Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:24]2NN=[N:26][N:25]=2)([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:1]1([C:7]([C:24]2[O:31][C:29]([CH3:30])=[N:26][N:25]=2)([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(CCN2CC3CCC2CC3)(c2cccnc2)c2nnn[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nnc(C(CCN2CC3CCC2CC3)(c2ccccc2)c2cccnc2)o1

Procedure:
α-Phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in toluene to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. This nitrile is reacted with sodium azide in DMF containing lithium chloride to provide 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. Reaction this tetrazole with acetic anhydride in pyridine provides 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, the oxalate salt melts at 171°-172° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]1=[O:16].C(OCC)C>C(OCC)(=O)C>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:16]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCNCC1=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
14 ml of 3M hydrogen chloride in ethyl acetate were added to 3.0 g of the product obtained in step (1) above, and the mixture was stirred at 35° C. for one hour. Diethyl ether was added to the reaction mixture, and the crystals which precipitated out were collected by filtration, washed with diethyl ether and dried, to give 2.1 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33].C(Cl)[Cl:35]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[ClH:35].[ClH:35].[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: C#CCCCC
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: ClCCl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cncc(OC[C@@H]2CCN2)c1
Product: Cl
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (180 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.05 mmol), copper (I) iodide (2 mg) and triethylamine (1.0 mL) in CH2Cl2 (3 mL) was added 1-hexyne (8.3 mL, 0.72 mmol). The mixture was refluxed overnight and cooled to room temperature. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with EtOAc:hexane 1:1 to afford the title compound (102 mg, 56% yield). MS (CI/NH3) m/z 379 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.96 (t, J=6.6 Hz, 3H), 1.43 (s, 9H), 1.46-1.69 (m, 4H), 2.20-2.40 (m, 2H), 2.44-2.56 (m, 2H), 3.83-3.92 (m, 2H), 4.06-4.15 (m, 1H), 4.26-4.38 (m, 1H), 4.45-4.57 (m, 1H), 7.34 (br s, 1H), 7.51-7.58 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>C1COCC1>[Br:25][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2ccc(Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
To a refluxing solution of 0.76 g (2.2 mmol) of 6-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 30 mL of THF was added 0.77 g (4.3 mmol) of N-bromosuccinimide. The resultant mixture was further refluxed for 15 min. The reaction mixture was then poured into an ice-cooled mixture of 20 mL sat. NaHCO3 solution and 20 mL CHCl3. The CHCl3 layer was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, a crude product was obtained which was purified by flash column chromatography on silica with EtOAc/hexane (2:3) as the eluent. This gave 0.73 g (79%) of the title compound as an oil. 1H NMR (DMSO-d6) δ1.42 (d, 3H, CH3), 2 (s, 3H, COCH3), 2.1 (s, 3H, COCH3), 4.2 (quintet, 1H, CH), 5.2 (t, 1H, CH), 5.6 (t, 1H, CH), 6.1 (d, 1H, CH), 7.3 (d, 1H, aromatic), 7.6 (d, 1H, aromatic), 7.82 (s, 1H, aromatic).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C(Cl)CCl>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][N:12]([C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:29]=[CH:30][CH:31]=[C:19]([C:18]([F:17])([F:33])[F:32])[CH:20]=2)[C@H:11]([CH:14]([CH3:16])[CH3:15])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
(2S,4R)-4-(Benzyloxy)-2-isopropylpyrrolidine (0.410 g, 1.90 mmol) was dissolved in dichloromethane (30 mL) under nitrogen. (3-Trifluoromethyl-benzoylamino)-acetic acid (0.462 g, 1.90 mmol) was added followed by EDC (0.394 g, 2.06 mmol) and the mixture was stirred at room temperature-overnight. LC/MS revealed the reaction was not yet complete. More (3-Trifluoromethyl-benzoylamino)-acetic acid (0.12 g, 0.48 mmoles) and more EDC (0.30 g, 1.6 mmoles) were added and stirring continued for 3 hours at room temperature, then at reflux for 1.5 hours. The mixture was chromatographed on silica gel eluting with 30% ethyl acetate/hexane to provide 0.66 g (79%) of the coupled product as a colorless oil. LC/MS (M+H)+ m/z=449.2; 1H NMR (CDCl3) δ 8.03 (m, 1H), 7.76 (m, 1H), 7.58 (m, 2H), 7.34 (m, 5H), 4.52 (m, 2H), 4.03-4.34 (m, 4H), 3.65 (m, 1H), 3.48 (m, 1H), 2.54 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 0.92 (d, 3H), 0.77 (d, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.[C:16]1(=[O:23])[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.C([O-])(=O)C.[NH4+:28]>C(O)C>[CH3:12][C:11]1[NH:28][C:18]2[CH2:19][CH2:20][CH2:21][C:16](=[O:23])[C:17]=2[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[CH:10]=1
Reactant: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CC1=CC(c2cccc(C(F)(F)F)c2)C2=C(CCCC2=O)N1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A mixture of 4-(3-trifluoromethylphenyl)-3-butene-2-one (4.9 g), 1,3-cyclohexanedione (2.68 g), ammonium acetate (2.65 g) and 75 mL of ethanol were heated at reflux for eight hours and then cooled to room temperature. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was dried, filtered, and evaporated to yield a yellow solid. Recrystallization from ethyl acetate provided the title compound (2.8 g) as an off-white solid; mp 184°-185° C.; NMR: 1.74 (s,3, CH3), 1.87-1.98 (m,2, CH2), 2.13-2.19 (m,2, CH2), 2.42-2.49 (m,2, CH2), 4.50 (d,1, J=4.9, CH), 4.63 (d,1, J=4.9, CH), 7.45 (s,4, Ar), 8.53 (s,1, NH); (CI, CH4) MS: m/z=308(M+1). Analysis for C17H16F3NO: Calculated: C, 66.44; H, 5.25; N, 4.56; Found: C, 65.90; H, 5.33; N, 4.43.
Reaction SMILES: [CH2:1]([CH:5]([C:8](=O)[CH3:9])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[Na].[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].C([O-])(=O)C.C(O)(=O)C>O>[C:12]([C:14]1[C:15](=[O:16])[NH:17][C:8]([CH3:9])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)#[N:13]
