Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(O)(O)O.C1N2CN3CN(C2)CN1C3.[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1O)([CH3:18])[CH3:17].OS(O)(=O)=O.C(O)[CH2:36][OH:37]>>[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)[CH:36]=[O:37])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: OCCO
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Temperature: 149 °C
Reaction time: 0.5 h

Procedure:
3.5 g of boric acid was heated in 150 ml of ethylene glycol at 150° C. for 30 minutes, in a 500 cc flask equipped with a reflux condenser. 25 g of hexamethylenetetramine and 21 g of 2,6-bis(1,1-dimethylethyl)phenol were then added and the solution maintained at 148-150° C. for 15 minutes. After cooling to 125° C. at which stage the first crystals appeared, 150 ml of H2SO4 (30%0 was added and stirring was continued for another 30 minutes. The resulting slurry was filtered and washed with warm water. After drying, 22 g of 3,5-bis(1,1-dimethylethyl)benzaldehyde was obtained.
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]>C1COCC1.[Pd]>[C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC(=O)N(C)c1ccc(N)cc1

Procedure:
The reaction is carried out using an analogous method to (9b), using N-propionyl-N-methyl-4-nitroaniline (10a)(6.8 g, 32.86 mmol), 10%Pd on carbon (447 mg) in THF (75 ml). The hydrogenation yields an oil. ES+ (M+1) 178.87.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][OH:29].Cl.[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20](/[C:23](=[N:28]/[OH:29])/[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NO
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.5, 491 mg, 1.390 mmol) in methanol (30 mL) was added hydroxylamine hydrochloride (140 mg, 2.015 mmol), followed by hydrochloride dropwise to give a pale yellow clear solution. The reaction mixture was stirred at it overnight. LCMS showed the reaction was complete. Aqueous NaOH (1N) solution was added at 0° C. until pH 8-9. Solvent was evaporated, and the residue was purified by column chromatography to afford 410 mg (88% yield) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 8.22 (d, 1H), 7.57-7.71 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS (method A): [MH]+=369, tR=5.45 min.
Reaction SMILES: CO.C[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[C:8]([Cl:14])[CH:7]=1.[BH4-].[Na+].C(O)(C)(C)C>O>[Cl:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([Cl:14])[C:9]=1[NH2:13])[CH2:5][OH:4]
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1c(Cl)cc(CO)cc1Cl
Yield: 92.7 %

Procedure:
Methanol (400 ml) was added dropwise over 2 hours to a mixture of methyl-3,5-dichloro-4-aminobenzoate (110 g), NaBH4 (142.5 g) and t-butanol (1.1 L). At the end of the addition, the mixture was refluxed 3 hours, cooled, then H2O (1.2 L) was carefully added. The resulting layers were separated and the organic phase was washed with H2O (2×200 mL), separated, dried (MgSO4), filtered and evaporated to afford the desired product (89 g), mp 110-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH:16]2[CH:14]([CH2:15]2)[CH2:13]1.[Cl-].[NH4+].N1C=CC=CC=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(O)C.O.ClCCl.[Fe]>[CH2:30]([O:29][C:27](=[O:28])[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:12]2[CH2:17][CH:16]3[CH:14]([CH2:15]3)[CH2:13]2)=[C:4]([F:11])[CH:5]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=[N+]([O-])c1cc(F)c(N2CC3CC3C2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(F)c(N2CC3CC3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Iron metal (0.120 g, 2.15 mmol) was added in five portions over 1 h to a refluxing solution of 3-(2,6-difluoro-4-nitro-phenyl)-3-aza-bicyclo[3.1.0]hexane (0.172 g, 0.72 mmol) and ammonium chloride (0.385 g, 7.2 mmol) in 6.0 mL of 2:1 ethanol-H2O. The rust colored mixture was refluxed for another 30 min and then cooled and filtered to remove iron oxide. H2O was added to the filtrate and the mixture concentrated to remove ethanol. The resulting aqueous solution was extracted with three 20 mL portions of ethyl acetate and the combined organic phases washed with H2O, brine, and dried (MgSO4). Filtration and concentration gave the crude amine (0.145 g, 0.69 mmol) which was dissolved in 5.0 mL of dichloromethane. Pyridine (0.111 mL, 1.38 mmol) was added to the amine solution and after cooling to 0° C., benzyl chloroformate (0.113 mL, 0.79 mmol) was added. The mixture was stirred for 30 min at 0° C. and for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane and washed with H2O, brine and then dried (MgSO4). Concentration gave a yellow oil that was triturated with hexane to afford [4-(3-aza-bicyclo[3.1.0]hex-3-yl)-3,5-difluoro-phenyl]-carbamic acid benzyl ester as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:10])=[O:9].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([S:28]([O-:30])=[O:29])[CH:22]=[CH:21]3)=[CH:14][CH:13]=1.[Na+]>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([S:28]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[S:8]([CH3:10])=[O:9])(=[O:30])=[O:29])[CH:24]=3)[CH:19]=2)=[CH:14][CH:13]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: CS(=O)c1ccccc1I
Agent: [Na+]
Product: CS(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
The title compound was prepared from 1-iodo-2-(methylsulfinyl)benzene (Step 1) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (prepared according to the method of Example 6 Steps 1-3). 1H NMR (500 MHz, CDCl3) δ 8.61 (1H, s), 8.31 (1H, d, J=7.8 Hz), 8.21 (1H, d, J=7.8 Hz), 8.06 (1H, d, J=8.5 Hz), 8.01 (1H, s), 7.97 (1H, d, J=8.7 Hz), 7.88-7.82 (3H, m), 7.71-7.65 (3H, m), 7.19 (2H, t, J=8.6 Hz), 3.03 (3H, s); m/z (ES+) 425 [MH+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([OH:19])[CH:18]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:18]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1cncc(Cl)c1
Product: Cc1cc([N+](=O)[O-])ccc1Oc1cncc(Cl)c1
Yield: 81.9 %

