Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:30])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CCCCCC.O1CCCC1.C(OCC)C>[CH2:9]([O:16][C:17]([NH:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:7][C:6]#[N:8])([OH:30])[CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC#N
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC1(O)CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: -80 °C
Reaction time: 1 h

Procedure:
To a stirred solution of n-butyllithium in hexane (42 mL, 1.6 M) under nitrogen at −80° C., was added dry tetrahydrofuran (40 mL). To this was added over a 7 min period a solution of dry acetonitrile (2.8 g, distilled from phosphorus pentoxide) in dry tetrahydrofuran (40 mL). The resulting white suspension was stirred for 1 h at −80° C. After this time, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (9.9 g) in dry tetrahydrofuran (40 mL) was added over a 5 min period. Additional tetrahydrofuran (40 mL) was introduced to facilitate stirring. After an additional 10 min at −80° C., the reaction mixture was allowed to slowly warm to room temperature during a 15 min period. Once at room temperature, the reaction mixture was poured into a mixture of ice, concentrated aqueous hydrochloric acid solution (10 mL), and diethyl ether (100 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (50 mL twice). The combined organic layers were washed with water (50 mL twice), dried, and evaporated to yield a residue. The residue was chromatographed on silica gel to obtain the title compound as a mixture of diastereomers (7.5 g).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(CCc2ccccc2OCC2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2OCC2CN(C)CCO2)c1
Yield: 89.2 %

Procedure:
Following a procedure similar to that described in Example 38, 870 mg of 4-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}morpholine [prepared as described in Example 45(a)] were reacted with a dispersion of 113 mg of lithium aluminum hydride in 15 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 620 mg (yield 94%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[N:25]([CH3:27])[CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:37][C:38]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]([CH3:41])[N:40]=3)[CH2:14][C@H:13]2[N:25]([CH3:26])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N(C)C)nc1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](N(C)C)C2)nc1C
Yield: 90.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(dimethylamino)-piperidine-1-carboxylate obtained in Example (200d) (104 mg, 0.260 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (71.6 mg, 0.286 mmol) and sodium carbonate (551 mg, 5.20 mmol), to obtain 110 mg of the title compound (90%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=1.79 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]([CH2:17][CH2:18][C:19]([O:21]C)=O)[C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([Cl:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Fe]>[Cl:16][C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:19](=[O:21])[CH2:18][CH2:17][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:7]=2[N:8]=1
Reactant: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 30.7 %

Procedure:
Methyl 3-(N-cyclopentyl-N-(2-chloro-5-nitropyrimidin-4-yl)amino)propionate (2.0 g, 6.1 mmol) in glacial acetic acid at 70° C. was treated in portions with iron powder (0.7 g, 12.4 mmol) over 6 hours. The mixture was concentrated and triturated with dichloromethane and filtered. The filtrate was absorbed onto silica gel and soxhlet extracted over 7 hours with ethyl acetate. The extract was concentrated to a black oil and triturated with methanol to give pale brown crystals of 2-chloro-9-cyclopentyl-8,9-dihydro-5H-pyrimido[4.5-b][1,4]diazepin-6(7H)-one (499 mg, 31%). NMR 1.46-1.58 (4H, m), 1.60-1.72 (2H, m), 1.75-1.85 (2H, m), 2.64 H, d), 3.55 (2H, d), 4.92-5.03 (1H, m), 7.83 (1H, s), 9.72 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][C:15]#[N:16])=[CH:4][CH:3]=1.[CH:17](=[O:22])[CH2:18][CH2:19][CH:20]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:10]3=[C:14]([C:15]#[N:16])[CH:20]4[O:22][CH:17]([N:11]3[CH2:12][CH2:13]2)[CH2:18][CH2:19]4)=[CH:4][CH:3]=1
Reactant: O=CCCC=O
Reactant: N#CC=C1NCCN1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CC#N
Product: N#CC1=C2N(Cc3ccc(Cl)nc3)CCN2C2CCC1O2
Temperature: 25 °C
Yield: 66 %

Procedure:
To a 50 ml round bottom flask was added 1.17 g (0.005 mol) 2-(1-((6-chloropyridin-3-yl)methyl)imidazolidin-2-ylidene)acetonitrile, 30 ml dry acetonitrile and 0.860 g (0.01 mol) succinaldehyde and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 66% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[I-].[N:23]1([C:33](N2C=C[N+](C)=C2)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([C:6]=2[CH3:21])=[CH:4][CH:3]=[C:2]([O:1][C:33]([N:23]2[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]2)=[O:34])[CH:11]=3)=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCCc5ccccc54)cc3oc2=O)cc1
Yield: 58.9 %

