Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1/[C:17](=[CH:19]/[CH:20]([CH3:22])[CH3:21])/[CH3:18].NC1C=CSC=1/C(=C\C(C)C)/C>>[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH2:18]
Reactant: C/C(=C\C(C)C)c1sccc1N
Agent: C/C(=C/C(C)C)c1sccc1N
Agent: O=S(=O)(O)c1ccccc1
Product: C=C(CC(C)C)c1sccc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
Into a solution obtained by dissolving 3-aminothiophene (2.0 g, 20.4 mmol) in 4-methyl-2-pentanone (30.0 g), which was obtained in the same manner as in Example 14 using methyl 3-aminothiophene-2-carboxylate as a starting material was added anhydrous benzenesulfonic acid (3.9 g, 24.5 mmol) at room temperature, and the resulting solution was stirred under nitrogen atmosphere at 60 degree centigrade for 15 hours. The reaction solution was cooled to room temperature, and then washed with a 10% aqueous sodium hydroxide solution, and separated. As a result of the analysis by the HPLC internal standard method of the obtained organic layer, 2.4 g was produced as a mixture of three compounds including 3-amino-2-{(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-amino-2-{(Z)-(4-methyl-2-penten-2-yl)}thiophene and 3-amino-2-(4-methyl-1-penten-2-yl)thiophene (yield: 65%).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH:14]=O)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(OC)(OC)OC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[N:1]([C@@H:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([CH2:14][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:7]=[CH:6][C:5]1=2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(C=O)ccc21
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Solvent: CC(=O)O
Product: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 100 mL flame dry round bottom flask was added (R)-5-azido-5,6,7,8-tetrahydro-naphthalene-2-carbaldehyde (200 mg, 0.99 mmol), piperidine (0.5 mL, 5 mmol), dry DCM (10 mL), HOAc (1 drop), and CH(OMe)3. The resulting mixture was stirred under N2 for 3 h at RT. Then, NaBH(OAc)3 (632 mg, 2.98 mmol) was added and stirred for 20 h. The reaction mixture was quenched with 5% NaHCO3 and concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 (95% DCM:5% MeOH) to afford the title compound. MS (m/z): 271.2 (M+H) (Calc'd. for C16H22N4:270.37).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(CNc2ncc(C(=O)[O-])cc2Cl)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CNc2ncc(C(=O)O)cc2Cl)c(OC)c1

Procedure:
5-Chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinate was treated with sodium hydroxide in ethanol to obtain 5-chloro-6-[(2,4-dimethoxybenzyl)amino]nicotinic acid. To the compound were added toluene, diphenylphosphoryl azide (DPPA), tert-butyl alcohol, and triethylamine, and the whole was stirred under reflux with heating. The resulting compound was treated with trifluoroacetic acid to obtain 3-chloropyridin-2,5-diamine.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C=O.[C:66](OCC)(=[O:68])C>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:66][OH:68])[CH:51]=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: CCOC(C)=O
Agent: C=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 21l (0.52 g, 0.68 mmol) in N,N-dimethyl formamide (20 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.34 mmol) and formaldehyde (0.83 mL, 10.28 mmol, 37 wt % solution) in turn at room temperature. The mixture was stirred at room temperature for 16 hours, and then ethyl acetate (50 mL) was added. The resulting mixture was washed with water (60 mL×5), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21m as yellow oil (0.52 g, 100%). This material was not further purified.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=O)C.O.[NH2:20][NH2:21]>C(O)C>[O:18]=[C:7]1[C:6]([C:4]([NH:20][NH2:21])=[O:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][NH:8]1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