Procedure:
2-Fluoro-5-nitrotoluene (5.08 g) and 3-chloro-5-hydroxypyridine (4.25 g) were combined at 80° C. using a method similar to that of Example 21.2 to provide 7.1 g of 2-(3-chloro-5-pyridyloxy)-5-nitrotoluene. mp 80-82° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[C:17]([CH:27]([OH:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:16][N:15]=1
Reactant: O=Cc1ccccn1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccn1)c1cnc(Cl)nc1Cl
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a 1.6 M solution of n-butyl lithium in hexane 19.3 ml is dropped over a period of 10 minutes a solution of diisopropylamine 3.1 g in tetrahydrofuran 80 ml in a dry ice-acetone bath and the mixture is stirred for 30 minutes. To the mixture is dropped over a period of 2.5 hours a solution of 2,4-dichloropyrimidine 2 g in tetrahydrofuran 70 ml and the mixture is stirred at the same temperature for 1 hour. To the mixture is dropped pyridine-2-aldehyde 2.2 g in tetrahydrofuran 20 ml over a period of 50 minutes, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into a 10% aqueous citric acid solution and the organic layer is separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; chloroform:methanol=10:1, hexane:ethyl acetate=3:2, hexane:ethyl acetate=2:1) to give crude 2,4-dichloro-5-[(hydroxy)(2-pyridyl)methyl]pyrimidine 480 mg.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12](OCC)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].COCC1CC2C=C(C(OCC)=O)C=CC=2O1.II>O1CCCC1.C(OCC)(=O)C.CCCCCC>[OH:1][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Agent: CCOC(=O)c1ccc2c(c1)CC(COC)O2
Agent: II
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1ccc2c(c1)CC(CO)O2
Yield: 83.2 %

Procedure:
Reduction of 444 mg (2 mmole) ethyl 2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate, Preparation A, Part (iii), in 15 ml tetrahydrofuran with lithium aluminum hydride, 155 mg (4 mmole), by the method of Preparation A, Part iv), afforded 0.3 g of 2,5-bis-hydroxymethyl-2,3-dihydrobenzofuran as an oil, TLC 1:2 ethyl acetate/hexane, Rf 0.2, iodine positive. 1H-NMR(CDCl3)ppm(delta): 3.6 (CH2OH at 2-position), 4.6 (CH2OH at 5-position).
Reaction SMILES: C12CC1CNC2.C12CC1CNC2C(O)=O.[C@@H:16]1([C:22]([OH:24])=O)[CH2:18][C@@H:17]1[C:19](O)=[O:20].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:22](=[O:24])[CH:16]2[CH:17]([CH2:18]2)[C:19]1=[O:20])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)[C@H]1C[C@H]1C(=O)O
Reactant: NCc1ccccc1
Agent: C1NCC2CC12
Agent: O=C(O)C1NCC2CC21
Product: O=C1C2CC2C(=O)N1Cc1ccccc1

Procedure:
3-Azabicyclo(3.1.0)hexane, a precursor for preparing 3-azabicyclo(3.1.0)hexane-2-carboxylic acid, a plant gametocide, is prepared by (a) treating cis-1,2-cyclopropanedicarboxylic acid with benzylamine, to form 3-(benzyl)-3-azabicyclo(3.1.0)hexane-2,4-dione, (b) selectively reducing the dione to 3-(benzyl)-3-azabicyclo(3.1.0)hexane, and (c) hydrogenolysis of that compound to 3-azabicyclo(3.1.0)hexane.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:19]([CH3:20])[S:16]([C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)=[CH:28][CH:29]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(-c5ccc(S(=O)(=O)N(C)C)cc5)cccn4n3)cc2)CC1