Procedure:
The title compound (130 mg, 59% yield, white solid) was prepared from 7-hydroxy-3-(4-methoxy-phenyl)-4-methyl-chromen-2-one (141 mg, 0.50 mmol) and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (188 mg, 0.51 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[CH2:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C=O)C>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@H:13]([C:27]([O:29][CH3:30])=[O:28])[CH2:14][C:15]1[CH:20]=[C:19]([C:31]#[N:32])[CH:18]=[CH:17][C:16]=1[O:22][CH2:23][CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOc1ccc(I)cc1C[C@@H](C(=O)OC)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COCCOc1ccc(C#N)cc1C[C@@H](C(=O)OC)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 73 °C

Procedure:
2-(R)-{2-[5-Iodo-2-(2-methoxyethoxy)phenyl]-1-(R)-methyoxycarbonylethyl}pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.44 mmol) is dissolved in DMF (5 mL), degassed, and treated with tetrakis(triphenylphosphine) palladium zero (0.05 g, 0.044 mmol) and zinc cyanide (0.156 g, 1.33 mmol) under nitrogen. The reaction mixture is warmed to 73° C. for 2.5 h, cooled and diluted with ethyl acetate (100 mL). The resulting precipitate is removed and the filtrate is washed with water and brine and dried over MgSO4. The solvent is removed in vacuo and the residue is subjected to flash chromatography (ethyl acetate/hexane/methylene chloride: 1/2/1). The title compound is isolated a syrup (0.15 g, mmol). 1H NMR (CDCl3, 300 MHz) □ 7.50-7.38(m, 2H), 7.15(d, 1H), 5.31(s, 2H), 4.23-4.11(m, 1H), 3.83-3.76(m, 2H), 3.57(s, 3H), 3.56-3.48(m, 2H), 3.37(s, 3H), 3.36-3.26(m, 3H), 2.94-2.78(m, 1H), 2.76-2.61(m, 1H), 2.03-1.75(m, 4H), 1.45(s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[N:16]1([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17]1>ClC(Cl)C>[C:1]([C:20]1[N:16]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-n2cccc2C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (1.3 ml) was added to a mixture of aluminum chloride (2.7 g) and 1,2-dichloroethane (10 ml) under ice-cooling and the mixture was stirred for 20 minutes at the same temperature. To the mixture was added dropwise a mixture of methyl 3-(pyrrol-1-yl)benzoate (2.0 g) in dichloroethane (3 ml) for 10 minutes at 0° to 5° C., and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into an ice-water and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-acetylpyrrol-1-yl)benzoate (0.94 g).
Reaction SMILES: C(O)C.[OH-].[Na+].C([N:8]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29])[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:10]([OH:12])=[O:11])C>O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:9]([C:10]([OH:12])=[O:11])[NH:8][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([Cl:28])=[CH:23][C:22]=1[Cl:29]
Reactant: CCN(c1cc(Cl)c(Cl)cc1Cl)C(C(=O)O)c1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1C(Nc1cc(Cl)c(Cl)cc1Cl)C(=O)O
Reaction time: 4 h

Procedure:
To a stirred and refluxed solution of 40 parts of ethanol, 25 parts of water and 2 parts of sodium hydroxide are added 5 parts of ethyl 2-(o-methoxyphenyl)-N-(2,4,5-trichlorophenyl)glycine and stirring at reflux temperature is continued for 4 hours. The reaction mixture is evaporated. The residue is dissolved in 250 parts of water. The solution is shaken with 80 parts of ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted twice with 80 parts of ether. The combined extracts are dried and evaporated. The solid residue is crystallized from 50 parts of glacial acetic acid at room temperature, yielding 3.2 parts of 2-(o-methoxyphenyl)-N-(2,4,5-trichlorophenyl)glycine; mp. 188.3° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(CC(=O)NNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95.5 %

Procedure:
To a solution of tert-butyl 2-({4-[(trimethylsilyl)ethynyl]phenyl}acetyl)hydrazinecarboxylate (10.1 g, 29.4 mmol) in anhydrous tetrahydrofuran (150 ml) was added at 0° C. tetra-n-butylammonium fluoride (1M tetrahydrofuran solution, 29.4 ml, 29.4 mmol). After stirring at 0° C. for 45 mins, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give tert-butyl 2-[(4-ethynylphenyl)acetyl]hydrazinecarboxylate (7.7 g, yield 96%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][NH:19][CH:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1cccs1)c1ccc(Br)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Brc1ccc(C2=CC(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
1-(4-Bromophenyl)-3-(2-thienyl)-2-propen-1-one (3.0 g, 10.2 mmol) and hydrazine hydrate (1.0 g, 20 mmol) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.0 g (98%) of the desired 3-(4-bromophenyl)-5-(2-thienyl)-pyrazoline in the form of a resinous material.
Reaction SMILES: [N+:1]([C:4]1[C:5]([Br:16])=[C:6]([Cl:15])[C:7]2[O:11][C:10]([F:13])([F:12])[O:9][C:8]=2[CH:14]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[C:5]([Br:16])=[C:6]([Cl:15])[C:7]2[O:11][C:10]([F:13])([F:12])[O:9][C:8]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc2c(c(Cl)c1Br)OC(F)(F)O2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc2c(c(Cl)c1Br)OC(F)(F)O2
Temperature: 90 °C
Yield: 100 %