10 g of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester are dissolved in 150 ml of ethanol, 4.2 ml of hydrazine hydrate is added and the mixture is refluxed for 5 hours. After cooling to room temperature, the solid is collected by filtration and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH2:21][CH2:22][CH3:23])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCCCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: CCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 60.8 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using butyl iodide (1.8 ml; 15.4 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 20 h. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) the alkylated acetamide (0.94 g; 2.93 mmol) is de-acetylated under reflux conditions in 2-propanol (3 ml) and hydrochloric acid (6 N; 11 ml). Pure 5-amino-1-butyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.64 g) is obtained by flash chromatography on silica gel eluted with CH2Cl2/MeOH (50:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:38](=O)[CH2:39][CH:40]([CH3:42])[CH3:41]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)[CH:12]=[C:13]([N:15]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CC=O
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C(F)(F)F)cc2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 4-Methyl-2-[4′-trifluoromethyl-5-(4-trifluoromethyl-benzylamino)-biphenyl-3-yl]-pentanoic acid methyl ester, compound 44a with isovaleraldehyde gave the title compound; Calcd.MW 593.66. Found MH+ 594.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7](C1C=C(F)C(OCCCCl)=C(F)C=1)=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1(S([O-])(=O)=O)C=CC=CC=1>CC#N.[Na+].[I-]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1cc(F)c(OCCCCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CCC=O
Yield: 204.7 %

Procedure:
A mixture of 4-[4-(3-chloropropoxy)-3,5-difluorophenyl]-4-oxo-butyric acid ethyl ester (5 g, 14.9 mmol), K2CO3 (7.2 g, 52.1 mmol), NaI (220 mg, 1.4 mmol), and Benzenesulfonate; (R)-methylpyrrolidinium (8 g, 33 mmol) in CH3CN (110 mL) was heated under argon at 80° C. for 36 h. The reaction was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material (96% purity). The crude material was purified by ISCO (80 g silica gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 0.1% ammonium hydroxide in methylene chloride. The isolated material was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The isolated material was crystallized with a mixture of methylene chloride, ether and hexane to obtain 4-{3,5-difluoro-4-[3-(R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (3.97 g, 70%, 99% purity), MS m/z=384 (M+H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:13][C:12](=[O:14])[NH:11][N:10]=1.Br[CH2:16][CH2:17][CH3:18].C(OCC)C>CN(C)C=O.O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:13][C:12](=[O:14])[N:11]([CH2:16][CH2:17][CH3:18])[N:10]=1
Reactant: O=C1CC(c2ccccn2)=NN1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1N=C(c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.1 %

Procedure:
To a suspension of 0.29 g (7.3 mmol) of 60% oily sodium hydride in 10 ml of anhydrous dimethylformamide was added dropwise a solution of 1.2 g (6.2 mmol) of 3-(2-pyridyl)-4, 5-dihydropyrazol-5-one in dimethylformamide (10 ml) at 0° C. After one hour of stirring at room temperature, 0.92 g (7.5 mmol) of 1-bromopropane was added dropwise and stirring was continued for another 18 hours. To the reaction solution was added 50 ml of diethyl ether and 50 ml of water, and vigorously agitated. The resultant solution was separated, and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was combined and washed successively with water and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 1.4 g of the object compound as a colorless oil (yield 96%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]([CH3:31])([CH2:29][CH3:30])[C:26](O)=[O:27]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:26](=[O:27])[C:25]([CH3:31])([CH3:24])[CH2:29][CH3:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCC(C)(C)C(=O)O
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)CC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,2-dimethylbutyric acid (110 μl, 0.89 mmol). The title compound was obtained as yellow powder (186 mg, 56%).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=2)[CH:5]=1.[CH2:14]([N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][N:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH:33](OC)OC)[CH2:26]2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>S(=O)(=O)(O)O>[CH2:14]([N:21]1[CH2:28][C@@H:27]2[CH2:26][N:25]([CH2:29][CH2:30][CH2:31][C:32]3[C:10]4[C:9](=[CH:8][CH:7]=[C:6]([N:4]5[CH:3]=[N:2][N:1]=[CH:5]5)[CH:11]=4)[NH:12][CH:33]=3)[CH2:24][C@@H:23]2[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: COC(CCCCN1CC2CN(Cc3ccccc3)CC2C1)OC
