Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([O:23]CC)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[CH2:35][N:34]([CH3:39])[CH2:33]2>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:28]([CH3:27])[CH2:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[CH2:35][N:34]([CH3:39])[CH2:33]4)=[O:23])=[N:18][N:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc2c(c1)CN(C)C2
Reactant: CCOC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc4c(c3)CN(C)C4)o2)c(C)c1
Temperature: 0 °C

Procedure:
Ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.081 mmol) and N-methyl-1-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)methanamine (29 mg, 0.162 mmol) were dissolved in DCE (5 mL) and stirred at 0° C. prior to being degassed with N2. Trimethylaluminium (2M in toluene, 80 μl) was added dropwise to this solution. Upon completion of addition, the reaction was heated to 60° C. and stirred for 1 h. The reaction was cooled, and saturated aqueous NaHCO3 (10 mL) was added. The aqueous layer was extracted with DCM (3×10 mL) and the combined organic extracts dried over Na2SO4 and concentrated in vacuo. The resulting brown oil was purified by FCC, eluting with 99:1 DCM:7M NH3 in MeOH followed by purification using prep method D to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)(=[O:3])[NH2:2].Cl>C(O)C>[NH:12]1[CH2:13][CH2:14][CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(N)=O)C1
Agent: Cl
Solvent: CCO
Product: NC(=O)c1ccccc1C1CCNC1
Reaction time: 20 h

Procedure:
Tert-butyl 3-(2-carbamoylphenyl)pyrrolidine-1-carboxylate, enantiomer 1 a1-5 (2.5 g, 8.61 mmol, 1 eq) is dissolved in ethanol (100 ml). A saturated solution of HCl in EtOH is added (10 ml). The reaction mixture is stirred for 20 h and evaporated to dryness to afford 1.64 g of 2-(pyrrolidin-3-yl)benzamide, enantiomer 1 a1-8 which is used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.FC(F)(F)C(O)=O.[I:19]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([I:19])[C:5]([NH2:11])=[N:6][C:7]=1[CH:8]1[CH2:9][CH2:10]1
Reactant: Nc1ccc(Br)c(C2CC2)n1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(C2CC2)c(Br)cc1I
Yield: 99.2 %

Procedure:
A solution of 5-bromo-6-cyclopropylpyridin-2-amine (2.1 g, 9.81 mmol), trifluoroaceticacid (170 mg, 1.47 mmol), N-iodosuccinimide (2.2 g, 9.81 mmol) stirred at room temperature for 30 minutes. Reaction mass was quenched with water, basified with ammonium hydroxide solution. Solid separated was filtered and dried to get 3.3 g (100% yield) of titled compound. 1H NMR (CDCl3, 300 MHz): δ 7.85 (s, 1H), 4.80-4.65 (bs, 2H), 2.39-2.25 (m, 1H), 1.0-0.90 (m, 4H). MS: m/z=338.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>ClCCCl.CC(O)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[N:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Fc1ccc(-c2nc3c(Cl)ncnc3o2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2nc3c(Nc4ccc(F)c(Cl)c4)ncnc3o2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine (85 mg, 0.34 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (50 mg, 0.34 mmol). The mixture was heated at 90° C. for 1 day. After cooling down to room temperature, the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (0.1 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[CH:12]([N:15]=[C:16]=S)([CH3:14])[CH3:13].CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([F:10])[C:5]2[N:9]=[C:16]([NH:15][CH:12]([CH3:14])[CH3:13])[NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(F)c(F)c1N
Reactant: CC(C)N=C=S
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(F)c(F)c(Cl)cc2[nH]1
Yield: 21 %

