Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Li+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[Mg]Br>C1COCC1.[Cu]Br>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][C:15]=1[O:17][CH3:18]
Reactant: BrCCCCBr
Reactant: COc1ccc([Mg]Br)c(OC)c1
Agent: [Cu]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCCCBr)c(OC)c1
Temperature: 40 °C
Yield: 73.2 %

Procedure:
Commercially available copper(I)bromide (7.17 g, 50 mmol) and anhydrous lithium bromide (8.68 g, 100 mmol) were added to anhydrous THF (100 mL). Vigorous shaking gave a dark greenish solution. 11.5 mL (5.75 mmol) of this solution was added to a mixture of 1,4-dibromobutane (74.8 g, 346 mmol) in THF (90 mL). The mixture was warmed to 40°C, after which a solution of 2,4-dimethoxyphenylmagnesium bromide (115 mmol) in THF (100 mL), prepared by standard methods, was added over 45 min. The temperature was never more than 50° C. After the addition, the mixture was stirred for an additional 1 h at 50° C. The reaction mixture was allowed to reach 30° C. after which it was poured into ice water (200 mL). Effective stirring for 10 min gave a deep blue color. The mixture was extracted with diethyl ether (2×250 mL), dried (MgSO4) and evaporated. The excess of 1,4-dibromobutane was distilled off, and the residue was filtered through a short column of silica gel (hexane-EtOAC, 95:5). Evaporation gave the title compound as a colorless liquid (23.0 g): 1H NMR (CDCl3 -d) 7.00 (d, J=8.0 Hz, 1 H), 6.44-6.39 (m, 2 H), 3.79 (s, 6 H), 3.42 (t, J=6.9 Hz, 2 H), 2.56 (t, J=7.5 Hz, 2 H), 1.90-1.83 (m, 2 H), 1.73-1.62 (m, 2 H); 13C NMR (CDCl3 -d) 159.13, 158.24, 129.90, 122.56, 103.74, 98.44, 55.30, 55.22, 33.87, 32.47, 28.56 (two overlapping carbon); MS (EI, 70 eV): m/z (rel.int.) 274/272 (M+, 100/96), 151 (54), 121 (43), 91 (14).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[NH:21]([C:28]1[N:29]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH3:39])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C[O:49]CC1>>[NH:21]([C:28]1[N:29]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:30]2[C:35]([C:36](=[O:38])[CH:37]=1)=[C:34]([CH2:39][OH:49])[CH:33]=[CH:32][N:31]=2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nccc(CO)c12
Temperature: -78 °C
Yield: 53 %

