Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][NH:9][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(C)(C)OC(=O)NCCNc1cncc(Br)c1
Temperature: 100 °C
Yield: 42.6 %

Procedure:
A 50 mL RBF was charged with 3,5-dibromopyridine (3.70 g, 15.6 mmol), t-butyl N-(2-aminoethyl)carbamate (2.50 g, 15.6 mmol), Pd2(dba)3 (714 mg, 0.78 mmol), (R)-BINAP (1.46 g, 2.34 mol) and Cs2CO3 (7.62 g, 23.4 mmol), and was purged with N2. Anhydrous toluene (120 mL) was added via syringe. The solution was purged with N2 again, and was heated at 100° C. overnight. After cooled, ethyl acetate (500 mL) was added and the mixture was washed with water. The EtOAc solution was concentrated and the residue was separated by flash chromatography (20-80% EtOAc in hexane) to provide the desried product (2.1 g, 43%). MS (DCI) m/z 316, 318 (M+1)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH2:16][CH2:15][C:14](=[O:17])[CH:13]=2)[CH:8]=[CH:7][N:6]=1.CC1CCCO1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42]S(C2C=CC=CC=2)(=O)=O)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[C:30]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:29]=1)#[N:27]>C(OCC)(=O)C.O>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:42][C:13]2[C:14](=[O:17])[CH2:15][CH2:16][C:12]=2[NH:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:18])[F:19])[CH:10]=2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[C:30]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:29]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
Sodium hydride (60% in mineral oil, 515 mg, 12.9 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17, 2.60 g, 10.7 mmol) and 2-methyltetrahydrofuran (40 mL). After 10 min tert-butyl (4-cyano-2-(methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 4.83 g, 10.7 mmol) is added, and the mixture is stirred at room temperature for 30 min Water and ethyl acetate are added, and the phases are separated. The organic phases is washed twice with water and concentrated under reduced pressure. Yield: 6.20 g; ESI mass spectrum [M+H]+=551; Retention time HPLC: 1.12 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]([OH:19])=O)[S:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:49])[CH3:48].CCN(CC)CC>C(Cl)Cl>[CH:47]([N:50]1[CH2:55][CH2:54][N:53]([C:17]([C:4]2[S:5][C:6]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[N:3]=2)=[O:19])[CH2:52][CH2:51]1)([CH3:49])[CH3:48]
Reactant: CC(C)N1CCNCC1
Reactant: Cc1nc(C(=O)O)sc1-c1cccc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCN(C(C)C)CC2)sc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methyl-5-naphthalen-1-yl-thiazole-2-carboxylic acid in methylene chloride (2 ml) is added BOP (44 mg, 0.10 mmol), isopropylpiperazine (13 mg, 0.10 mmol) and Et3N (20 mg, 0.20 mmol). The reaction mixture is stirred at rt for 2 hr. Solvent is removed and the resulting mixture is purified by PTLC to give the title compound. LC-MS M+1 380.03. 1H NMR δ (CDCl3) 7.90-7.96 (m, 2H), 7.68-7.72 (m, 1H), 7.46-7.56 (m, 4H), 4.51 (brs, 2H), 3.85 (brs, 2H), 2.77 (m, 1H), 2.67 (brs, 4H), 2.25 (s, 3H), 1.10 (d, 6H). LC-MS (M+1) 380.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([NH2:20])=O)=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]#[N:20])=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nn2ccc(OCc3ccccc3)cc2c1C#N
Yield: 79.1 %