Procedure:
4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (150.0 mg, 0.7041 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (210.0 mg, 0.6748 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a tan solid (0.074 g, 34%). MP=188-190° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.4 Hz, 1H), 8.38 (d, J=8.2 Hz, 2H), 7.88-7.82 (m, 3H), 7.03 (t, J=6.8 Hz, 1H), 6.21 (br s, 2H), 2.66 (s, 6H). MS=318 (MH)+. 54b) N,N-Dimethyl-4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-benzenesulfonamide was prepared from 4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N,N-dimethyl-benzenesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (75.0 mg, 0.294 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (48.0 mg, 0.0878 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.034 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.45 (d, J=6.7 Hz, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.91 (d, J=7.8 Hz, 2H), 7.63 (d, J=6.3 Hz, 1H), 7.49 (d, J=7.8 Hz, 2H), 7.00-6.95 (m, 3H), 6.69 (s, 1H), 3.20-3.15 (m, 4H), 2.78 (s, 6H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:26])=[C:11]([C:15]2[O:16][C@H:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][N:19]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:26][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[CH:12][C:11]=1[C:15]1[O:16][C@H:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][N:19]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
To a solution of 2-(3-tert-butyldimethylsilyloxy-2-fluorophenyl)-4,5-dihydro-5(R)-phenyloxazole (2.2 g, 5.8 mmol) in THF (20 ml) was added dropwise tetrabutylammonium fluoride (1M in THF, 7 ml). The reaction mixture was stirred at ambient temperature for 10 min., volatiles removed by evaporation and the resulting residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (3:2) to afford the title compound (1.3 g, 86%) as colorless solids.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][C:11]1[S:15][C:14]([O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=[O:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([NH:9][CH2:10][C:11]1[S:15][C:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)s2)cc1
Temperature: 0 °C
Yield: 75 %

Procedure:
Combine 4-[5-(phenethylamino-methyl)-thiophen-2-yloxy]-benzonitrile ((139 mg, 0.415 mmol), K2CO3 (powder, 28 mg, 50 mol %) and DMSO (4 mL). Cool down to 0° C. Add hydrogen peroxide (0.124 mL) dropwise. Stir the resulting reaction mixture for 2.5 h. Partition the reaction mixture between H2O (5 mL) and CH2Cl2 (3×5 mL). Dry over sodium sulfate, filter and concentrate. Purify the residue through an SCX column with ammonia (2.0 M in methanol) to provide 105 mg (75%) of the title compound. Mass spectrum (ion spray): m/z=353.0 (M+1). 1H NMR (Cl3CD): 7.80 (d, J=8.7 Hz, 2H), 7.34-7.22 (m, 5H), 7.12 (d, J=8.7 Hz, 2H), 6.65 (d, J=3.37 Hz, 1H), 6.44 (d, J=3.7 Hz, 1H), 5.96 (bs, 2H), 3.93 (s, 2H), 2.97 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.5 Hz, 2H).
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][Mg]Br>[Pd]>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:18][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: Fc1ccc(C[Mg]Br)cc1F
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(F)c1

Procedure:
The title compound was synthesized from methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.60 g, 3.35 mmol) was reacted with 3,4-difluorobenzylmagnesium bromide (0.25 M in diethyl ether, 33.5 mL, 8.4 mmol) according to General Procedure 3. The resulting olefin was then converted to the title compound by hydrogenation according to General Procedure 6 (5% Pd on carbon). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane to afford the title compound: 0.100 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.18 (m, 1 H) 2.48-2.64 (m, 1H) 2.64-2.83 (m, 4H) 3.27 (quin, J=7.00 Hz, 1H) 3.81 (s, 3H) 6.29-6.41 (m, 1H) 6.89 (ddd, J=6.19, 4.14, 2.03 Hz, 1H) 6.94-7.14 (m, 2H) 9.01 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[OH:19])[CH:3]=1.Br[CH2:21][CH2:22][F:23].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[O:19][CH2:21][CH2:22][F:23])[CH:3]=1
Reactant: FCCBr
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCF
Yield: 99.5 %

