Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[N:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[N:31]=2)=[CH:34][CH:35]=1
Reactant: Cc1cc(C)nc(Oc2ccc(I)cc2)n1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(Oc2nc(C)cc(C)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 56.5 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (47 mg) was reacted with 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (56 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4,6-dimethylpyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (44 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2cccc(OCCOC)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2cccc(OCCOC)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogen carbonate (1.40 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[3-(2-methoxyethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.69 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.34 g, 44%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][N:11]([C:21]2[C:22]([Cl:37])=[C:23]([NH:29]C(=O)OC(C)(C)C)[CH:24]=[C:25]([C:27]#[N:28])[CH:26]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:29][C:23]1[CH:24]=[C:25]([CH:26]=[C:21]([N:11]2[CH2:12][CH2:13][C@@H:14]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10]2)[C:22]=1[Cl:37])[C:27]#[N:28]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CC[C@@H](N3CCOCC3)[C@H](O[Si](C)(C)C(C)(C)C)C2)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1N1CCOCC1
Yield: 94 %

Procedure:
(+/−)-tert-butyl (3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (138 mg, 0.250 mmol) was treated with TFA (25% in 1,2-dichloroethane, 3 mL, 9.73 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The layers were separated and aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 5-40% ethyl acetate/hexanes). (+/−)-3-amino-5-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidin-1-yl)-4-chlorobenzonitrile (106 mg) was obtained as a yellow/brown solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][CH2:30][NH2:31].C(N(CC)CC)C>CCO>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:31][CH2:30][CH2:29][NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: NCCNc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(NCCNc3ccccn3)c(F)c(F)c2c1=O
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A solution of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (3.70 g, 12.3 mmol), N-2-pyridyl-1,2-ethanediamine (1.77 g, 12.9 mmol) and triethylamine (3.50 mL) in EtOH (50 mL) was stirred at room temperature for 3 h, and refluxed for 1 h. The reaction mixture was cooled at room temperature. The resulting precipitate was combined by filtration. The cake washed with EtOH and collected by filtration and then dried to give 1-cyclopropyl-1,4-dihydro-5,6,8-trifluoro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (2.90 g, 56%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:30][C:31]1[CH:36]=[C:35]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][N:11]=[C:12]4[C:17]=3[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]4)[CH:4]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol), 3-chlorobenzeneboronic acid (13.9 mg, 0.089 mmol), dichlorobis-(triphenylphosphine)palladium(II) (5.0 mg, 7.1 μmol) and 2 M sodium carbonate solution (0.5 mL) in DME (3 mL) was irradiated in a microwave reactor at 150° C. for 10 min. After cooling to room temperature, the mixture was diluted with dichloromethane (3 mL) and water (3 mL), and was filtered through a PTFE cartridge. The separated organic phase was concentrated in vacuo, and the residual material was purified by preparative thin layer chromatography on silica gel, eluting with 5% ethyl acetate in dichloromethane, affording 5-(3′-chloro-6-fluorobiphenyl-3-yl)-2-trifluoromethyl[1,8]naphthyridine as a white solid (12.7 mg, 46%). δH (360 MHz, CDCl3) 7.33-7.50 (5H, m), 7.57 (1H, dd, J 1.8 and 7.0), 7.59-7.60 (2H, m), 7.84 (1H, d, J 8.8), 8.54 (1H, d, J 8.8), 9.29 (1H, d, J 4.2). m/z (ES+) 403, 405 [MH]+.
