Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:17]1[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[C:18]1[C:25]([OH:27])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22]([C:21]1[S:17][C:18]([C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:19][CH:20]=1)=[O:24])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(=O)O)s1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)s1
Yield: 82.1 %

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) thiophene-2,5-dicarboxylic acid afforded, after flash chromatography (EtOAc), 1.84 g (84%) of the title compound as a yellow crystalline solid. MS m/e (%): 564 (M+NH4+, 70), 547 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[O:10][CH3:11]
Reactant: [C-]#N
Reactant: COc1ncc(CBr)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COc1ncc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 3-bromo-5-bromomethyl-2-methoxy-pyridine (1.42 g, 5.05 mmol) in EtOH (14 mL) and H2O (1.5 mL) was added sodium cyanide (0.25 g, 5.05 mmol), and the reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and worked up with CH2Cl2 and saturated aqueous NaHCO3. The combined organic layers were dried, filtered, and concentrated to give (5-bromo-6-methoxy-pyridin-3-yl)-acetonitrile.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[Cl:9][CH2:10][C:11](=[O:14])[CH2:12]Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:9][CH2:10][C:11]1([OH:14])[CH2:12][S:7][C:6]([CH2:5][N:3]([CH3:4])[CH3:2])=[N:8]1
Reactant: CN(C)CC(N)=S
Reactant: O=C(CCl)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CC1=NC(O)(CCl)CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask were added 44.5 g. of dimethylaminothioacetamide, hydrochloride, 40.4 g. of 1,3-dichloropropanone, 224 ml. of 1,2-dichloroethane and 53.4 g. of sodium bicarbonate. An endothermic reaction took place and cooled the mixture to 13° on initial mixing. The mixture was then stirred overnight at ambient temperature, and the reaction was found to be essentially complete after 24 hours, by thin layer chromatography. The tlc system is silica gel, eluting with chloroform:methanol:ammonium hydroxide, 36:4:1. The mixture was then filtered, and the filter cake was washed with 1,2-dichloroethane. The filtrate was evaporated to dryness under vacuum to obtain 59.5 g. of crude product, which was washed with ethyl acetate. The washed solids were dried in air, to obtain 52.5 g. of substantially pure product, m.p. 90°-92°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:22][C:23]([F:29])([F:28])[CH2:24][CH2:25][CH:26]=O.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33]>O.[Au](Br)(Br)Br>[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[C:33][C@@H:26]([N:10]1[CH2:11][CH2:12][CH2:13][C@H:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:8][CH:7]=1)[CH2:25][CH2:24][C:23]([F:29])([F:28])[F:22]
Reactant: C#CC(C)(C)C
Reactant: O=CCCC(F)(F)F
Reactant: COC(=O)C[C@H]1CCCN[C@@H]1c1ccc(C(F)(F)F)cc1
Agent: Br[Au](Br)Br
Solvent: O
Product: COC(=O)C[C@H]1CCCN([C@H](C#CC(C)(C)C)CCC(F)(F)F)[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C

Procedure:
A solution of methyl {(2S,3R)-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetate (2.1 g, 7.0 mmol), 4,4,4-trifluorobutanal (1.76 g, 13.9 mmol) and gold(III) bromide (0.3 g, 0.7 mmol) in water (50 mL) was degassed with nitrogen for 1.5 hours. To this solution was added 3,3-dimethylbut-1-yne (4.3 mL, 34.8 mmol) and the reaction was sealed and heated to 70° C. for 16 hours. The reaction was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (3% ethyl acetate/hexanes) gave methyl {(2S,3R)-1-[(1S)-4,4-dimethyl-1-(3,3,3-trifluoropropyl)pent-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetate as a clear oil. LC/MS (EIMS, M+H)=492.1.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:37])[CH2:14][CH2:15][N:16]([CH2:21][CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30]([O:32]C(C)(C)C)=[O:31])=[O:24])[CH2:17][CH2:18][O:19][CH3:20])=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl.O>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:30]([C@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:23](=[O:24])[CH2:22][CH2:21][N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:37])([OH:32])=[O:31]
Reactant: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of 150 mg (0.29 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(2-methoxy-ethyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and subsequent lyophilisation, 100 mg (67%) of the title compound as a yellow oil. MS m/e (%): 436 (M+Na+, 35), 414 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.[CH:11]([O:14][B:15](OC(C)C)[O:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12].[Li]CCCC.CCCCCC>C1COCC1>[CH3:9][N:8]([CH2:7][C:4]1[S:5][CH:6]=[C:2]([B:15]([O:16][CH:17]([CH3:19])[CH3:18])[O:14][CH:11]([CH3:13])[CH3:12])[CH:3]=1)[CH3:10]
Reactant: CN(C)Cc1cc(Br)cs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)OB(OC(C)C)c1csc(CN(C)C)c1
Temperature: -78 °C
Reaction time: 6.5 h