Reactant: N#CCC(N)=O
Reactant: CCCCC(C=O)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
According to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture of crude sodium 2-butyl-3-oxobutanal (7.39 g), cyanoacetamide (4.15 g, 39 mmol), aqueous piperidinum acetate (3.5 mL) [prepared from glacial acetic acid (0.85 ml), water (2.0 mL) and piperidine (1.45 ml)] in water (32 mL) was refluxed for 3 hours. Acetic acid (2.5 mL) was cautiously added. After cooling to room temperature and stirring overnight, the precipitated solids were collected by filtration. These residues (2.87 g) was chromatographed on silica gel by gradient elution with 1-3% methanol/ethyl acetate. The appropriate fractions were combined and evaporated. Crystallization from methanol gave 1.01 g of pure product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[S:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:5][CH:6]=1)(=[O:10])(=[O:11])[NH2:12]
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: NS(=O)(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
1.3 g (7.3 mmol) of 2-phenylethanesulfonamide was added to 2.4 g (36.5 mmol) of chlorosulfonic acid under ice-cooling over 20 minutes, followed by stirring at room temperature for further 90 minutes. The reaction mixture solution was poured into ice-water, and then extracted with ethyl acetate. The extract was successively washed with an aqueous saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1.6 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(Cl)CCl>[N+:13]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12])([O-:15])=[O:14]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
Next is the mixing of one part 4-tert-butylanisole with between substantially 0-9 parts (by volume) organic solvent such as ethylene dichloride. Next is the cooling of the reaction mixture of 4-tert-butylamine and organic solvent to a temperature below 5° C. This is followed by the adding of 70% concentrated nitric acid while maintaining the temperature of the reaction mixture below 10° C. to produce 2-nitro-4-tertbutylanisole and a 4-nitroanisole byproduct. These are separated by means of vacuum distillation. Specifically, the 4-nitroanisole byproduct has a boiling point of 86° C. while the desired 2-nitro-4-tertbutylanisole has a boiling point of 102°-105° C. at a pressure of 1 mmHg.
Reaction SMILES: [CH:1]12[CH2:8][C:7](=O)[CH2:6][CH:5]1[CH2:4]C(=O)[CH2:2]2.Cl.[NH2:12]O.[CH3:14][C:15]([O-:17])=O.[Na+]>CO>[CH:2]1[CH:14]=[C:15]([OH:17])[C:4]2[N:12]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:1]=1
Reactant: NO
Reactant: CC(=O)[O-]
Reactant: O=C1CC2CC(=O)CC2C1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cccc2cccnc12
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To bicyclo[3.3.0]octane-3,7-dione (0.25 g, 1.81 mmol) in dry MeOH (3 mL) at 0° C. was added hydroxylamine hydrochloride (0.28 g, 4.30 mmol) and NaOAc (0.65 g, 7.92 mmol). After 1 h, the solvent was removed under vacuum. Triturate the resulting residue with a minimum of ice-cold water to give a white precipitate. Collect and dry the precipitate under vacuum to give 0.16 g of the crude oxine.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[C:15]([NH:18][CH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]([F:33])=[CH:31][C:27](C(Cl)=O)=[C:26]([F:34])[CH:25]=2)[CH2:20]1)(=[O:17])[CH3:16].Cl>CCCCCC.O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1.O>[C:15]([NH:18][CH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]([F:33])=[CH:31][C:27]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[C:26]([F:34])[CH:25]=2)[CH2:20]1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(=O)NC1CCC(c2cc(F)c(C(=O)Cl)cc2F)C1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A solution of 26.4 g (0.2 mol) of monoethyl malonate, 0.1 g of 2,2'-bipyridyl and 350 ml of dry tetrahydrofuran was cooled to -35° under a nitrogen atmosphere and treated dropwise with 80 ml (0.2 mol) of a 2.5 M solution of n-butyl lithium in hexane. After the addition was complete, the reaction mixture was allowed to warm to -5° where it was treated dropwise with 80 ml (0.2 mol) of 2.5 M n-butyl lithium in hexane, titrating the final addition to a pale pink color which persisted for 5 minutes. The mixture was cooled to -78° and treated with a solution of 30.2 g (0.1 mol) of 4-[3-(acetylamino) cyclopentyl]-2,5 difluorobenzoyl chloride in 150 ml of dry tetrahydrofuran. The suspension was stirred at -78° for 45 minutes, then allowed to warm to -35° and poured into a mixture of ice, water, and concentrated hydrochloric acid (17 ml-0.20 mol). The organic phase was separated, washed with water, 5% sodium bicarbonate, dilute hydrochloric acid and water. After drying over magnesium sulfate, the solvent was removed in vacuo to give 31.8 g of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])(=O)=O.[C-:23]#[N:24].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH:8]([CH3:9])[CH2:7][CH2:6][C:23]#[N:24])[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: CC(CCOS(C)(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(CCC#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a stirred solution of 3-(4-(4-fluorophenyl) piperazin-1-yl)butyl methanesulfonate (4.5 g, 13.62 mmol) in N,N-dimethylformamide (30 ml) was added potassium cyanide (2.66 g, 40.9 mmol) at 25° C. under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 15 h. Progress of reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (4×50 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get oily compound. The resulting crude compound was purified over silica gel (100-200 mesh) by flash chromatography using 30% ethyl acetate in hexane as an eluent to obtain title compound (2.6 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[O:8]=[O:9]>>[OH:8][OH:9].[CH3:5][N+:4]([CH2:3][CH:2]=[O:1])([CH3:7])[CH3:6]
Reactant: C[N+](C)(C)CCO
Reactant: O=O
Product: C[N+](C)(C)CC=O
Product: OO