Reaction SMILES: C(OC([CH:8]([C:40]1[N:41]=[CH:42][NH:43][CH:44]=1)[O:9][C:10]([NH:12][C:13]1[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:11])=O)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[NH:43]1[CH:44]=[C:40]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])[N:41]=[CH:42]1.[F:45][C:46]([F:51])([F:50])[C:47]([O-:49])=[O:48]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OC(C(=O)OC(C)(C)C)c2c[nH]cn2)c1=O)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2c[nH]cn2)c1=O)C(=O)C(F)(F)F
Product: O=C([O-])C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2-[3-(1-tert-butoxycarbonylimidazol-4-ylmethoxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.134 g) in dry dichloromethane was added trifluoroacetic acid (0.018 mL). After stirring for 1 h, the reaction was not complete; so additional trifluoracetic acid (0.018 mL) was added. Following 17 h more stirring, the reaction was still incomplete. Additional trifluoroacetic acid (0.036 mL) was added and the reaction mixture was stirred 6 h (complete deprotection), evaporated and dried under high vacuum to give the title compound as a trifluoroacetate salt; TLC: Rf =O.10, dichloromethane:methanol (94:6); MS: 520(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:3]=1[F:15].C([Li])CCC.B(OC)(OC)[O:22]C.Cl>C(OCC)(=O)C.C1COCC1>[F:1][C:2]1([OH:22])[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[F:15]
Reactant: CCCCCCOc1cccc(F)c1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCOC1=CC=CC(O)(F)C1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
1,2-Difluoro-3-hexyloxybenzene (s-1) (17.8 g) and THF (500 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.57M; n-hexane and cyclohexane solution; 58.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Trimethyl borate (9.5 g) in a THF (50 ml) solution was added dropwise in the temperature range of −74° C. to −65° C., and the stirring was continued for 8 hours while the mixture was allowed to return to 25° C. The reaction mixture was poured into a vessel containing 1N-hydrochloric acid (100 ml) and ice-water (500 ml) and mixed with them. Ethyl acetate (300 ml) was added, and mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue and acetic acid (100 ml) were placed in a reaction vessel at room temperature under an atmosphere of nitrogen, and an aqueous solution of hydrogen peroxide (31%; 10.1 ml) was added dropwise in the temperature range of 25° C. to 30° C., and the stirring was continued for another 2 hours. The reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogen sulfite (100 ml) and ethyl acetate (300 ml) and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous layers, and the extraction was carried out. The resulting organic layers were separated, and washed successively with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 1,2-difluoro-3-hexyloxyphenol (s-20) (12.8 g). The yield based on the compound (s-1) was 66.6%.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C.O>[Br:1][C:2]1[CH:23]=[N:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]3[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:8]=3[N:9]([CH3:26])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CCN1c2nc(C(F)(F)F)ccc2NC(=O)c2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ncc(Br)cc2C(=O)N(C)c2ccc(C(F)(F)F)nc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
To a solution of the 8-bromo-5,11-dihydro-11-ethyl-2-(trifluoromethyl)-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (200 mg, 0.52 mmol) in DMF (2.6 mL) was added NaH (20 mg, 0.78 mmol), and the mixture was heated to 50° C. for 30 min. The reaction mixture was cooled to room temperature and treated with MeI (97 μL, 1.56 mmol). After 16 h, the reaction mixture was diluted with water. The resulting mixture was extracted with EtOAc (3×). The combined organic layer was successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 8.5:1.5) to give the title compound (110 mg 53% yield) as a white foam.
Reaction SMILES: CS(C)=O.[Cl-].[CH2:6]([N:13]([CH3:30])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]([OH:29])[C:26]([OH:28])=[O:27])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:31](N(CC)CC)[CH3:32]>C(Cl)Cl.O>[CH2:31]([O:27][C:26](=[O:28])[C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17][CH2:16][C:14](=[O:15])[N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:30])=[O:29])[CH3:32]
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)O
Reactant: CCN(CC)CC
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (443 μl) was added dropwise to a solution of oxyalyl chloride (260 μl) in methylene chloride (10 ml) cooled to -78° C. The solution was stirred for 15 mins at the same temperature. A solution of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl]propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid theyl ester (700 mg) in methylene chloride (6 ml) was added dropwise to the solution at the same temperature. The mixture was stirred for 20 mins. Triethylamine (1.42 ml) was added dropwise to the solution. The solution was stirred for 10 mins at the same temperature, and for 30 mins. at 0° C. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (627 mg) having the following physical data:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:12][C:13]1[C:14]([NH2:20])=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1.[ClH:21].Cl.[C:23](=N)(OCC)[CH2:24][C:25](=N)OCC.C(O)(=O)C>Cl>[ClH:21].[ClH:21].[CH3:12][C:13]1[C:14]2[N:20]=[C:23]([CH2:24][C:25]3[NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=4[N:11]=3)[NH:19][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=N)CC(=N)OCC
Reactant: Cc1cccc(N)c1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cccc2[nH]c(Cc3nc4c(N)cccc4[nH]3)nc12
Yield: 66.6 %

Procedure:
The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.5 g; 3.26 mmoles), 3-methyl-1,2-phenylenediamine (0.4 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (15 to 75% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.42 g of pure 2-[(4-methyl-1H-benzimidazol-2-yl)methyl]-1H-benzimidazol-4-ylamine dihydrochloride in 37% yield. It had MS: m/z=278.2 [N+1] amu and gave one peak on HPLC at both 210 and 280 nm (12.01 minutes using the JWTFACN gradient).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[F:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(F)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(F)c(CBr)c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
3.00 g of ethyl 4-fluoro-3-methylbenzoate was dissolved in 50.0 mL of carbon tetrachloride, and 4.40 g of N-bromosuccinimide and 1.35 g of 2,2′-azobisisobutyronitrile were added thereto, followed by heating under reflux for 4 hours. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 1.73 g of ethyl 3-(bromomethyl)-4-fluorobenzoate.