Procedure:
To a mixture of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carboxamide (1.3 g, 4.8 mmol) produced above, pyridine (1.2 mL, 14 mmol) and tetrahydrofuran (20 mL) was added dropwise under ice-cooling a solution of trifluoroacetic anhydride (1.0 mL, 7.2 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred under ice-cooling for 0.5 hr. Triethylamine (2.0 mL, 14 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr. Trifluoroacetic anhydride (1.0 mL, 7.2 mmol) was added dropwise at room temperature, and the mixture was stirred at room temperature for 0.5 hr and concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0). The obtained solution was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether/hexane to give the title compound (1.0 g, 79%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CO.[Pd]>[NH2:20][CH2:19][C:3]1[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1
Reactant: COC(=O)c1cc(Cl)c(C#N)nc1-c1cccc(F)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Cl)c(CN)nc1-c1cccc(F)c1
Reaction time: 4 h

Procedure:
Methyl 5-chloro-6-cyano-2-(3-fluorophenyl)nicotinate (1.3 g, 4.5 mmol) was stirred in methanol (60 mL), and 5% palladium on carbon (1.0 g) was added. The mixture was degassed three times and placed under a balloon pressure of hydrogen for 4 hours. A solution of 0.5 M sodium methoxide in methanol (45 mL) was added and the mixture was filtered through celite. The filtrates were evaporated and the residue was triturated with dichloromethane. The solids were filtered and washed with dichloromethane to give the desired compound contaminated with 30% dechlorinated byproduct (1.3 g, 100%). LCMS calculated for C14H13ClFN2O2 (M+H)+: m/z=295.1. found: 295.0.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:13][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=[C:1]1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CNc1ccccc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc(-c2nc3ccccc3n2C)cc1
Temperature: 145 °C
Yield: 65 %

Procedure:
A mixture of methyl 4-formylbenzoate (5.0 g, 0.03 mol) and N-methyl-1,2-phenylene diamine (3.7 g, 0.03 mol) in nitrobenzene was heated at 140-150° C. overnight, cooled to room temperature, filtered and the filtercake washed with hexane. The combined filtrates were evaporated to dryness under reduced pressure. The resultant residue was purified by flash chromatography (silica, CHCl3:MeOH 95:5) to afford the title compound in 65% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 8.2 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 7.83 (s, 1H), 7.37 (m, 1H), 7.35 (m, 2H), 3.96 (s, 3H), 3.9 (s, 3H). LCMS (ESI+) 267 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([NH:22][CH3:21])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of N-(4-bromo-phenyl)-4-fluoro-3-nitro-benzamide (1.5 g, 4.4 mmol) and 40 mL liquid methyl amine was stirred for 20 h at 60° C. The mixture was cooled to −78° C., diluted with ethyl acetate and filtered with celite and silica gel. The filtrate was concentrated i.vac.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:13][C:12]2[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][C:5]=2[O:4]1.O.Cl[CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][O:21][CH:22]([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([O:21][CH2:20][CH2:19][C:18]([CH3:25])=[CH:17][CH2:16][O:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]2[O:13][CH2:3][O:4][C:5]=2[CH:6]=1)([CH3:24])[CH3:23]
Reactant: CC(=CCCl)CCOC(C)C
Reactant: OCc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CC(=CCOCc1ccc2c(c1)OCO2)CCOC(C)C

Procedure:
8.0 g (0.2 mol) of sodium hydroxide are added to a solution of 30.4 g (0.2 mol) of 3,4 -methylendioxy-benzylalcohol in 300 cc of benzene. The mixture is heated while stirring vigorously and kept at reflux temperature whereby the water condensing in a refrigerator is separated by means of a water separator. After 24 hours 35.3 g (0.2 mol) of 1-chloro-5-isopropoxy-3-methyl-2-pentene are added dropwise during the course of 1 hour and the mixture is stirred under reflux for a further 16 hours.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)=[O:3].[CH2:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1)[CH2:11][CH3:12].C(=O)(O)[O-].[K+].O>C1(C)C=CC=CC=1>[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)=[O:3]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCOc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(CN2CCC(C(N)=O)CC2)cc1
Yield: 79.1 %