Procedure:
A solution of LDA (38.2 mmol, freshly prepared from n-BuLi and diisopropylamine) in THF (53 mL) was added to a cooled (−78° C.) and stirred suspension of 2-anilino-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (2.50 g, 7.64 mmol) in THF (100 mL). The resulting mixture was stirred for 1 h, and then oxygen gas was bubbled, through a flitted glass tube, into the bottom of the reaction vessel. The mixture was stirred overnight, with continued bubbling of oxygen with slow warming to room temperature. The reaction was quenched with water and 1M HCl (5 mL), and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated in vacuo to afford an orange solid which was recrystalized from EtOAc to obtain 2-anilino-5-(hydroxymethyl)-1-phenyl-1,8-naphthyridin-4(1H)-one (1.38 g, 53%): LCMS RT: 2.01 min, MH+: 344.3, Rf=0.22 (95:5 CH2Cl2:MeOH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (40 mg, 0.18 mmol) was suspended in CH2Cl2 (2 ml) and treated with triethylamine (52.6 μl, 0.378 mmol) followed by 4-fluorobenzenesulfonyl chloride (38.6 mg, 0.198 mmol). The reaction was stirred 1 hr at ambient temperature and chromatographed on a silica gel column eluted with 20% hexane in CH2Cl2. The product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to provide the title compound: (mp 169°-174°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Yield: 27.4 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and piperidine (0.38 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromophenyl)sulfonyl]piperidine (0.13 g) was provided after purification. HRMS: calcd for C11H14BrNO2S+H+, 304.00014; found (ESI, [M+H]+), 304.0009. HPLC purity 99.2% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[CH3:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Br
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM) in dried tetrahydrofuran (100 ml) was cooled to 0° C., a tetrahydrofuran solution of methyl magnesium bromide (136.20 mM) was dropped into this solution, and the resultant mixture was stirred at that temperature for 2 hours. A aqueous ammonium chloride was added to the solution obtained, which was then warmed to room temperature and extracted with ethyl acetate. The extract was successively washed with brine and water. The organic solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain crude product of 1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol 10.67 g as a light yellow oil. The crude product thus obtained of 1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol (10.67 g) was dissolved in dried methylene chloride (200 ml). Manganese dioxide (39.2 g) was added to this solution. The resultant product was stirred vigorously at room temperature for 16 hours. The undissolved material in the solution was removed by filtration through Celite, then the filtrate was concentrated in vacuo to obtain residue as a yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 25% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxyacetophenone 10.00 g (yield 94.4%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].CC(C)([O-])C.[K+]>C1COCC1>[CH:3]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[CH2:2]
Reactant: COC(=O)c1cccc(OCCCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=COc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of methyl 3-(2-chloroethoxy)benzoate (5.61 g, 26.1 mmol) in THF (50 mL) was added potassium tert-butoxide (3.67 g, 32.7 mmol). When the addition was complete the reaction was allowed to warm to rt. After stirring at rt overnight the reaction was quenched with water. The solution was extracted with diethyl ether (three times), dried over MgSO4, and concentrated under vacuum. Purification by silica gel chromatography afforded the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([OH:21])=[O:20])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.[F:37][C:38]1[C:43](O)=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][C:43]1[C:42]([F:45])=[C:41]([F:46])[C:40]([F:47])=[C:39]([F:48])[C:38]=1[F:37])=[O:20])[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pentafluorphenyl 6-n-heptyloxy-2-naphthoate is prepared as follows. To a suspension of 6-n-heptyloxy-2-naphthoic acid (10.5 mmol) and dicyclohexylcarbodiimide (10.5 mmol) in ethyl acetate at 0° C. is added pentafluorophenol (11.5 mmol). The mixture is stirred at 25° C. for a period of 18 h. Any precipitate is removed by filtration. The filtrate is washed twice with water and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gives the desired pentafluorphenyl 6-n-heptyloxy-2-naphthoate.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]3[S:22][C:21]4[N:23]5[C:14](=[CH:15][N:16]=[C:17]5[CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.675 g (1.756 mM) of (E)-1-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)propen-1-one dihydrochloride, 0.52 g (2.63 mM) of 1-bromo-3-phenylpropane, and 0.86 ml (6.15 mM) of triethylamine in 30 ml of acetonitrile, and the mixture was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol: 4/1) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[CH2:6][N:7]([CH3:9])[CH3:8].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:9][N:7]([CH2:6][C:5]1[CH:10]=[CH:11][C:12]([NH2:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:8]
Reactant: [H][H]
Reactant: COc1cc(CN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CN(C)C)ccc1N
Yield: 93.8 %

Procedure:
A mixture of (3-methoxy-4-nitrobenzyl)dimethylamine (1.5 g, 7.1 mmol) and 5% Pd—C (0.2 g) in ethyl acetate (75 mL) was shaken under 50 psi of hydrogen for 24 hours. The mixture was filtered through Celite and evaporated, providing 1.2 g of the product as a light grey oil, in 93% yield: 1H NMR (CDCl3) δ 2.22 (s, 6H), 3.32 (s, 2H), 3.74 (br, 2H), 3.86 (s, 3H), 6.62-6.67 (m, 2H), 6.78 (s, 1H).
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C)[CH:13]=1)[C:6]([O:8]C)=O.COC(=O)C1C(=CC(N(C)C2C=CC=CC=2)=C([NH:44]C2C=CC=CC=2)C=1)C(OC)=O>>[CH3:29][N:22]([C:11]1[CH:10]=[C:5]2[C:6](=[O:8])[NH:44][C:3](=[O:30])[C:4]2=[CH:13][C:12]=1[NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Product: CN(c1ccccc1)c1cc2c(cc1Nc1ccccc1)C(=O)NC2=O

