Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2c([N+](=O)[O-])cccc2[N+](=O)[O-])CC1
Yield: 74.4 %

Procedure:
To a stirred solution of 1.01 g (5.0 mmol) of 1-chloro-2, 6-dinitrobenzene and 0.93 g (5.0 mmol) of 1-tert-butyloxycarbonylpiperazine in acetonitrile (5 mL) was added 1.38 g (10 mmol) of K2CO3. The mixture was heated to reflux for 48 h. The solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (100 mL) and 20 mL of H2O. The organic layer was washed with H2O (2×20 mL), dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% EtOAc/hexanes) provided 1.31 g (85%) of 4-(2,6-dinitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester TLC (silica, 20% EtOAc/hexanes): Rf=0.35. 1H NMR (400 MHz, CDCl3): 7.75 (d, J=8.2 Hz, 2H), 7.25 (t, J=8.2 Hz, 1H), 3.30 (m, 4H), 2.95 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+].[Br:37]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:37])[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(OCCOC)nc32)cc1)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1ccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
To a solution of diethyl 4-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzylphosphonate (1 equiv.) in acetic acid (0.20 M) was added sodium acetate (15 equiv.) and bromine (13 equiv.). The reaction mixture was then allowed to stir at room temperature for 18 h. At this point the reaction was quenched by the addition of sodium thiosulfate. The mixture was then diluted with water and DCM. This mixture was transferred to a separatory funnel and washed with DCM three times. The combined organic layers were then dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (14%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[N:23]=[N:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1C=C(c2ccccc2)C(=O)N=N1
Yield: 33.9 %

Procedure:
Phenylmaleic anhydride (20 g, 115 mmol), sodium acetate trihydrate (18.75 g, 138 mmol), hydrazine monohydrate (6.68 ml, 133 mmol) and 40% aqueous acetic acid (400 ml) were heated at reflux for 15 h then allowed to cool. The reaction mixture was left to cool in the fridge for 1h. The solid produced was filtered and washed with water and diethyl ether before drying in a vacuum oven at 40° C. to give the required product (7.26 g). 1H NMR (250 MHz, DMSO) 8 3.43 (2H, broad peak), 7.17 (1H, s), 7.44 (3H, m), 7.81 (2H, m); MS (ES+) m/e 189 [MH+].
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.Cl.[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([NH:26][CH3:27])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>O>[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([N:26]([CH3:27])[CH:8]=[O:10])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Reactant: O=CO
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C=O)C1CCCCC21
Reaction time: 15 h

Procedure:
2.0 Milliliters of acetic anhydride and 1.0 ml of 98% formic acid were mixed and the mixture was stirred under heating for 2 hours and left to stand of cooling. To the resulting solution were added 3.0 g of 8-hydroxy-5-methyl-9-methylamino-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene hydrochloride and 10 ml of acetic anhydride and reaction was carried out at 60° C. for 2 hours and at room temperature for 15 hours. To the reaction mixture was added water and the separated solid was collected by filtration, washed with water and once dissolved in chloroform and the solution was dried with magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethanol to obtain 1.42 g of 8-hydroxy-5-methyl-9-(N-methyl-N-formylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[CH3:13][O:14][C:15](=[O:36])[CH:16]=[C:10]1[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9]1
Reactant: O=C1CC(c2cccc(Br)c2)C1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)C=C1CC(c2cccc(Br)c2)C1
Yield: 99.6 %

Procedure:
3-(3-Bromo-phenyl)-cyclobutanone (2.00 g, 8.89 mmol) and Triphenyl-phosphoranylidene acetic acid methyl ester (8.33 g, 24.9 mmol) were dissolved in dichloromethane (30 mL) inside a CEM 80 ml microwave vessel. The solution was irradiated in a CEM Discover™ microwave instrument for 30 minutes at 120° C. Pressure reached a maximum of 180 PSI. Purification by column chromatography (isocratic elution; 10% diethyl ether in hexanes) afforded 2.49 gm of a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.90-3.00 (m, 1H) 3.02-3.14 (m, 1H) 3.17-3.28 (m, 1H) 3.46-3.58 (m, 1H) 3.62 (s, 3H) 3.63-3.71 (m, 1H) 5.74 (q, J=3.0 Hz, 1H) 7.27-7.35 (m, 2H) 7.39-7.43 (m, 1H) 7.50 (t, J=1.9 Hz, 1H); MS (EI) m/z 280 [M+.].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12]>O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: OCC(F)(F)F
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
To a mixture of sodium hydride (1.648 g, 68.66 mmol) in tetrahydrofuran (220 mL) at 0° C. was added 2,2,2-trifluoroethanol (5.0 mL, 68.66 mmol). After 5 minutes, the reaction was allowed to warm to room temperature and methyl 2-bromoacetate (6.2 mL, 65.39 mmol) was added. After stirring for 72 hours, the mixture was filtered through diatomaceous earth with ether washes. The filtrate was concentrated and distilled to afford the title compound as a colorless oil (8.26 g, 73%), bp 155°-60° C., MS(CI): 173(M+H); H-NMR (300 MHz, DMSO-d6): 3.68(s, 3H), 4.16(q, J=9.2 Hz, 2H), 4.33(s, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BH4-].[Na+].C(O)(=O)C>CO>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]1[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(O)/C=C/C1CCC(=O)C1CC/C=C\CCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC(O)/C=C/C1CCC(O)C1CC/C=C\CCC(=O)O

