mixture solution, which was then stirred for 1 hour. The separated dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure to give 63.6 g of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[Cl:11].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C.O>[Cl:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH:7]=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=Cc1ccc(CBr)c(Cl)c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 60 °C
Yield: 66.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with water (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH2:14].ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]1[CH2:14][O:20]1
Reactant: C=Cc1c(C)cc2ccccc2c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C1CO1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-chloro-3-methyl-2-vinyl-naphthalene (3.0 g, 14.8 mmol) in CH2Cl2 (120 mL) was added 3-chloroperoxybenzoic acid (3.8 g, 22.0 mmol) at 0° C. and allowed to warm to room temperature overnight. The reaction mixture was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)oxirane. 1H-NMR: 400 MHz, (CDCl3) δ 8.26 (d, J=7.2 Hz, 1H), 7.74 (dd, J=7.2, 2.0 Hz, 1H), 7.57-7.48 (m, 3H), 4.13 (t, J=3.6 Hz, 1H), 3.34 (t, J=5.6 Hz, 1H), 2.97 (dd, J=5.2, 2.8 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: CC(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(C)C(=O)NCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)isobutyramide (0.125 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 14.5 mg of 147 following reverse phase HPLC purification. MS (Q1) 449.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:15]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.ClC1C=C2C(C(CC(O)=O)=[C:31]([C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=3)=[O:36])N2)=CC=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[C:13]([Cl:14])[CH:12]=2)[NH:15][C:31]=1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)c1
Reactant: COC(=O)/C=C/c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)ccn2)[nH]c2cc(Cl)c(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4,5-dichloro-2-(phenylsulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (Preparation is described in step 2 of Example 31).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH2:22]([O:24][C:25](=[O:37])[CH:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[CH3:23].[NH4+].[Cl-]>C1COCC1>[CH2:22]([O:24][C:25](=[O:37])[CH2:26][C@@H:27]([C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH3:23]
Reactant: CCOC(=O)C=Cc1ccc2ccoc2c1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](c1ccc2ccoc2c1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (1.32 g, 6.30 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (2.52 mL of a 2.5M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to -78° C. A solution of acrylate 3-4 (0.681 g, 3.15 mmol) in THF (5 mL) was added. After stirring for 15 min at -78° C., satd. aq. NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to give the β-aminoester 3-5 as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>C1COCC1>[Br:19][CH2:20][C:21]([NH:1][C@H:2]([CH2:3][OH:4])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N[C@H](CO)Cc1ccccc1
Reaction time: 1.25 h
Yield: 88.4 %

Procedure:
To a solution of (S)-2-amino-3-phenyl-1-propanol (1.00 g, 6.61 mmol) and triethylamine (1 mL, 7.17 mmol) in THF (70 mL) at −78° C. was added dropwise bromoacetyl bromide (0.60 mL, 6.9 mmol). After 1.25 hours at −78° C., the resultant mixture was partitioned between 1M pH7 phosphate buffer (100 mL) and hexanes (100 mL). The aqueous layer was extracted with EtOAc:hex (2:1, 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 1.59 g (85%) of 2-bromo-N-(1(S)-hydroxymethyl-2-phenylethyl)acetamide as a solid, mp 83-5° C. 1H NMR (DMSO-d6): δ 8.15 (d, 1H, J=8.1 Hz), 7.32-7.11 (m, 5H), 4.82 (t, 1H, J=5.3 Hz), 3.83-3.74 (m, 3H), 2.80 (dd, 1H, J=5.9, 13.6 Hz), 2.59 (dd, 1H, J=8.9, 13.6 Hz). Anal. Calculated for C11H14NO2Br: C, 48.55; H, 5.19; N, 5.15; Br, 29.36. Found: C, 48.69; H, 5.13; N, 5.13; Br, 29.30.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1>>[I:1][C:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[NH:9][N:10]=1
Reactant: c1cnc2cn[nH]c2c1
Reactant: O=C1CCC(=O)N1I
Product: Ic1n[nH]c2cccnc12
Yield: 57.4 %

Procedure:
In the similar method as described in Production example 206, 9.5 g of N-iodosuccinimide was reacted on 5 g of 1H-pyrazolo[4,3-b]pyridine, to afford 5.9 g of the title compound as a colorless powder.
Reaction SMILES: [S:1](/[CH:4]=[CH:5]\[C:6]([OH:8])=O)[C:2]#[N:3].C(N(CC)CC)C.ClC(OCC)=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[S:1](/[CH:4]=[CH:5]\[C:6]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:8])[C:2]#[N:3]
Reactant: N#CS/C=C\C(=O)O
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CS/C=C\C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of compound 2 (3.06 g., 0.023 mole) in 60 ml of dry toluene, triethylamine (2.35 g., 0.023 mole) in 10 ml of dry toluene was added dropwise, keeping the temperature of the mixture at 0°-5° C. To the resulting solution was added dropwise, ethyl chloroformate (2.53 g., 0.023 mole) in 15 ml of dry toluene at 0°-5° C. After stirring the mixture for 15 minutes, piperidine (2.0 g., 0.023 mole) in 15 ml of dry toluene was added dropwise at 0°-5° C. The mixture was allowed to warm to room temperature, stirred for an additional 2 hours and filtered. The filtrate was washed with water, dried (MgSO4) and concentrated to give an oil which solidified, 2.6 g. The solid was recrystallized from ethanol: mp 88°-90° C.; IR (KBr) 2175, 1630 cm-1
Reaction SMILES: [O:1]=[C:2]1[C@H:6]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:9][CH2:10][C@@H:5]2[CH2:4][CH2:3]1>C(N(CC)CC)C>[O:1]=[C:2]1[C@@H:6]2[CH2:7][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:9][CH2:10][C@@H:5]2[CH2:4][CH2:3]1
Reactant: O=C1CC[C@H]2CCN(C(=O)OCc3ccccc3)C[C@H]12
Solvent: CCN(CC)CC
Product: O=C1CC[C@H]2CCN(C(=O)OCc3ccccc3)C[C@@H]12

Procedure:
Azabicycles of general formula (114), (115), (116) and (117), wherein R is aryl or heterocycle, R′ is alkyl and R1 is as defined in formula (I), may be prepared as described in Scheme 27. Benzyl (trans)-7-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate, prepared as described in Eur. J. Med. Chem. (1991) 26, 889–906, may be epimerized with a base such as, but not limited to, triethylamine to provide benzyl (cis)-7-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate. Benzyl (cis)-7-oxooctahydro-2H-cyclopenta[c]pyridine-2-carboxylate may be processed as described in Schemes 2–8 to provide azabicycles of general formula (114), (115), (116) and (117).