Procedure:
A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example 1b) in 5 ml of acetonitrile is heated at 80° C. for 16 hours with 0.93 ml (15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube. The reaction mixture is concentrated to dryness by evaporation, the residue is twice digested in dichloromethane and filtered, and the filtrate is concentrated by evaporation. Repeated chromatography on silica gel with hexane/ethyl acetate yields the title compounds in the form of slightly yellowish powders. (A): FAB-MS: 405 [M+ +H]; (B): FAB-MS: 391 [M+ +H].
Reaction SMILES: [C:1]1([CH:7]([O:10][Si](C)(C)C)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].BrC[C:27]1[CH:28]=[C:29]([F:36])[C:30]([S:34][CH3:35])=[C:31]([F:33])[CH:32]=1.Cl>C1COCC1>[F:36][C:29]1[CH:28]=[C:27]([CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])[CH:32]=[C:31]([F:33])[C:30]=1[S:34][CH3:35]
Reactant: CSc1c(F)cc(CBr)cc1F
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(F)cc(CC(=O)c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of phenyl[(trimethylsilyl)-oxy]aceto-nitrile (13.7 g, 60.7 mmol) in anhydrous THF (140 mL) cooled in a dry ice/acetone bath, was added a ThF solution of lithium bis(trimethylsilyl)amide(62 mL 1.0 M) slowly over 15 minutes. The reaction mixture was stirred for 45 minutes cooling at −78° C., then a solution of 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene (14.7 g, 58 mmol) in anhydrous THF (20 mL) was added over 10 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 18 hours. To this mixture was added 5% HCl (300 mL) and the mixture stirred for one hour. The resulting oil was extracted with ethyl acetate (1×400 mL, 2×100 mL). To the combined extracts was added 5% sodium hydroxide (200 mL), and the mixture stirred for one hour. Additional water (200 mL) was added, the organic phase was separated, and the aqueous phase extracted with ethyl acetate (2×150 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Chromatography on silica gel with 15% dichloromethane in hexanes initially and eluting the product with 30% gave 2-[3,5-difluoro-4-(methylthio)phenyl]-1-phenylethanone as light yelow solid (11.0 g, 68%). MP 71.8-71.9° C. 1H NMR (CDCl3/400 MHz) 7.96-7.99 (m, 2H), 7.57-7.61 (m, 1H), 7.24-7.50 (m, 2H), 6.80-6.85 (m, 2H), 4.24 (s, 2H), 2.42 (s, 3H). HRMS m/z 279.0667 (M+H+, calcd 279.0655). Anal. Calcd for C15H12F2OS: C, 64.73; H, 4.35; Found: C, 64.70; H, 4.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Fc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cc1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-fluorophenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:19][N:18]=1
Reactant: NN
Reactant: Fc1ccccc1C#Cc1nccnc1Cl
Solvent: O
Solvent: CCCCO
Product: Fc1ccccc1Cc1n[nH]c2nccnc12

Procedure:
A solution of 550 mg (2.36 mmol) of 2-chloro-3-[(2-fluorophenyl)ethynyl]pyrazine from example 13A and 592 mg (11.8 mmol) of hydrazine hydrate in 12 ml of n-butanol is heated in a microwave at 140° C. for 30 min. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 150 mg (26% of theory) of the desired compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].C([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCNCC2)cc1Cl