Procedure:
4-Chloro-2-(3-formyl-2-hydroxyphenoxy)benzonitrile (0.29 g, 1.1 mmol), 1-bromo-2-fluoroethane (0.20 mL, 0.34 g, 2.7 mmol) and cesium carbonate (0.41 g, 1.3 mmol) were heated with stirring in dry DMF (5 mL) at 50° C. for 23 h. The reaction mixture was cooled, poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separate d, washed with 1N sodium hydroxide solution (3×), water (4×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-[2-(2-fluoroethoxy)-3-formylphenoxy]benzonitrile (0.35 g) as a tan solid, which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=2)[CH:16]=1)[CH2:12][CH3:13])(C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH:39][C:23]2[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][NH2:7])[C:26]([F:27])=[CH:25][N:24]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1cccc(-c2nc(Cl)ncc2F)c1
Reactant: NCCc1cccc(Cl)c1
Product: CCN(CCCN)Cc1cccc(-c2nc(NCCc3cccc(Cl)c3)ncc2F)c1

Procedure:
Intermediate 78 was coupled with 2-(3-chloro-phenyl)-ethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 442. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.30 (d, 1H), 8.18 (s, 2H), 7.66 (m, 2H), 7.12 (m, 4H), 4.49 (s, 2H), 3.63 (t, 2H), 3.24 (m, 4H), 2.98 (t, 2H), 2.90 (t, 2H), 2.08 (m, 2H), 1.36 (t, 3H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]4[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=4)[O:18][N:17]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(CNc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(CNc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 20.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylaminomethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 73-1-6 and 3-ethynyl-pyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (104 μL, 0.748 mmol). This mixture was stirred for 7 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1 to 1:2 ˜ethyl acetate) to obtain the title compound (26 mg, 13%).
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12].[CH:14]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[CH:14]1([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#CCCC(=O)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: C#CCCC(=O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of pent-4-ynethioic acid S-pyridin-2-yl ester (17.9 g, 94 mmol), dissolved in THF (900 mL) cooled to −78° C. was added cyclopentylmagnesium bromide (2.0 M, 94 mL, 188.5 mmol). The reaction was stirred for 15 minutes, and then warmed to −50° C. The reaction was poured into 500 mL 1 N HCl and the layers were separated. The aqueous layer was extracted with 2×200 mL diethyl ether and the organic layers were combined. The organics were then washed with 300 mL of 1 N NaOH. The organic layer was dried over Mg SO4, and the solids were removed by filtration. The solvent was removed by rotary evaporation to give the desired compound (14.0 g, 99% yield). 1H NMR (CDCl3) δ: 1.54-1.87 (m, 8H), 1.94 (t, J=2.65 Hz, 1H), 2.45 (dt, J1=7.33 Hz, J2=2.78 Hz, 2H), 2.71 (t, J=7.58 Hz, 2H), 2.87 (p, J=7.96 Hz, 1H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7](=O)[CH2:8][N+:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.Cl.[NH2:24]O>O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:7]2[N:24]=[C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:9]3[CH:8]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: NO
Reactant: COc1cccc(C(=O)C[n+]2cccc3ccccc32)c1
Agent: Cl
Agent: [Br-]
Solvent: O
Product: COc1cccc(-c2cn3c(ccc4ccccc43)n2)c1

Procedure:
In a steel bomb having an internal glass coating, 9.34 g. of 1-(3-methoxyphenacyl)quinolinium bromide is heated at 130° C. for 24 hours together with 2.17 g. of hydroxylamine hydrochloride dissolved in 39 ml. of water. After cooling, the resulting solid precipitate is boiled with 60 ml. of water and recovered by filtration. The solid product is suspended in 50 ml. of water and concentrated ammonium hydroxide is added to the suspension. The mixture is extracted with dichloromethane and the organic extract is evaporated to dryness. By crystallization from methanol, 4.5 g. of the title product is obtained which melts at 129°-31° C.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](O)(=[O:10])[C:7]([CH3:9])=[O:8].N1C=CC=CC=1.COC(Cl)Cl>C(Cl)Cl>[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:10])[C:7]([CH3:9])=[O:8]
Reactant: CC(C)(C)O
Reactant: CC(=O)C(=O)O
Agent: COC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl pyruvate was prepared as follows: tert-butyl alcohol (444 mg, 6 mmol) and pyruvic acid (528 mg, 6 mmol) were dissolved in methylene chloride (30 mL) and cooled on an ice bath. Pyridine (948 mg. 0.97 mL, 12 mmol) was added, followed by addition of 1,1-dichloromethyl methyl ether (690 mg, 0.53 mL, 6 mmol). The reaction mixture was stirred for 1 h on an ice bath, warmed to room temperature and washed with 30 mL of 5% aqueous HCl, 30 mL of saturated aqueous NaHCO3, and 30 mL of saturated aqueous NaCl. The organic layer was dried over anhydrous MgSO4, filtered and solvent removed on a rotary evaporator to give tert-butyl pyruvate in quantitative yield, slightly contaminated with methylene chloride (as 1H NMR). Aliquots used for biological analyses were cleared of methylene chloride by short path vacuum distillation.