Procedure:
To a solution of 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine (2.8 g, 12.8 mmol) in THF (130 mL) at −78° C. under N2 was added tri-isopropylborate (4.4 mL, 19.2 mmol). The reaction mixture was stirred briefly before nBuLi (12 mL of a 1.6 M hexane solution) was added dropwise via syringe. The reaction mixture then stirred for 6.5 h at −78° C. before being concentrated by rotary evaporation. The resulting white solid was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][O:9][C:10]1[C:15]2[N:16]=[C:17]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]NC)[CH:22]=3)[S:18][C:14]=2[C:13]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:12][CH:11]=1.ClCCl.CO>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:20]([NH:19][C:17]1[S:18][C:14]2[C:13]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:12][CH:11]=[C:10]([O:9][CH3:8])[C:15]=2[N:16]=1)=[O:30]
Reactant: COCCO
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCOCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48 %

Procedure:
2-Methoxyethanol (2.6 ml, 48 mmol) is treated at 0° C. with sodium hydride (38 mg, 0.95 mmol, 60% in mineral oil) and the remaining solution allowed to warm to ambient temperature over 1 h. N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (200 mg, 0.48 mmol, dissolved in tetrahydrofurane (2.0 ml), is added and the mixture stirred at 80° C. for 15 h. The mixture is then evaporated to dryness, treated with saturated sodium carbonate (20 ml) and extracted four times with each 20 ml dichloromethane. The combined organic phases are dryed and evaporated. Flash chromatography (SiO2, eluent: dichloromethane/methanol 20:0 to 19:1) afforded the title compound as light yellow crystals (104 mg, 48% yield). MS: m/e=459 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)O1.[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32](Cl)=[CH:33][C:34]=1[NH:35][CH3:36].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>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].O>[NH2:28][C:29]1[C:30]([C:38]#[N:39])=[N:31][C:32]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:11]([C:23]([F:24])([F:25])[F:26])[CH:10]=2)=[CH:33][C:34]=1[NH:35][CH3:36]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC1(C)OB(c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2ccc(OCc3ccccn3)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C

Procedure:
The mixture of 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)methyl)pyridine (1.35 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (0.5 g), tris(dibenzylideneacetone)dipalladium (125 mg), tricyclohexylphosphine (92 mg) in a mixed solvent of dioxane (15 ml) and water (10 ml) was heated under nitrogen at 100° C. for 3 hours. After cooling to room temperature, the mixture extracted with ethyl acetate (200 ml), organic layer dried over sodium sulphate, solvent removed under reduced pressure, residue was used for next step without further purification. MS m/z 400 (M+H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.ClCC(C1CCC(CCCCC)CC1)=O.C([C@H]1CC[C@H](C(O)=O)CC1)CCCC>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCCCCC1CCC(C(=O)CCl)CC1
Agent: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 25 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (160 mg, 0.50 mmol), and triethylamine (352 uL, 2.53 mmol, 5.0 eq), in THF (2 mL), was treated with 232 mg (1.0 mmol) of 1-chloro-2-(4-pentylcyclohexyl)-2-oxoethane (prepared from trans-4-pentylcyclohexanecarboxylic acid using the procedure described in example 1) to provide 154 mg, (25%) of L-isoleucine, N-[1-(2-(4-pentylycyclohexyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH:19]=[CH2:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:20][CH:19]=[CH2:18])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2s1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)sc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
5-Chloro-1,3-benzothiazol-2(3H)-one (1.85 g, 10 mmol) was dissolved in DMF (50 ml) and treated with potassium carbonate (1.66 g, 12 mmol) and allyl iodide (1.1 ml, 12 mmol) then heated at 100° C. for 18 hrs. The solvent was then removed in-vacuo and the residue partitioned between water (100 ml) and ethyl acetate (2×100 ml). The organic layer was washed with saturated brine, separated and dried. Chromatography on silica gel eluting with a gradient of 10-50% ethyl acetate/40-60 petroleum ether gave the title compound as an oil that crystalised on standing (2.14 g, 95%).
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([CH:9]2[NH:13]C(=O)N[C:10]2=[O:15])=[C:5]([CH3:16])[CH:4]=1)#N.[C:17]([OH:20])(=[O:19])[CH3:18].[OH-:21].[Na+]>>[C:17]([C:18]1[CH:8]=[CH:7][C:6]([CH:9]([C:10]([OH:15])=[O:21])[NH2:13])=[C:5]([CH3:16])[CH:4]=1)([OH:20])=[O:19]
Reactant: [OH-]
Reactant: Cc1cc(C#N)ccc1C1NC(=O)NC1=O
Reactant: CC(=O)O
Agent: [Na+]
Product: Cc1cc(C(=O)O)ccc1C(N)C(=O)O