Procedure:
Choline oxidase catalyzes the interaction of choline and oxygen to produce hydrogen peroxide and betaine aldehyde;
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][P:28](=[O:31])([OH:30])[OH:29].[BH3-]C#N.[Na+]>CO>[C:1]1([C:7]2[N:12]=[C:11]([CH2:13][NH:24][CH2:25][CH2:26][CH2:27][P:28](=[O:29])([OH:31])[OH:30])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCP(=O)(O)O
Reactant: CCCc1ccc(-c2ccc(C=O)nc2-c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCc1ccc(-c2ccc(CNCCCP(=O)(O)O)nc2-c2ccccc2)cc1

Procedure:
Following General Procedure M, 6-phenyl-5-(4-propylphenyl)pyridine-2-carbaldehyde (Compound 59, 74 mg, 0.25 mmol), (3-amino-propyl)phosphonic acid (34 mg, 0.25 mmol), Bu4NOH (0.25 ml, 0.25 mmol, 1M in MeOH) and NaCNBH3 (15 mg, 0.25 mmol) in MeOH (5 ml) were reacted to produce the title compound as a white solid.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1[O:34][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>P([O-])([O-])([O-])=O.C(#N)C1C=CC=CC=1>[C:13]([NH2:20])(=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
TG1/pNHJ10H and TG1/pNEJ20L were inoculated into 10 ml of 2×YT medium containing 50 μg/ml of ampicillin and incubated at 30° C. overnight (12 hours). 1 ml of the resultant culture was added to 100 ml of 2×YT medium (50 μg/ml of ampicillin, 0.1 g of CoCl2.6H2O/l). The mixture was incubated at 30° C. for 4 hours. IPTG was added to the mixture to a final concentration of 1 mM. The mixture was incubated at 30° C. for 10 hours. After harvesting the cells, the cells were suspended in 5 ml of 0.1M phosphate buffer (pH 7.5). The suspensions were disrupted by sonification for 5 min and centrifuged at 12,000×g for 30 min. The resulting supernatants were used for the enzyme assay. The enzyme assay was carried out in a reaction mixture (12 ml) containing 50 mM potassium phosphate buffer (pH 7.5), 6 mM benzonitrile and an appropriate amount of the enzyme. The reaction was carried out at 20° C. for 30 min and stopped by the addition of 0.2 ml 1M HCl. The amount of benzamide formed in the reaction mixture was determined by HPLC. As a control, the mixture obtained by the same procedure as described above but from E. coli TG1 was used. The levels of nitrile hydratase activity in cell-free extracts of E. coli containing pNHJ10H and pNHJ20L were 1.75×10-3 and 6.99×10-3 units/mg, respectively, when cultured in 2×YT medium in the presence of CoCl2 and IPTG. Benzamide was found in the reaction mixture of TG1/pNHJ10H and pNHJ20L, whereas no benzamide was found in the reaction mixture of TG1. A number of references are cited herein, the disclosures of which are incorporated in their entirities, by reference herein.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:23][Mg]Br.O>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:23])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: C[Mg]Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 500 mg, 1.62 mmol) was dissolved in anhydrous THF (10 mL) and cooled down to 0° C. Methylmagnesium bromide in toluene/THF (1.4 M, 1.27 mL) was slowly added and the RM was then warmed up to rt and stirred for 4 h. Water (2 mL) was added and the precipitate formed was filtered off. The filtrate was concentrated to give the title compound as a brown solid (tR 0.50 min (conditions 2), (MH+=325).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH:13]([CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:13]([CH3:14])[CH2:15][CH2:16][CH:17]([CH3:21])[CH:18]([CH3:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: CC(Br)CCC(C)C(C)C
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OC(C)CCC(C)C(C)C)cc1

