Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.[C:22]1(=[O:29])CCCC[CH:24]=[CH:23]1>CCOCC.[Cu]I>[CH2:16]([C@H:11]1[CH2:3][CH2:4][CH2:24][CH2:23][C:22](=[O:29])[CH2:12]1)[CH2:15][CH2:14][CH3:13]
Reactant: O=C1C=CCCCC1
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[C@H]1CCCCC(=O)C1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (348.4 mg, 1.60 mmol) was dissolved in ether (12 mL) and n-butyl lithium (2.5M in hexanes, 0.61 mL, 1.53 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., gradually (for 20 min) warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (254 mg, 1.33 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.51 mL, 1.28 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 30 min, 2-cycloheptenone (141 mg, 1.28 mmol) was added slowly at -78° C. The reaction mixture was quenched after 1 hr by adding 4N NH4Cl (15 mL) at -78° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (10:1=hexanes/ethyl acetate) to afford (S)-3-n-butylcycloheptanone (136 mg, 63% chemical yield, 96% ee, [α]D =-33.0 (c= 3.2, chloroform)).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Cl>CO>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:1])([CH3:13])[CH3:12])=[CH:6][CH:7]=1
Reactant: COC(CCl)OC
Reactant: CC(C)(O)C(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(COc1ccc(C(=O)C(C)(C)O)cc1)OC

Procedure:
10 g (55.5 mmol) of 2-hydroxy-1-(4-hydroxyphenyl)-2-methylpropan-1-one are dissolved in 50 g of methanol together with 2.22 g (55.5 mmol) of NaOH, and kept at 150° C. for 5 hours in a bomb tube with 20 g of chloroacetaldehyde dimethyl acetal. The reaction mixture is evaporated, and the residue is dissolved in ether and washed with 0.1 N NaOH. The crude product (14.8 g) is crystallized from ether/petroleum ether, giving 9.8 g (65% of theory) of a beige product of m.p. 52-53° C.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([S:13](Cl)(=O)=O)[C:8]([CH3:12])=[CH:9][C:10]=1[F:11])[C:2]([CH3:4])=[O:3].II>C(O)(=O)C>[NH:1]([C:5]1[C:10]([F:11])=[CH:9][C:8]([CH3:12])=[C:7]([SH:13])[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1cc(S(=O)(=O)Cl)c(C)cc1F
Agent: II
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(S)c(C)cc1F

Procedure:
3-Acetamino-4-fluoro-6-methyl-phenylsulfonylchloride (500 g, 1.89 mol) was dissolved in 2 L of acetic acid. Red phosphorus (100 g, 3.22 mmol) and iodine (10 g, 39 mmol) were added to the solution, and the mixture was refluxed for 3 hours. The acetic acid was removed under reduced pressure, water was added and the residue extracted with ethyl acetate. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to give 5-acetamino-4-fluoro-2-methyl-benzenethiol as a crude intermediate (270 g, 72%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].[Li][CH3:17].[NH4+].[Cl-].O>C1COCC1>[NH:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4](=[O:5])[CH3:17])[C:14]=2[N:13]=[CH:12]1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1cccc2[nH]cnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc2[nH]cnc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide (742 mg, 3.62 mmol) in THF (36 mL) at −78° C. was added MeLi (1.6M; 2.49 mL, 3.98 mmol) dropwise. The mixture was stirred at −78° C. for 2 hours before an additional 1.0 mol. eq. MeLi (2.3 mL) was added dropwise. The mixture was stirred at −78° C. for a further 2 hours before saturated aqueous NH4Cl solution was added and the mixture warmed to room temperature. Enough water was added to dissolve all solids and the phases were separated. The aqueous phase was extracted into CHCl3 (×3), dried and concentrated in vacuo to give a white solid. Trituration with EtOAc (5 mL) followed by collection by filtration and washing with 4:1 Et2O/EtOAc (5 mL) provided 1-(1H-benzoimidazol-4-yl)-ethanone (487 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1.[C:35](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]2[CH3:35])=[C:4]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(-c3ccc(F)cc3)[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccc(F)cc2)nc2c(N3CCN(C(=O)COc4ccc(Cl)cc4)CC3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of 2-amino-6-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]-8-(4-fluorophenyl)-9H-purine (48 mg, 0.1 mmol) in DMF (2 ml) was added potassium carbonate (28 mg, 0.2 mmol) and methyl iodide (6 μl, 0.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:50), yielding the pure title compound (40 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[C:15]2=[O:20])[C@H:10]([CH2:21][CH2:22][CH3:23])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([Cl:43])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[Cl:43][C:40]1[CH:41]=[C:42]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][N:34]=[C:33]2[NH:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:11]2[CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:24])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][C@H:10]2[CH2:21][CH2:22][CH3:23])[C:15]1=[O:20]
Reactant: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(Cl)cc23)C1=O
Temperature: 80 °C