Procedure:
150 mg of 7-[2-(3-hydroxy-3-pentyl-trans-1-propenyl)-5-oxocyclopentyl]-cis-4-heptenoic acid were dissolved in 20 ml of methanol and three times each time 150 mg of NaBH4 were added within the course 11/2 hours. The reaction solution was adjusted to pH 7 by means of glacial acetic acid, the solvent was removed by distillation under reduced pressure, the residue was acidified with 2N-HCl to pH 1 and extracted thrice with 150 ml of ether. After washing, the organic phase was concentrated.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12](O)=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1.[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:28])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc3cc(C(=O)O)[nH]c3c(O)c2F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc3cc(C(N)=O)[nH]c3c(O)c2F)cn1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
To an ice-cooled and stirred mixture of 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (2.5 g) in N,N-dimethylformamide (30 mL) were added 1-hydroxybenzotriazole ammonium salt (1.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.57 g). After stirred at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light brown solid, which was washed with tetrahydrofuran-ethyl acetate to give the title compound (0.55 g, 22%) as a light pink solid. MS 366 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)cc1-c1nc(-c2ccccn2)no1
Temperature: 80 °C
Yield: 12 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (66.4 mg, 0.2 mmol), zinc cyanide (35.1 mg, 0.3 mmol), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.1 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 30% ethyl acetate in hexane afforded 6.9 mg (12%) of 3-(2-pyridyl)-5-(5-cyano-2-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: [S:1]=[C:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:6]2[O:5][C:4](=[O:7])[NH:3][C:2]2=[S:1])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1NC(=S)CO1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)O1
Temperature: 100 °C

Procedure:
A solution containing 0.25 g of 4-thioxo-2-oxazolone 0.38 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.1 ml of piperidine in 5 ml of acetic acid was heated overnight at 100° C. The product was filtered and washed with actic acid. Yield 0.05 g, mp 245° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].ClC(Cl)C.[C:10]([OH:20])(=[O:19])[C:11]1[C:12]([O:17][CH3:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-].[Na+]>>[Cl:1][S:2]([C:15]1[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]([CH:16]=1)[C:10]([OH:20])=[O:19])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 65 %

Procedure:
Chlorosulphonic acid (55 ml) was added over 6 hrs at 20° to a stirred mixture of dichloroethane (72 ml), o-anisic acid (26.8 g) and sodium chloride (10 g). The mixture was warmed to 40° and after a further hour warmed to 65°. The mixture was maintained at 65°-70° for 17 hrs, cooled and poured into ice water (300 g) to give the title compound as a colourless solid (28.7 g; 65%). ##STR16##
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[CH:8]=[C:7]3[CH2:10][CH2:11][CH2:12][CH2:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:2]2[C:1](=[O:14])[C:9]3[CH:8]=[C:7]4[CH2:10][CH2:11][CH2:12][CH2:13][C:6]4=[CH:5][C:4]=3[CH2:3]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1CCc2cc3c(cc21)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(C=C2Cc3cc4c(cc3C2=O)CCCC4)cc1