Procedure:
A stirred mixture of 5-(4-cyano-2-methylphenyl)hydantoin (1.1 g, 5.2 mmol) in aqueous sodium hydroxide (2M, 12 ml) was heated to 120° C. for 17 hours in a PTFE lined stainless steel sealed reaction vessel. The cooled mixture was acidified with glacial acetic acid (1.4 ml) and chromatographed on ion exchange (Dowex 50×8-100 resin). The column was eluted sequentially with water, tetrahydrofuran-water (1:1), water and 10% pyridine in water. Fractions collected from the pyridine-water elution were combined and evaporated to dryness, redissolved in water and freeze-dried to give the title compound as a white powder, m.p. >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].O>C(Cl)Cl>[CH2:19]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5])=[O:24])[CH3:20]
Reactant: CCNc1cccc(N)c1C#N
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCNc1cccc(NC(=O)COCC)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(ethylamino)benzonitrile (4 g) in methylene chloride (100 ml) is added pyridine (2.8 ml), and thereto is added dropwise ethoxyacetyl chloride (3.9 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethyl acetate-hexane to give the title compound (4.1 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][CH:28]([NH:33][CH3:34])[CH2:27][CH2:26]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:29]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNC1CCc2cc(OC)ccc2C1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC(N(C)CCCN1CCc3cc(OC)c(OC)cc3CC1=O)C2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 6-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 122°-123° C. (decomp.).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](C)=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[C:23](=O)[C:24](=[CH2:27])[CH2:25][CH3:26])[O:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].[CH2:31](O)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[C:23]1[CH:24]([CH2:27][CH3:31])[CH2:25][CH2:26][C:4](=[O:5])[CH:3]=1)[O:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: C=C(CC)C(=O)c1ccc(OCC(=O)O)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: CCO
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)cc1Cl