Procedure:
5-Chloro-3,4difluoro-1,2-phenylenediamine (11.6 g, crude material), isopropyl isothiocyanate (6.3 g, 62.1 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (28.0 g, 66.2 mmol) and pyridine (250 mL) were used according to general procedure I. The title compound was recrystallized from 1,4-dioxane to provide a tan solid (3.2 g, 25%); m.p. 175-178° C.; 1H NMR (DMSO-d6) δ: 11.0 (br s, 1H, NH), 7.07 (d, J=5.4 Hz, 1H, Ar—H), 6.96 (br s, 1H, NH), 3.93 (m, 1H, CH), 1.23 (d, J=6.5 Hz, 6H, overlapping CH3). Anal. Calcd. for C10H10F2ClN3-(0.6 C4H8O2): C, 49.89; H, 5.00; N, 14.08. Found: C, 50.29; H, 4.99; N, 14.47.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:27])[NH:6][C:7]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[S:17][CH:16]=2)=[N:8][CH:9]=1)([O-])=O.Cl>[Ni].CO>[NH2:1][C:4]1[C:5](=[O:27])[NH:6][C:7]([NH:10][CH2:11][CH2:12][S:13][CH2:14][C:15]2[CH:19]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[S:17][CH:16]=2)=[N:8][CH:9]=1
Reactant: O=c1[nH]c(NCCSCc2csc(CN3CCCCC3)c2)ncc1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Nc1cnc(NCCSCc2csc(CN3CCCCC3)c2)[nH]c1=O
Yield: 47.8 %

Procedure:
A mixture of 5-nitro-2-{2-[(5-piperidinomethyl-3-thienyl)methylthio]ethylamino}-4(3H)-pyrimidone (5.32 g; 12.96 mmoles) and a catalytic amount of Raney nickel No. 28 (approximately 3.5 cm3) in 300 ml of methanol was hydrogenated in a Parr apparatus at 50 psi for 3.0 hours. The reaction mixture was filtered, treated with 1.55N methanolic HCl (24.0 ml; 37.2 meq.) and evaporated under reduced pressure. The residue was placed on 180 g of silica gel and chromatographed by flash chromatography using a gradient elution of methanol-methylene chloride. The appropriate fractions were combined, evaporated and then rechromatographed using a gradient elution of CH3CN:CH3OH:CH2Cl2 from 7:14:86 to 8:18:80. The appropriate fractions were combined and treated with 20 ml of 1.55N methanolic HCl, and then evaporated under reduced pressure and dried under high vacuum at 56° C. to give 2.35 g of the title compound as a trihydrochloride, mp 150°-155° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: O=C(CN1CCOCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of morpholine (16.0 g) in toluene (100 ml) is slowly added to a solution of 2-bromo-1-(4-fluorophenyl)-ethanone (20.0 g) in toluene (250 ml). The mixture is stirred overnight at room temperature and extracted with a 1-N aqueous solution of hydrochlorid acid (3×250 ml). The mixed aqueous phases are alcalinized with a 50% aqueous solution of sodium hydroxide (55 ml) and extracted with ethyl acetate (3×250 ml). The mixed organic phases are washed with water (3×100 ml) and dried over magnesium sulphate. The solvent is distilled in vacuo and the residue is dried in vacuo to constant weight to give 1-(4-fluorophenyl)-2-morpholino-ethanone which is a liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][NH:19]3)=[CH:14][C:13]=2[F:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O>[CH2:35]([N:19]1[C:20]2[C:15](=[CH:14][C:13]([F:28])=[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)[N:21]=2)[C:16](=[O:27])[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18]1)[CH3:36]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(=O)OCC)CC3)c(F)cc2c1=O
Reaction time: 0.17 h