Agent: O=S(=O)(O)O
Product: c1ccc(CN2C[C@H]3CN(CCCc4c[nH]c5ccc(-n6cnnc6)cc45)C[C@H]3C2)cc1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
4-(1,2,4-Triazol-4-yl)phenylhydrazine (EP581538) (1.48 g, 8.4 mmol) was added in one portion to a stirred solution of 2-benzyl-5-(5,5-dimethoxypentyl)octahydro-pyrrolo[3,4-c]pyrrole (2.8 g, 8.4 mmol) in 4% sulphuric acid (50 ml) at room temperature. After 30 minutes at room temperature the mixture was heated to reflux under nitrogen for 72h. The reaction was then cooled to 0° C. and quenched with solid potassium carbonate. The aqueous was then extracted with in-butanol (x4). The combined extracts were evaporated and the residue purified by chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (94:5:1→91:8:1→89:10:1) to give the title indole (1.3 g, 35%) as a yellow foam. An analytically pure sample was obtained by further chromatography of a small portion of the above sample on silica gel, eluting with Et2O/EtOH/NH3 (40:10:1) to give the title indole (150 mg) as a colourless solid. The 1.5 hydrogen oxalate. 0.5 hydrate. 0.1 etherate was prepared (Et2O/MeOH): mp 149-153° C. (Found: C, 61.12; H, 6.25; N, 14.07. C26H30N6.1.5(C2H2O4).0.5(H2O). 0.1(C4H10O) requires C, 61.16; H, 6.24; N, 14.26%). δ (360 MHz, d6 -DMSO) 1.98-2.08 (2H, m), 2.50-2.60 (1H, m), 2.70-2.82 (5H, m), 2.86-3.00 (5H, m), 3.06-3.14 (2H, m), 3.38-3.50 (1H, br m), 3.76 (2H, br s, CH2Ph), 7.26-7.38 (7H, m, Ar--H), 7.51 (1H, d, J=8.6 Hz, Ar--H), 7.82 (1H, d, J=2.0 Hz, Ar--H), 9.02 (2H, s, Triazole-H), 11.19 (1H, br s, N--H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.[CH2:15]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[N:23][C:22]2=O)[CH2:16][CH3:17].CN(C)C1C=CC=CC=1>O=P(Cl)(Cl)Cl>[Cl:3][C:22]1[C:21]2[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:15][CH2:16][CH3:17])[CH:20]=2)[N:25]=[C:24]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[N:23]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCOc1ccc2[nH]c(-c3cccnc3)nc(=O)c2c1
Solvent: CN(C)c1ccccc1
Product: CCCOc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
(This method is representative of method F1, F2, F3 and F4. These three methods can be implemented in a similar way except for substitution of the appropriate chlorinating reagent, solvent and temperature) To a mixture of 6-propoxy-2-pyridin-3-yl-1H-quinazolin-4-one (1.00 g, 3.56 mmol) in POCl3 (10 mL) was added N,N-dimethylaniline (0.1 mL). The resulting mixture was stirred at 120° C. for 2 h. After the reaction was completed, POCl3 was removed in vacuo, and the residue was added to ice-water slowly. The pH was adjusted to around 7 by slowly adding NaHCO3 (sat.) at 0 (C. The resultant solid was collected and purified by chromatography on silica gel eluted with petroleum ether/ethyl acetate (v/v=4:1 to 1:1) to give 580 mg of v-a as a pale yellow solid (54.7%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:26]#[N:27])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:24][CH2:25][C:26]([NH2:27])=[O:29])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC#N)ccc3c2)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(N)=O)ccc3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanenitrile (233 mg, 0.64 mmol) in DMSO (2 mL) was added K2CO3 (265 mg, 2 mmol, 3.0 eq), the mixture was then cooled to 0° C., and followed by addition of aq. 30% H2O2 (0.3 mL). The reaction mixture was stirred at rt for 1 h, and quenched with water (10 mL). The solvent was removed by freezen-dried. The crude product was purified by flash chromatography to give the title compound as a white solid (111 mg, 45%) mobile phase: MeOH/H2O: 0%˜80%). ESI-MS (M+1)+: 383.3. HPLC: 97.84%. 1H NMR (400 MHz, CD3OD) δ: 7.86˜7.79 (m, 3H), 7.53˜7.50 (m, 1H), 7.33˜7.30 (m, 1H), 7.21˜7.16 (m, 1H), 4.42˜4.35 (m, 3H), 3.34˜3.27 (m, 2H), 2.71 (t, 2H), 2.32˜2.24 (m, 2H), 1.96˜1.87 (m, 2H), 1.51˜1.39 (m, 2H), 1.33˜1.20 (m, 2H), 1.17˜1.09 (m, 1H), 0.92 (s, 9H).