Procedure:
A solution of 1.84 g (10 mmoles) of 2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one (12), 1.49 g (10 mmoles) of p-dimethylaminobenzaldehyde, and 0.44 g of sodium hydroxide in 25 ml ethanol was stirred under nitrogen at 50° to 60° for 19 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 2-[4-(dimethylamino)phenyl)-methylene]-2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one was collected by filtration and washed with cold ethanol. Yield: 2.5 g (79%); m.p. 161° to 163°. λmax (EtOH): 274 nm (ε=16,700); 422 nm (36,500). Calcd for C22H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.01; H, 7.73; N, 4.34.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4]3=[C:5]([C:19](=[O:23])[C:20](=[O:21])[N:3]13)[CH:6]=[CH:7][CH:8]=2
Reactant: CC1(C)C=C(c2ccccc2)c2ccccc2N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)C=C(c2ccccc2)c2cccc3c2N1C(=O)C3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of 1,2-dihydro-2,2-dimethyl-4-phenylquinoline (5.0 g., 21.2 mMole) in 50 ml. dry methylene chloride was added dropwise with stirring to oxalyl chloride (2.77 g., 22.0 mMole) in 200 ml. dry methylene chloride at 30° C. and protected from moisture. Addition required one hour, and when complete the orange solution was stirred 30 minutes at ambient temperature and two hours at reflux. The solvent was removed at reduced pressure and the purple-brown crystalline residue air dried. A single recrystallization from chloroform/60°-110° C. ligroine produced a solid 3.97 g. (63.5%) melting at 210.5°-212° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(F)cn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (69 mg) in ethyl acetate (1.5 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 31 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][N:42]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:31])[F:29])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:24])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Reactant: BrCCCCCCCc1ccccc1
Product: O=C(CCCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 41 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 7-bromoheptylbenzene, the title compound (25 mg, 41%) was obtained as a white solid, using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.38 (m, 6H), 1.63 (quintet, J=7.3 Hz, 2H), 1.80 (quintet, J=7.0 Hz, 2H), 2.61 (dd, J=7.9, 7.6 Hz, 2H), 3.21 (t, J=7.5 Hz, 2H), 7.16-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.54 (ddd, J=7.6, 4.7, 0.9 Hz, 1H), 7.94 (td, J=7.8,1.8 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.9, 29.0, 29.1, 31.4, 35.7, 35.9, 40.1, 124.0, 125.6, 126.7, 128.2, 128.4, 137.3, 142.6, 142.7, 150.8, 161.2, 165.1, 187.2; MALDI-FTMS m/z 350.1859 (C21H23N3O2+H+ requires 350.1863).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C[Al](C)C.C([O:14][C:15]([C:17]1[S:21][C:20](/[CH:22]=[CH:23]/[C:24]2[C:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:26][O:27][C:28]=2[CH3:29])=[N:19][CH:18]=1)=O)C>O1CCOCC1.C1(C)C=CC=CC=1>[O:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:15]([C:17]2[S:21][C:20](/[CH:22]=[CH:23]/[C:24]3[C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:26][O:27][C:28]=3[CH3:29])=[N:19][CH:18]=2)=[O:14])[CH2:3][CH2:4]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC2CCOCC2)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a stirred solution of 4-aminotetrahydropyran (123 mg, 1.22 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.6 mL of a 2M solution in toluene, 1.2 mmol). After 1 h, a solution of 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.15 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. for 3 h. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 2.5% methanol in dichloromethane) gave the title compound (34 mg, 59%) as a white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][N:21]=2)[C:11]1=[O:29])[CH2:7][CH2:8][CH3:9])C.O.[OH-].[Li+]>C1COCC1.O>[O:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:30])=[O:3])[C:11]2=[O:29])=[N:21]1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2noc3ccccc23)c2ccccc21
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 3-(3-1,2-benzisoxazol-3-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (70 mg, 0.17 mmol) in THF (5 ml) and water (0.5 ml) was added lithium hydroxide monohydrate (22 mg, 0.52 mmol). Upon complete consumption of the starting material, the reaction was concentrated to low volume and diluted with water (20 ml) and acetic acid (0.5 ml). The resulting heterogeneous mixture was stirred for 1 h after which time the precipitated product was collected via filtration. The solid was washed with water and dried on house vacuum at 40° C. (18 h, over P2O5) to give 52 mg (80%) of the desired product. LCMS (ESMS): m/z 380.41 (M+H+).
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[O-:9]P(OP([O-])([O-])=O)(=O)[O-]>>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:9])#[N:7]
Reactant: N#CCCCCC#N
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: N#CCCCCC(N)=O
Temperature: 5 °C
Reaction time: 24 h

Procedure:
Various Pseudomonas strains were grown on 10 mM adipontrile in PR Basal medium for 24 h and harvested by centrifugation. Wet cell pastes were frozen for storage. To test for biocatalyst reaction, 50 mg of frozen cell paste was resuspended in 1 mL of 50 mM pyrophosphate buffer, pH 7.5. Adiponitrile substrate was added to a final concentration of 100 mM and the cell suspensions were shaken at 200 rpm at 5° C. for 4-7 h. Cells were removed by centrifugation and the clarified supernatant was analyzed for the presence of 5-cyanopentanamide by gas chromatography. The following Pseudomonas strains were found to produce the desired product: P. putida 5B-MGN-2p (NRRL-18668), Pseudomonas sp. 3L-H-2-6-1p, P. putida 20-5-SBN-1b (ATCC 55735), P. putida 3L-G-1-5-1a-1 (ATCC 55736), P. chlororaphis B23 (FERM-B187), Pseudomonas sp. 3L-H-9-6-2p, and P. putida 2-H-9-5-1a.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([O:26]C)=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 247.2 %

Procedure:
A mixture of lithium hydroxide (0.5 g) and methyl cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonyl-amino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 58, 0.217 g) in a mixture of dioxane (13 mL) and water (4 mL) was divided between two microwave vials and the mixtures were irradiated in the microwave at 150° C. for 10 minutes. After cooling, the combined mixture was acidified by addition of 10% aqueous citric acid (2 mL), extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylic acid (0.518 g) as a glass.