Procedure:
Ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was suspended in dimethylformamide (10 ml) and to the suspension was added potassium carbonate (0.53 g). After the mixture was kept at 60° C. for 10 minutes with stirring, ethyl iodide (1.2 g) was added to the solution. The mixture was stirred for 2 hours at 60°-70° C. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue. After extraction with chloroform, the chloroform extract was dried over anhydrous potassium carbonate. After removal of the chloroform by distillation, the resulting precipitate was recrystallized from a mixture of dichloromethane and n-hexane to give 0.89 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethoxycarbonyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate (mp 171°-173° C.). A mixture of the above ethyl ester (0.8 g), 10% sodium hydroxide (6 ml) and ethanol (2 ml) was refluxed by heating for 3 hours. After cooling, the solution was adjusted to pH 7.0-7.5 with 10% acetic acid. The precipitate was collected by filtration, washed with ethanol and recrystallized from a mixture of dimethylformamide and ethanol to give 0.57 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid. m.p. 220°-224° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][N:20]=[C:21]4[CH:27]=[CH:26][C:25](Cl)=[CH:24][C:22]4=3)[CH:17]=[CH:16][C:15]2=[O:29])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.CCO.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>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:23]3[C:18](=[CH:19][N:20]=[C:21]4[CH:27]=[CH:26][C:25]([C:34]5[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=5)=[CH:24][C:22]4=3)[CH:17]=[CH:16][C:15]2=[O:29])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2cnc3ccc(Cl)cc3c2n1-c1ccc(Cc2ccccc2)cc1
Reactant: OB(O)c1ccc(O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1ccc2cnc3ccc(-c4ccc(O)cc4)cc3c2n1-c1ccc(Cc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-(4-benzylphenyl)-9-chlorobenzo[h][1,6]naphthyridin-2(1H)-one (100 mg, 0.22 mmol) in 1,4-dioxane (0.6 mL) was added 4-hydroxyphenylboronic acid (45 mg, 0.33 mmol) and 1 N Na2CO3 (0.66 mL, 0.66 mmol). The reaction mixture was degassed using Argon gas for 10 min and added Pd(PPh3)2Cl2 (15 mg, 0.02 mmol) and di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (15 mg, 0.04 mmol). The reaction flask was put into the preheated oil-bath at 100° C. The reaction mixture was further stirred at 100° C. a period of 8 hours after which, it was filtered and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Mg504, filtered and concentrated. The crude product was purified by flash column chromatography using a 97:3 v/v CH2Cl2:EtOH as solvent to afford title compound (64 mg, 64% yield) as a yellow solid. 1H NMR 600 MHz (CDCl3) δ 9.08 (s, 1H), 8.42 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.61 (dd, J=2.1, 6.6 Hz, 1H), 7.25 (m, 2H), 7.12 (m, 4H), 7.00 (m, 5H), 6.75 (d, J=8.4 Hz, 2H), 6.48 (dd, J=2.4, 6.2 Hz, 1H), 3.88 (s, 2H), MS m/z: 455.27 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH2:44][O:45][CH3:46])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH2:44][O:45][CH3:46])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: COCSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1
Yield: 93.5 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (303 mg, 1.0 mmol) and 3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H12) (512 mg, 1.41 mmol) according to the general procedure K. Obtained as a light yellow solid (552 mg).
Reaction SMILES: Cl[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C-:17]#[N:18].[Na+]>CS(C)=O>[C:17]([CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc2c1CCCC2Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc2c1CCCC2C#N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In 44 ml. of dimethylsulfoxide is dissolved 4.4 g. of ethyl 1-chloro-1,2,3,4-tetrahydro-5-naphthoate, followed by the addition of 2 g. of sodium cyanide. The mixture is stirred at 50°C for 3 hours and following the addition of 450 ml. of 0.2N hydrochloric acid, the mixture is extracted with ethyl ether. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resultant oily residue is purified by column chromatography on silica gel (100 g. silica gel; eluted with benzene). The procedure gives ethyl 1-cyano-1,2,3,4-tetrahydro-5-naphthoate as an oily product.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:6][CH:5]=[CH:4][CH2:3][CH:2]=1.[H][H]>[C].[Pd]>[C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: [H][H]
Reactant: O=C(O)[C@@H]1C[C@H](C2=CCC=CC2)CN1
Agent: [Pd]
Product: O=C(O)[C@@H]1C[C@H](C2=CCCCC2)CN1