Reaction SMILES: [C:1]([C:9]([O-:11])=[O:10])(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.OC1C(C)=[N:15]C=C(C([O-])=O)C=1C([O-])=O.C([O-])(=O)C1C=C(O)C(O)=C(O)C=1.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.C1(CC(=O)C([O-])=O)C=CC=CC=1.OC1C=C(C([O-])=O)C(=CC=1O)C([O-])=O.N1C=C(C([O-])=O)C(=O)NC1=O.C1C=C[C@](O)(C(O)=O)[C@@H](O)C=1>O>[NH2:15][CH2:5][CH2:4]/[CH:3]=[CH:2]/[C:1](=[O:8])[C:9]([OH:11])=[O:10]
Reactant: Cc1ncc(C(=O)[O-])c(C(=O)[O-])c1O
Reactant: O=C([O-])C(=O)c1ccccc1
Agent: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C(O)[C@@]1(O)C=CC=C[C@@H]1O
Agent: O=C([O-])C(=O)Cc1ccccc1
Solvent: O
Product: NCC/C=C/C(=O)C(=O)O

Procedure:
There are no enzymes known in the art that catalyze the substrate L-2,3-dihydropicolinate to produce 5,6-dihydropyridine-2-carboxylate. However, there are a few decarboxylases that are able to decarboxylate ring mounted carboxylic acids. One skilled in the art would appreciate that it is likely that these enzymes may have, or could be engineered to have, activity towards L-2,3-dihydropicolinate. Examples of such decarboxylases include, but are not limited to, benzoylformate decarboxylase (EC 4.1.1.7), 3-hydroxy-2-methylpyridine-4,5-dicarboxylate decarboxylase (EC 4.1.1.51), pyrrole-2-carboxylase (EC 4.1.1.-), gallate decarboxylase (4.1.1.59), Dopa decarboxylase (EC 4.1.1.28), Phenylpyruvate decarboxylase (EC 4.1.1.43), 4,5-dihydroxyphthalate decarboxylase (EC 4.1.1.55), 5-dihydroxybenzoate decarboxylase (EC 4.1.1.62), Uracil-5-carboxylate decarboxylase (EC 4.1.1.66), and Cis-1,2-dihydroxycyclohexa-3,5-diene-1-carboxylate dehydrogenase (EC 1.3.1.25). In a subsequent step, the 5,6-dihydropyridine-2-carboxylic acid ring is opened in the presence of water to produce (E)-6-amino-2-oxohex-3-enoic acid. This reaction is similar to the hydration of 2,3,4,5-terahydropyridine-2-carboxylic acid (in the lysine degradation pathway) and is likely to be spontaneous in the presence of water.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)#[N:2].CN(C)C=O.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(P(=O)(OCC)OCC)#N>O.C(N(CC)CC)C>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([NH:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=1)=[O:11])#[N:2]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CC#N)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CC#N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 2.55 g of publicly known 5-cyanomethyl-2-methoxybenzoic acid were added 50 ml of dimethylformamide, 2.57 g of 4-trifluoromethylbenzylamine, 2.66 g of diethyl cyanophosphonate and 2.00 ml of triethylamine, and the mixture was stirred for 20 minutes under cooling with ice and for 6 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After washed with water, then with saturated brine, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue was crystallized from hexane-diethyl ether and collected by filtration to obtain 4.44 g of 5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals. Melting point 124-125° C. Elemental analysis (%) C16H15F3N2O2 Calcd.(%) C, 62.07; H, 4.34; N, 8.04 Found (%) C, 62.03; H, 4.27; N, 7.99
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13](OC)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]12([CH2:11][CH2:12][CH2:13][OH:14])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COC(=O)CCC12CC3CC(CC(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Intermediate 47 (3.89 g, 17.49 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added under argon at 0° C. to a solution of lithium aluminium hydride (0.74 g, 19.5 mmol) in tetrahydrofuran (22 mL). The resulting mixture was stirred at room temperature for 5 hours. Then water (20 mL), sodium hydroxide 4N (20 mL) and finally water again (40 mL) were added into the solution at 0° C. The mixture was stirred for some minutes and the resulting salts were filtered through a pad of Celite®. The solvent was removed under reduced pressure and the title compound was obtained as a colourless solid (3.3 g, 97%) and used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2Br)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:30]2[CH2:32][CH2:31]2)[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A mixture of 3-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 0.17 mmol), cyclopropyl boronic acid (0.044 g, 0.52 mmol), K2CO3 (0.047 g, 0.34 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.014 g, 0.017 mmol) in dioxane (3 mL) and H2O (0.5 mL) was stirred at 100° C. for 15 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 4) to give 3-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.029 g, 33%). LC/MS (Table 1, Method 2) Rt=1.228 min.; MS m/z: 429 [M+H]+.