Procedure:
Examples 2r and 2s, Step 1: A solution of (1R,3R,4S)-{4-[(3S)-3-amino-2-oxo-pyrrolidin-1-yl]-3-propyl-cyclohexyl}-carbamic acid tert-butyl ester (0.66 mmol) in EtOH (8 mL) was charged with triethylamine (0.5 mL, 3.3 mmol) and 4,6-dichloroquinazoline (200 mg, 1.0 mmol) before being heated at 80° C. for 12 h. The reaction mixture was cooled and purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-(6-chloroquinazolin-4-ylamino)-2-oxopyrrolidin-1-yl)-3-propylcyclohexylcarbamate. MS found: (M+H)+=502.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37]C(=O)C(F)(F)F.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[NH2:37][CH2:36][CH2:35][O:34][C:21]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:19]([Cl:33])[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: O=C(NCCO)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (49 mg, 0.30 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask and heated at reflux for 48 hours under an N2 atmosphere. Analysis after overnight reaction showed only partial conversion, so additional N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (33 mg, 0.21 mmol) and sodium hydride (60% dispersion in mineral oil, 25 mg, 1.03 mmol) were added and the vessel was resealed and heated at reflux for an additional 48 hours. The reaction solution was then cooled to room temperature, diluted with EtOAc, transferred to a separatory funnel, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H24Cl2N4O2, 518.1; m/z found, 519.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.69 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H), 7.39-7.33 (m, 6H), 6.26 (s, 1H), 4.67-4.60 (m, 2H), 3.47 (s, 3H), 3.20 (t, J=5.3 Hz, 2H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[CH:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([CH2:20][C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: N#CC=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Yield: 99.2 %

Procedure:
(7-Benzenesulfonyl-chroman-4-ylidene)-acetonitrile (395 mg, 1.27 mmol) was dissolved in 4 mL EtOAc and placed in a Parr flask containing 40 g of Pd (10% wt) on carbon. The flask was sealed and shaken overnight under 50 psi of hydrogen. The Pd/C was removed by filtration and the solvent was evaporated under reduced pressure to afford 397 mg (1.26 mmol, 99%) of (7-benzenesulfonyl-chroman-4-yl)-acetonitrile. MS: 314 (M+H)+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH3:35])[C:14](=[O:34])[C:15]4[CH:25]=[C:24]([CH2:26][CH2:27][C:28]5[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=5)[CH:23]=[N:22][C:16]=4[N:17]([CH2:20][CH3:21])[C:18]=3[N:19]=2)=CC=1.FC(F)(F)C(O)=O>>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([CH3:35])[C:14](=[O:34])[C:15]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH:23]=[N:22][C:16]=3[N:17]([CH2:20][CH3:21])[C:18]=2[N:19]=1
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(NCc3ccc(OC)cc3)nc21
Solvent: O=C(O)C(F)(F)F
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(N)nc21
Reaction time: 5 h
Yield: 71.2 %