Reaction SMILES: [N:1]1([C:6]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCCCC)CCC.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C1COCC1.CO>[N:1]1([C:6]2([CH:11]([NH2:12])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: N#CC1(N2CC=CC2)CCCC1
Reactant: [Li]c1ccccc1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: NC(c1ccccc1)C1(N2CC=CC2)CCCC1
Yield: 45 %

Procedure:
The title compound (1.35 g; 45%) was prepared from 1-(2,5-dihydro-1H-pyrrol-1-yl)cyclopentanecarbonitrile D37 (2.0 g; 12.3 mmol), and phenyllithium in di-n-butylether (7.5 ml of 1.8M solution; 13.5 mmol) in THF (20 ml), followed by reaction with sodium borohydride (1.402 g; 36.9 mmol) in methanol (20 ml) in a similar manner to that described in D2. Mass Spectrum (Electrospray LC/MS): Found 243 (MH+). C16H22N2 requires 242. Ret. time 1.02 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2CCCO.[C:15]([Br:19])(Br)(Br)Br.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:15]([Br:19])[CH2:20][CH3:21])=[CH:5]2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCCc1c[nH]c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: CCC(Br)c1cc2cc(F)ccc2[nH]1
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (Intermediate 6) prepared in accordance with the procedures set forth in Demerson et al., J. Med. Chem., 19:391-395 (1976). (25.4 g, 0.13 mol), carbon tetrabromide (65.5 g, 0.2 mol) and triphenylphosphine (52 g, 0.2 mol) in methylene chloride (156 ml) was allowed to stir for 2 hours. The solvent was evaporated and the product chromatographed (30% ethyl acetate-hexanes) to afford 33.5 g (99%) of product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)c(C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a solution of 2-isopropyl-4-methoxy-phenol (56.91 g, 342 mmol) triethylamine (57.3.0 ml, 411 mmol) in 750 ml CH2Cl2 was cooled to 0° C. p-Toluenesulfonyl chloride (68.54 g, 360 mmol) in 250 ml CH2Cl2 was added drop-wise at a rate that maintained the internal temperature <10° C. The mixture was allowed to warm to rt. After 16 h, H2O was added and the mixture was extracted with CH2Cl2. The combined organics were washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford a crude solid. Recrystallization from hexanes afforded toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester (81.67 g, 74%) as white needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]>C(=O)(O)[O-].[Na+].O1CCCC1>[C:14]([CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11])([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15]
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(CC(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 4 h
Yield: 80.9 %

Procedure:
3-(4-aminophenyl)propionic acid (250 mg, 1.5 mmol) in a 10 mL flask was dissolved in a mixture of 10% aqueous sodium bicarbonate (0.32 mL) and tetrahydrofuran (2.2 mL) then cooled in an ice/water bath. 9-fluorenylmethyl chloroformate (422 mg, 1.5 mmol) was added in small portions over 3 min. After 4 h the cooling bath was removed. After additional 4 h at room temperature, the reaction was extracted with deionized water (2 mL) and ethyl ether (2 mL) and the aqueous layer was brought to pH 4 with dilute HCl and placed in a refrigerator. After 1 h solid was collected by vacuum filtration and washed with deionized water then dried under vacuum to give 470 mg of product (80% yield). Mass spectrum (M+Na)+ calcd for C24H21NO4, 400.1. found 410.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24](=[O:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1.[N+:27]([CH3:30])([O-:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:25][C:24]([CH2:30][N+:27]([O-:29])=[O:28])([OH:26])[CH2:23]5)[CH:19]=[CH:18][CH:17]=4)[C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(=O)C3)n2)cn1
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CC(O)(C[N+](=O)[O-])C3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)azetidin-3-one (1.1 g) in DCM (10 mL) at 20° C. was added nitromethane (1 mL) and triethylamine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. It was concentrated under reduced pressure to afford a white solid. The crude product (1.3 g), 1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-3-(nitromethyl)azetidin-3-ol, was used for next step without further purification. MS (ESI) m/z: 407 [M+H]+.