Procedure:
cis-4-(1,4-Cyclohexadienyl)-L-proline is treated with a palladium-carbon catalyst and shaken on a Parr hydrogenator under 3 atmospheres of hydrogen to yield cis-4-(1-cyclohexenyl)-L-proline.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19](C2C=CC(O)=CC=2)=[CH:18][CH:17]=1.CCOC(C)=O>COCCOC.C([O-])([O-])=O.[K+].[K+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][C:14]([F:29])([F:30])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(Cc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 105 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
A solution of methyl 4-(bromomethyl)benzoate (93) (0.23 mL, 1.0 mmol) and 4-(trifluoromethoxy)phenylboronic acid (44) (0.24 g, 1.1 mmol) in DME (3 mL) and 2M aqueous K2CO3 (1 mL) was degassed, then treated with tetrakis(triphenylphosphine) palladium (58 mg, 50 μmol). The reaction mixture was stirred under N2 at 105° C. for 24 h, and then EtOAc (250 mL) was added. The organic layer was washed with water, the aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with petroleum ether/EtOAc (9:1), to give methyl 4-[4-(trifluoromethoxy)benzyl]benzoate (94) (215 mg, 68%) as a colourless oil; 1H NMR (CDCl3) δ 7.98-7.94 (m, 2H), 7.26-7.22 (m, 2H), 7.20-7.12 (m, 4H), 4.03 (s, 2H), 3.90 (s, 3H); HREIMS calcd for C16H13F3O3 m/z (TO 310.0817, found 310.0815.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:10])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(C(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
3-[1-(tert-Butoxycarbonylamino)ethyl]benzoic acid (7.57 g, 28.53 mmol) was dissolved in anhydrous THF (45 mL) and 2M borane-dimethylsulfide in THF (42.8 mL, 85.6 mmol) was added dropwise at ambient temperature. The reaction was stirred at this temperature for 3 hours then cooled to 0° C. and quenched with MeOH. The solvents were removed under reduced pressure and the resulting residue partitioned between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate (×1) and brine (×1), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™ eluting with 0 to 30% EtOAc/petroleum ether) to give the sub-title compound as a white solid (4.91 g, 68% Yield). 1H NMR (400 MHz, DMSO) δ 1.28 (d, 3H), 1.36 (s, 9H), 4.47 (d, 2H), 4.54-4.64 (m, 1H), 5.17 (t, 1H), 7.14 (d, 2H), 7.23 (d, 2H) and 7.38 (d, 1H) ppm; MS (ES+) 252.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([CH3:13])[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[NH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:13])[C:2]([F:15])([F:1])[F:14])=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: CC(Oc1ccc(C#N)nc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(CN)nc1)C(F)(F)F

Procedure:
Add (±)-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile (810 mg, 3.7 mmol), 10% Pd/C (Degussa type E101, 50% water by wt, 300 mg), and trifluoroacetic acid (4 mL) in methanol (50 mL) to a pressure vessel. Pressurize the vessel to 40 psi with hydrogen for 0.25 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product as a trifluoroacetic acid salt. Prepare the free base with SCX ion chromatography, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (676 mg, 82%). GC-MS m/z: 220 (M+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][S:11]([CH2:14][C:15]#[N:16])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:24]=O)([CH3:20])([CH3:19])[CH3:18]>>[C:30]([C:27]1[CH:26]=[C:23](/[CH:24]=[C:14](/[S:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:13])=[O:12])\[C:15]#[N:16])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:28]=1[OH:29])([CH3:33])([CH3:32])[CH3:31]
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
N-3-Phenyl-n-propyl cyanomethylsulfonamide and 3,5-di-t-butyl-4-hydroxybenzaldehyde was condensed under the similar conditions as described for example 12 (Part B) to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C1(C)C=CC(S(O[CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:38]=2)(=O)=O)=CC=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:38]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 70 °C
Yield: 98.3 %

Procedure:
Cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (1680 g, 8.04 M) was added to a solution of potassium carbonate (555 g, 4.02 M) in water (3800 ml). Toluene (7600 ml), tetra-n-butylammonium bromide (115 g, 0.4 M) and alpha-cyano-3-phenoxybenzyl p-toluenesulphonate (2902 g, 7.65 M; prepared as in Example 1(A) above) were added to the stirred mixture which was then heated at 70° C. for 5 hours. The mixture was cooled to ambient temperature and the organic phase was separated off, washed twice with aqueous potassium carbonate solution and twice with water, evaporated and degassed under vacuum to leave cis-alpha-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate as a yellow oil (3130 g, 99%), containing less than 1% trans-isomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1cccc(CBr)c1
Reactant: CCOC(=O)C[C@@H]1CCCN1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(COc2ccc(N3CCC[C@H]3CC(=O)O)cc2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
(13A, 24.93 mg, 0.10 mmol) in DMF (1 mL) was added 1-(bromomethyl)-3-methylbenzene (19.6 mg, 0.105 mmol) following with K2CO3 (28 mg, 0.200 mmol). The reaction was stirred at 80° C. for 18 h. Volatile solvents were evaporated and the residue was diluted with 1:1 methanol:dioxane (0.35 0 mL, 0.152 M). To this solution was added 1M NaOH (0.350 mL) and the reaction was stirred at rt for 18 h. Volatile solvents were evaporated and the residue was diluted in DMF (1.250 mL) and distilled water (0.250 mL) and purified using Waters Sunfire (19×100 mm, 5 nm C18, 5:95 CH3CN:Water, 0.05% TFA) to yield Example 69. LC-MS Anal. Calc'd for C20H23NO3 325.40. found [M+H] 326.23.