Procedure:
2-(4-methoxybenzylamino)-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.09 g, 0.18 mmol) was treated for 20 h with trifluoroacetic acid (1 mL) under argon. After removal of excess TFA, the residue was stirred in dilute ammonium hydroxide for 5 hours. The product was extracted with ethyl acetate and purified by flash chromatography (elution with methanol-dichloromethane) to give the title compound (48 mg, 71%), m.p. 94°-97° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:16]([NH:18][CH:19]([CH3:21])[CH3:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:16]([N:18]([CH:19]([CH3:21])[CH3:20])[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)SCCCCl)cc1
Reactant: CCNC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCSS(=O)(=O)c1ccc(C)cc1)C(C)C

Procedure:
Toluene-4-thiosulfonic acid S-(3-chloro-propyl) ester (12.0 g, 45.3 mol, 1.00 eq.), N-ethylisopropylamine (4.2 g, 48.0 mmol, 1.05 eq.) and potassium carbonate (6.9 g, 49.9 mmol, 1.10 eq.) were stirred together in acetonitrile (160 mL) at 60° C. for 18 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic solution was washed with brine (250 mL), dried (MgSO4) and the resulting oil was purified by MPLC chromatography to give an oil weighing 2.98 g (21%).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:21]1([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)COC2)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3(F)COC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 131b) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 66e) as starting materials and isolated (42 mg, 54%); MS (ESI, m/z): 459.6 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1.Cl.[N:24]1C=CC=C[CH:25]=1>>[C:25]([C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1)#[N:24]
Reactant: Brc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12
Reactant: c1ccncc1
Agent: Cl
Product: N#Cc1cc(-c2ccccc2)cc2c(-c3ccccc3)coc12

Procedure:
A mixture of 64 g. (0.18 mole) of the product of step B, 17.8 g. (0.2 mole) of cuprous cyanide and 35 ml. of pyridine is heated under a nitrogen atmosphere at 150° to 160° C. for one day. The mixture is poured into 1 liter of 3 N hydrochloric acid, extracted with 1 liter of dichloromethane, and the extracts are dried. Evaporation provides a residue which is chromatographed on silica gel, eluting with dichloromethane, to provide 7-cyano-3,5-diphenylbenzofuran as a pale yellow solid. The structural assignment is supported by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:2][CH:3]=1)[O:13][CH2:10][C:2]1[CH:9]=[C:8]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:7]=[CH:4][CH:3]=1)#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#Cc1cccc(OCc2cccc(-c3cccc(C#N)c3)c2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A solution of 500 mg of “B” and 238 mg of 3-hydroxybenzonitrile in 10 ml of acetonitrile is treated with 652 mg of caesium carbonate and stirred at room temperature for 40 hours. After customary working up, the residue is chromatographed on a reversed-phase column using acetonitrile/water 65:35. 3′-(3-Cyanophenoxymethyl)biphenyl-3-carbonitrile (“C”), FAB 311, is obtained as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]([OH:13])[CH2:11][CH3:12]>>[CH2:10]([O:13][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCCO
Product: CCCOc1ccc(N)cc1

Procedure:
The method of claim 1 wherein nitrobenzene is reacted with propanol to form p-propoxyaniline.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1ncc(Cl)nc1Br
Reactant: COc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(Cl)nc2Br)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A mixture of 3-bromo-5-chloropyrazin-2-amine (624 mg, 2.99 mmol, Ark Phar. Inc), 6-methoxypyridin-3-ylboronic acid (1374 mg, 8.98 mmol, Combi. Blocks), copper (II) acetate (896 mg, 4.49 mmol, Aldrich, St. Louis, Mo.), and N,N-diisopropylethylamine (2.083 mL, 11.97 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (20 mL) was stirred at room temperature for 48 h. The mixture was filtered through a pad of Celite® (diatomaceous earth) and washed with EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to give 3-bromo-5-chloro-N-(6-methoxypyridin-3-yl)pyrazin-2-amine (165 mg, 0.523 mmol, 17.47% yield). 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H) 6.79 (d, J=8.77 Hz, 1H) 6.92 (s, 1H) 7.77 (dd, J=8.84, 2.41 Hz, 1H) 8.01 (s, 1H) 8.29 (d, J=2.05 Hz, 1H). m/z (ESI, +ve ion) 316.9 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][O:10][C:11]2=[O:21])[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH:6]=[CH:5][C:4]4[C@:17]3([CH3:20])[CH:18]=[CH:19][C:2](=[O:1])[CH:3]=4)[C@@H:8]1[CH2:9][O:10][C:11]2=[O:21]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)OC[C@@H]12
Yield: 49 %