Procedure:
By utilizing the procedure of Example 19, by reacting p-hydroxybenzoic acid methyl ester with 2-bromo-5,6-dimethyl heptane, there is obtained p-[(1,4,5-trimethylhexyl)oxy]benzoic acid methyl ester; nD25 = 1.4938.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[CH:12][N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cnc2c(c1)c(-c1cnn(C)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1cnc2[nH]cc(-c3cnn(C)c3)c2c1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 97.3 %

Procedure:
To crude azaindole 62 (118 mg) in EtOH (6 mL) was added 10% NaOH (1 mL) and the mixture was stirred in an oil bath (90° C.) for 4.5 h. The mixture was then cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was partially purified by means of PTLC employing AcOEt as eluent to afford a semi-pure azaindole 63 (74 mg). A fraction (14 mg) of this material was further purified by means of preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give the desired azaindole 63 (5.6 mg, 25%); 1H NMR (400 MHz; CDCl3) δ 0.92 (s, 3H), 0.94 (s, 3H), 1.90 (m, 1H), 2.59 (d, J=7.2 Hz, 2H), 3.98 (s, 3H), 7.36 (d, J=2.1 Hz, 1H), 7.60 (s, 1H), 7.74 (d, J=0.6 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 9.62 (br s, 1H); MS (CI) m/z 255 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])=[O:4].[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].Cl.C(NCC)C>C1C=CC=CC=1.CCOCC>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8])=[O:4])[CH3:17]
Reactant: O=C(CCl)NCC(=O)Nc1ccccc1
Reactant: CCNCC
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCN(CC)CC(=O)NCC(=O)Nc1ccccc1

Procedure:
A solution of chloroacetylglycineanilide (10.0 g; 0.0443 mole) and diethylamine (9.7 g; 0.133 mole) in benzene (125 ml) was heated under reflux for 5 hours. The solution was cooled and diluted with ether (125 ml) whereby a crystalline mixture of diethylamine hydrochloride and N,N-diethylglycylglycineanilide (as base) was obtained. The mixture was shaken with cold water (2 × 100 ml) and the crystalline residue was recrystallized from water-isopropanol. The desired compound melted at 162°-164°C. Yield: 2.6 g (22.3 %).
Reaction SMILES: C1([N:7]=[C:8]=[S:9])C=CC=CC=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH2:18][C:19]1[N:23]=[CH:22][O:21][N:20]=1.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:21]1[CH:22]=[N:23][C:19]([CH2:18][S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]([NH2:7])=[S:9])=[N:20]1
Reactant: Nc1ccccc1SCc1ncon1
Reactant: S=C=Nc1ccccc1
Reactant: c1ccccc1
Product: NC(=S)N(c1ccccc1)c1ccccc1SCc1ncon1

Procedure:
Phenylisothiocyanate (1.31 g) in benzene (10 ml) was added dropwise to a stirred solution of 3-(2-aminophenylthiomethyl)-1,2,4-oxadiazole (20 g) in benzene (10 ml). The resultant solution was refluxed for 3 hours, the solvent removed by evaporation under reduced pressure to give a solid which was re-crystallised from isopropanol to give N-[2-(1,2,4-oxadiazol-3-yl-methylthio)phenyl]-N1 -phenylthiourea, m.p. 128°.