Procedure:
To the slurry of 6-nitro-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole (1.0 g, 3.16 mmol) in ethanol (4 mL) and water (1 mL) was added ammonium chloride (3.38 g, 63.2 mmol) and iron powder (1.06 g, 18.96 mmol). The mixture was warmed up to 90° C. for 1 h and then cooled down. Filtered through a Celite plug and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% ethyl acetate in hexanes) to afford 6-amino-5-bromo-4-chloro-2,2-diflouro-1,3-benzodioxole as a white solid (0.90 g, 3.16 mmol, 100%). MS: (ES) m/z calculated for C7H3BrClF2NO2 [M+H]+286.0. found 286.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13]2[CH:14]=[CH:15][NH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13]2[CH2:14][CH2:15][NH:16][C:17]=2[CH:18]=[CH:19][CH:20]=1)=[O:11]
Reactant: Cc1cccc(NC(=O)c2cccc3[nH]ccc23)c1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(NC(=O)c2cccc3c2CCN3)c1C
Reaction time: 0.17 h

Procedure:
To compound 11 (0.15 g) was added triethylsilane (0.36 mL) and trifluoroacetic acid (10 mL). After stirring for 10 min. the solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and sodium bicarbonate. The ethyl acetate layer was washed with saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to afford the crude product. Trituration with hexane/ethyl acetate 8/2 gave the product. NMR (300 MHz, CDCl3) δ 7.62 (1H, d, J=3 Hz), 7.53 (1H, s), 7.13 (2H, q, J=3 Hz), 7.04 (2H, m), 6.77 (1H, d, J=3 Hz), 3.62 (2H, t, J=3 Hz), 3.39 (2H, t, J=3 Hz), 2.33 (3H, s), 2.21 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([F:17])[CH:12]=2)=[O:10])[CH2:5][CH2:4]1.[F:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][N:14]=1)[C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=3)=[N:26][CH:27]=2)[CH2:4][CH2:5]1)=[O:10]
Reactant: NCC1CCN(C(=O)c2ccnc(F)c2)CC1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCN(C(=O)c2ccnc(F)c2)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-(aminomethyl)piperidin-1-yl)(2-fluoropyridin-4-yl)methanone 93-4 (47 mg, 0.20 mmol), 6-(3-fluorophenyl)nicotinic acid 93-5 (43 mg, 0.20 mmol) and HATU (76 mg, 0.20 mmol) in DMF (1 mL) was added DIEA (0.16 mL, 0.50 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-41-(2-fluoroisonicotinoyl)piperidin-4-yl)methyl)-6-(3-fluorophenyl)nicotinamide 93 as a white powder. MS m/z 437.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.14 (d, 1H, J=1.6 Hz), 8.83 (t, 1H, J=6.0 Hz), 8.39-8.33 (m, 2H), 8.20 (d, 1H, J=8.4 Hz), 8.07-8.00 (m, 2H), 7.65-7.59 (m, 1H), 7.42-7.37 (m, 2H), 7.30 (m, 1H), 4.52 (d, 1H, J=13.2 Hz), 3.45-3.27 (m, 3H), 3.12-3.06 (m, 1H), 2.88-2.84 (m, 1H), 1.94-1.86 (m, 2H), 1.70 (d, 1H, J=12.8 Hz), 1.29-1.22 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O.Cl[CH:12]([CH3:16])[C:13]([OH:15])=[O:14].C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:12]([C:13]([OH:15])=[O:14])[CH3:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 40 °C

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety. N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is warmed to 40° C. and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p.=148-149° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[Na+].[Na+]>>[CH2:20]([S:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: Oc1ccc(S)cc1
Reactant: C=CCCCCCCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCSc1ccc(O)cc1

Procedure:
A 4-(nonylthio)phenol was prepared as follows. 63 Grams of 4-mercaptophenol and 5 grams of toluene sulfonic acid were heated to 60° C. Then 76 grams of nonene (approximately 55 percent 2,4-di-methyl-1-heptene) were added over a 38 minute period. The flask contents were neutralized with 5 grams of Na2CO3 in aqueous solution, decanted and stripped to a pot temperature of 180° C. at 26 millimeters of mercury. The product weighed 113 grams.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(OC)c3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)c1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.084 mmol), β-alanine (600 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 30 mg of the title compound as a yellow solid. MS: (+) m/z 474.36 (M+1).