Procedure:
To a stirred solution of sodium (0.95 g, 0.0414 mole) in ethanol (75 ml) and ethyl acetoacetate (5.38 g, 0.0414 mole) was added [3-chloro-4-(2-methylene-1-oxobutyl)phenoxy]acetic acid (4.94 g, 0.0184 mole). The reaction mixture was heated at reflux for 3 hours. 1N sodium hydroxide (10 ml) and 55 ml of water was added and refluxing was continued for 11/2 hours, then the solvent was distilled at reduced pressure. The residue was acidified, extracted with ether, washed with water, dried over magnesium sulfate to give 4.1 g of [3-chloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 138°-140° C. after recrystallization from butyl chloride and methanol.
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[CH:33](=O)[CH3:34].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][CH3:34])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(4-benzylaminobutyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (0.5 g) as starting compound, acetaldehyde (0.07 ml) and sodium cyanoborohydride (0.15 g) were reacted and treated in the same manner as in Example 136 to give 0.35 g of 4-amino-5-chloro-N-((1-(4-(N-ethyl-N-benzylamino)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl.[CH:2]1([NH:8][CH:9]2[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl.O>[Br:18][CH2:19][C:20]([N:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[CH:9]1[CH2:11][CH2:10]1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: C1CCC(NC2CC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To an ice cooled mixture of 1.054 g (6 mmol) of N-cyclohexyl-N-cyclopropylamine hydrochloride, 2.07 g (15 mmol) of potassium carbonate in 15 ml of methylene chloride and 15 ml of water was added 1.2 g (6 mmol) of bromoacetyl bromide. Then the reaction mixture was stirred at RT for 20 h. The organic phase washed with water, dried over sodium sulphate and evaporated to dryness to give 1.33 g of crude compound. Flash chromatography using DCM as eluant afforded 1.12 g of the desiderated compound as colorless oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:33]2[C:28](=[CH:29][C:30]([F:53])=[C:31](OS(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)(=O)=O)[N:32]=2)[C:27](=[O:54])[C:26]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:25]1.O>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:31]2[N:32]=[C:33]3[C:28]([C:27](=[O:54])[C:26]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:25][N:24]3[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])=[CH:29][C:30]=2[F:53])[CH2:5]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c(F)cc2c1=O
Reactant: NC1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 96.3 %

Procedure:
In 5 ml of ethanol was suspended 150 mg of 3-aminopyrrolidine dihydrochloride, and 310 mg of triethylamine was added thereto to form a solution. Subsequently, 500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate was added thereto, and the resulting mixture was subjected to reaction at room temperature for 2 hours. Subsequently, 6 ml of water was added to the reaction mixture, and the crystals thus deposited were collected by filtration, and washed with 5 ml of water to obtain 330 mg (yield 96.3%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 200°-202° C.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:24][C:25]([N:27]=[C:28]=[O:29])=[O:26].[NH:30]1[CH2:35][CH:34]=[CH:33][CH2:32][CH2:31]1.C(OCC)(=O)C>O1CCCC1>[N:30]1([CH2:24][C:25]([NH:27][C:28]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:29])=[O:26])[CH2:31][CH:32]=[CH:33][CH2:34][CH2:35]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C=NC(=O)CCl
Reactant: C1=CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CN1CC=CCC1)NC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.22 g, 0.75 mmol) was dissolved in tetrahydrofuran (7.5 mL). 2-Chloroacetyl isocyanate (0.10 g, 0.83 mmol) was added thereto, and the mixture was stirred at −20° C. for 1 hour. 1,2,3,6-Tetrahydropyridine (0.27 mL, 3.0 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and then crystallized from ethyl acetate-hexane to obtain the title compound (0.25 g, yield 72%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH:18]1[CH2:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
TFA (5 mL) was added to tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1.9 g, 6.87 mmol, CAS 170011-57-1) in DCM (5 mL). The resulting solution was stirred at ambient temperature for 2 hours then added to an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and the solvent evaporated to dryness to give 4-(piperidin-4-yl)aniline (1.210 g, 100%) as a solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13]C=CN=1)=O>CO.C(Cl)Cl>[CH:3]1([CH2:4][CH2:5][CH2:6][NH2:1])[CH2:2][CH2:7][CH2:9][CH2:14][CH2:13]1
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: ClCCl
Solvent: CO
Product: NCCCC1CCCCC1
Yield: 335.5 %

Procedure:
Prepared as above from 464.9 mg (1.11 mmol) of the pyridyl ketone and 1.00 g (2.21 mmol) of the Wittig salt. Flash chromatography with 15% MeOH-CH2Cl2 afforded 526.0 mg (92%) of the product (E/Z=~4:1 by 1H NMR): 1H NMR (DMSO) δ8.66 (s, 1H), 8.52 (m, 1H), 8.40 (dd, J=4.5, 1.1 Hz, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.47 (m, 2H), 7.29 (d, J=8.1 Hz, 2H), 6.20 (t, J=7.4 Hz, 1H), 3.57 (br t, J=4.4 Hz, 4H), 3.28 (br dt, J=~6.2, 5.8 Hz, 2H), 2.30 (br s, 6H), 2.02 (m, 4H), 1.63 (br t, J=6.6 Hz, 2H), 1.40 (m, 4H); FDMS 519 (M+1). 97.5% pure by HPLC.