Procedure:
A mixture of 100 mg of 3β-hydroxy-16-oxaandrost-5-en-17-one, 370 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 10 ml of dioxane was refluxed overnight. After completion of the reaction, the insoluble matters were removed by filtration, and the filtrate was flowed into an activated alumina layer and eluted with methylene chloride. The solvent was distilled out, and the resultant crude product was purified by TLC [developing solvent; chloroform: acetone (19:1)] to obtain 48 mg of 16-oxaandrosta-1,4,6-triene-3,17-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12](/[CH:13]=[N:14]\[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:13](/[Cl:18])=[N:14]\[OH:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccc(OCc2ccccc2)cc1
Product: O/N=C(/Cl)c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To (Z)-4-(benzyloxy)benzaldehyde oxime (11.3 g) in N,N′-Dimethyl formamide (57 ml), N-Chlorosuccinimide (7.98 g) was added and the reaction mixture was stirred for 3 hours and then solvent was evaporated to dark brown residue. To this residue water was added and extracted with Ethyl acetate. Organic layer was collected and dried over Na2SO4 and concentrated to obtain pale brown solid, which was crystallized from DCM-Petroleum ether to obtain the title compound as white solid. Yield: 7.9 g (60%); 1HNMR (DMSO-d6; 300 MHz): δ 12.17 (s, 1H), 7.73 (d, 2H), 7.33-7.47 (m, 5H), 7.11 (d, 2H) 5.16 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([OH:13])[CH3:12]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:13][CH2:11][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)c1ccc(F)cc1

Procedure:
A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100% ethanol is refluxed for 15 minutes. 35 g of the ethyl 4-fluorobenzoate obtained are mixed with 22 g of imidazole and 61 g of potassium carbonate in 35 ml of DMSO. The mixture is heated for 18 hours at 120°-130° C. and 500 ml of iced water are then added. A precipitate forms and the expected product crystallizes from iso ether.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[CH3:20][O:21][C:22](=[O:29])[CH:23](Br)[CH2:24][CH2:25][CH2:26][Br:27]>>[CH3:20][O:21][C:22](=[O:29])[CH:23]([N:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:18])[F:19])[CH:5]=2)[CH2:11][CH2:12]1)[CH2:24][CH2:25][CH2:26][Br:27]
Reactant: COC(=O)C(Br)CCCBr
Reactant: O=C1CCN(c2cccc(OC(F)(F)F)c2)CCN1
Product: COC(=O)C(CCCBr)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Yield: 92 %

Procedure:
In analogy to the procedure described in example 15B, 1-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-5-one and (rac)-2,5-dibromo-pentanoic acid methyl ester gave the title compound in 92% yield as colorless oil. MS: 469.1 (1Br, MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Li+].[Cl-].[I:14]I>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[C:7]=1[I:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(I)c1F
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
2,4-Difluoro-1-nitrobenzene 15 (159 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 45 min according to TP 2. I2 (381 mg, 1.5 mmol) dissolved in dry THF (2 mL) was then dropwise added and the resulting mixture was stirred for 0.5 h. The reaction mixture was quenched with a sat. aq. Na2S2O3 solution (10 mL) and with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 17c (256 mg, 90%) as a colourless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1([CH:28]2[CH2:30][O:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:29][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:30][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)c3ccccc3)CC1)O2

Procedure:
Compound 167 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-phenyloxirane and conditions outlined in procedure X. M.p.=193-195° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.09-7.75 (m, 3H), 7.6-7.5 (m, 1H), 7.4-7.2 (m, 5H), 5.03 (br. s, 1H), 4.93 (br. s, 1H), 3.07 (s, 2H), 2.9-2.78 (m, 2H), 2.65-2.45 (m, 4H), 2.05-1.7 (m, 4H); LCMS: 422 [M+H].