Procedure:
The method taught by R. A. Farr et al, J. Org. Chem. 1981, 46, 1212-1215, was used in the following two-step preparation. A vigorously stirred solution of 16.5 grams (0.129 mole) of 4-aminocarbonylpiperidine, 25.0 grams (0.135 mole) of 4-propoxyphenylmethyl chloride, and 19.4 grams (0.193 mole) of potassium bicarbonate in 200 mL of toluene was heated at reflux for 6.5 hours. The reaction mixture was then cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a solid residue, which was slurried in pentane and collected by filtration, yielding 28.2 grams of 4-aminocarbonyl-N-(4-propoxyphenylmethyl)piperidine, mp 142°-146° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]([Cl:36])([Cl:35])[CH2:3][O:4][C:5](=[O:34])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH3:22])=[CH:16][C:15]=2[N+:31]([O-])=O)=[CH:9][CH:8]=1.[NH4+].[Cl-]>[Fe]>[Cl:35][C:2]([Cl:1])([Cl:36])[CH2:3][O:4][C:5](=[O:34])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH3:22])=[CH:16][C:15]=2[NH2:31])=[CH:9][CH:8]=1
Reactant: CN(C(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c([N+](=O)[O-])c1)c1ccc(F)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CN(C(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c(N)c1)c1ccc(F)cc1
Yield: 73.2 %

Procedure:
The product from Example 165A (295 mg, 0.516 mmol) was reduced with Fe and NH4Cl following the procedure from Example 9E to yield the title compound (205 mg, 73% yield)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH3:24])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:25]1([N:22]([CH2:23][CH3:24])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCCC1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(ethyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.3 g, 0.653 mmol) and (4-(morpholinomethyl)phenyl)boronic acid (0.216 g, 0.98 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.249 g, 2.35 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.075 g, 0.065 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 3 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.15 g, 41%). LCMS: 557.35 (M+1)+; HPLC: 99.13% (@254 nm) (Rt; 4.128; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (t, 1H), 7.57 (d, 2H, J=8 Hz), 7.41 (s, 1H), 7.37 (d, 2H, J=8 Hz), 7.20 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.56-3.57 (m, 4H), 3.48 (s, 3H), 3.00-3.02 (m, 2H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.69-1.70 (m, 2H), 1.60 (m, 2H), 1.47-1.48 (m, 4H), 0.81 (t, 3H, J=6.4 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:15])([CH3:14])[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[O:18].C(O)(C(F)(F)F)=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[C:5]([CH3:14])([CH3:15])[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: CSc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc2c(c1)C(O)=C(C(=O)NCC(=O)O)C(=O)C2(C)C
Yield: 97.2 %

Procedure:
A solution of 1,1-dimethylethyl N-((4-hydroxy-1,1-dimethyl-6-(methylthio)-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.180 g, 0.460 mmol) in TFA (0.0342 mL, 0.460 mmol) was stirred at 25° C. for 10 minutes. The solution was concentrated, azeotroped in DCM (2×300 mL), and dried in vacuo to give the title compound (0.150 g). MS m/e=336 (M+H)+. Calculated for C16H17NO5S 335.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O>[C:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:19])[CH3:18]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C
Temperature: 70 °C
Yield: 30 %

Procedure:
A solution of 3-hydroxy-4-methylbenzoic acid (3.0 g, 19.7 mmol) in acetic anhydride (5.6 mL) was treated with sulfuric acid (0.03 mL), heated to 70° C., cooled and diluted with water. The resulting solid was collected by filtration yielding 1.14 g (30%) of the title compound, which was used without further purification.
Reaction SMILES: [C:1]1(CCCC([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C[O:15][C:16]([C:18]1C=CC(O)=[CH:20][CH:19]=1)=[O:17].C(OC(C1C=CC(O)=CC=1)=O)CC.C(O)C(O)C.[OH-].[Na+]>>[C:1]1([O:17][C:16](=[O:15])[CH2:18][CH2:19][CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C([O-])CCCc1ccccc1
Agent: CCCOC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C

Procedure:
Part II: 5.739 g of sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g of methylparaben (Merck), 0.075 g of propylparaben (Merck), 83.5 g of 1,2-propandiol, and 20 g of 10% NaOH were mixed in a beaker and heated at 70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][N:10]=1>CO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][C:12]([NH2:16])=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(F)cc1F
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)cnc1-c1ccc(F)cc1F
Yield: 96.9 %

Procedure:
To a stirred solution of 2-(2,4-difluorophenyl)-3-methyl-5-nitropyridine (7.5 g, 30 mmol, 1 eq) in methanol (100 mL) in a 500 mL round bottom flask was added 7 g of Raney Nickel slurry. The flask was evacuated and charged with hydrogen 4 times. The mixture was stirred under H2. After 5 h the reaction flask was purged with nitrogen. The mixture was filtered and the methanol was removed under reduced pressure giving 6.4 g 6-(2,4-difluorophenyl)-5-methylpyridin-3-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][CH:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: COc1cc2c(cc1N1CCC(C)CC1)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Agent: [Ni]
Solvent: CO
Product: COc1cc2c(cc1N1CCC(C)CC1)CC(Cc1cccc(C(F)(F)F)c1)C2=O
Reaction time: 6 h

Procedure:
The 153 (100 mg, 0.240 mmol) was dissolved in methanol and Raney-Nickel (10 mg, 10% v/v) added and the reaction stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 154 which was purified by flash chromatography using 100-200 mesh silica gel. The compound 154 was eluted at 20% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-(4-methylpiperidin-1-yl)-2-(3-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one 154. 1HNMR (400 MHz, CDCl3) δ ppm 7.40 (m, 4H), 7.15 (s, 1H), 6.82 (s, 1H), 3.89 (s, 3H), 3.60 (s, 2H), 3.41 (dd, 1H), 2.94 (m, 2H), 2.62 (m, 4H), 0.92 (m, 4H), 0.85 (m, 3H); MS (ESI) m/z 418.0 (M+H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CCOCC.C(O)C>[NH2:4][C@H:5]([C:18]([O:20][CH3:3])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC#CC[C@H](N)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)[C@@H](N)CC#CCNC(=O)OC(C)(C)C

Procedure:
Titrate a solution of diazomethane in ether into a solution of 1-amino-1-(S)-carboxy-5-(t-butoxycarbonyl amino)-3-pentyne (4 g) in ethanol (200 ml) until a yellow color remains. Evaporate the solvent to obtain 1-amino-1-(s)-methoxycarbonyl-5-(t-butoxycarbonylamino)-3-pentyne.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:17]([CH2:18][CH2:19][O:20]CC3C=CC=CC=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:17]([CH2:18][CH2:19][OH:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2nc3cccnc3n2CCOCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2nc3cccnc3n2CCO)CC1
Yield: 46.1 %

Procedure:
A mixture of 16.7 parts of 2-[(4-methyl-1-piperazinyl)methyl]-3-[2-(phenylmethoxy)ethyl]-3H-imidazo[4,5-b]pyridine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5.84 parts (46.1%) of 2-[(4-methyl-1-piperazinyl)methyl]-3H-imidazo[4,5-b]pyridine-3-ethanol; mp. 89.5° C. (compound 129).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1cccc(Cl)c1Nc1ccccc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a mixture of (2-chloro-6-nitrophenyl)phenylamine (676 mg, 2.72 mmol) in MeOH (45 mL) and water (15 mL) were added NH4Cl (872 mg, 16.31 mol) and iron powder (607 mg, 10.87 mmol) and the reaction mixture was heated to reflux temperature for 4 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and then partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-100% DCM in cyclohexane). The product containing fractions were concentrated in vacuo affording 3-Chloro-N2-phenylbenzene-1,2-diamine as a pale orange solid (500 mg, 84%). LCMS: RT 3.45 min [M+H]+ 219.1.