Procedure:
50 mg 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to Boc-piperazine via Procedure G. The organic layer was evaporated to dryness and treated with TFA. After 1 h the TFA was removed and the crude was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazine-1-carbonyl)benzamide. MS (Q1) 455 (M)+.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3([CH2:13][CH2:12]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1C=CC(B(O)O)=CC=1>>[CH3:33][O:34][C:35]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]3([CH2:13][CH2:12]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:19][CH:20]=2)=[CH:5][CH:6]=1
Reactant: O=C1OC2(CC2)C(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC23CC3)cc1
Yield: 18 %

Procedure:
Following the procedure for the preparation of 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (Example 26) using 4-methoxyphenylboronic acid provided the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 (5.20 g, 24.4 mmol) in 50 mL of dry methanol and 50 mL of trimethylorthoformate was added aniline (2.50 g, 1.1 eq.), and the mixture was stirred at room temperature for 30 minutes. NaBH3CN (95%, 1.84 g, 1.1 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 30 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography (silica gel, hexane:ethyl acetate (1:1) to afford N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 as white solid (5.60 g, 79%). IR (film, cm−1) 3520, 3263, 3004, 2976, 2932, 2854, 1688, 1589, 1521, 1482, 1422, 1365, 1267, 1243, 1175, 1150, 794, 709; 1H NMR (CDCl3, ppm) 7.20 (t, 2H, J=7.8 Hz), 6.72 (t, 1H, J=6.8 Hz), 6.63 (d, 2H, J=8.3 Hz), 4.00-3.78 (m, 3H), 3.07-2.70 (m, 4H), 2.00-1.20 (m, 5H), 1.48 (s, overlap, 9H).
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH2:26])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[CH3:30][C:31]([CH3:33])=O.[BH3-]C#N.[Na+].C(OCC)(=O)C>CO>[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:23][C:24](=[O:27])[CH2:25][NH:26][CH:31]([CH3:33])[CH3:30])[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:8][CH:9]=1)[CH3:29]
Reactant: CC(C)=O
Reactant: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CN)CCc3ccccc3C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)c1ccc(NC(=O)C2(NC(=O)CNC(C)C)CCc3ccccc3C2)cc1
Yield: 23 %

Procedure:
The amine from Example 13A was dissolved in 1 M pH4 MeOH buffer (82 g NaOAc/L MeOH, add HOAc to pH 4.5) and acetone (12 mg, 0.2 mmol) and NaBH3CN (13 mg, 0.2 mmol) were added. Following stirring for 2 hours ethyl acetate (30 mL) was added and the resulting solution was washed with aqueous NaOH (1N, 2×10 mL). The organic phase was dried over MgSO4, concentrated, and purified by HPLC to provide the titled compound (30 mg, 23% over 3 steps). 1H NMR (300 MHz, DMSO-D6) δ 9.21 (s, 1H), 7.83 (s, 1H), 7.32 (d, J=9.3 Hz, 2H), 7.10 (m, 4H), 6.61 (d, J=9.0 Hz, 2H), 3.28 (q, J=6.9 Hz, 4H), 3.22 (d, J=18.9 Hz, 1H), 3.11 (d, J=18.9 Hz, 1H), 3.07 (s, 2H), 2.77 (m, 2H), 2.45 (m, 2H), 2.09 (m, 1H), 1.05 (t, J=7.2 Hz, 6H), 0.81 (d, J=6.3 Hz, 3H), 0.73 (d, J=6.3 Hz, 6H). MS (ESI) positive ion 437 (M+H)+; negative ion 435 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[CH3:13][NH2:14]>CO>[NH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:14][CH3:13]
Reactant: CN
Reactant: Nc1cccc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cccc(N)c1
Temperature: 100 °C

Procedure:
The 3-(3-chloropropoxy)phenylamine was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (4×30 mL). The aqueous layer was basified to pH 11 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 2.77 g of an oil.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[CH:12]=[C:11]([O:13]COC)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl.C(O)C>O>[F:1][CH:2]([F:17])[C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCOc1ccc(C(=O)OC)c(C(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(O)cc1C(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To methyl 2-(difluoromethyl)-4-(methoxymethoxy)benzoate (720 mg) were added 2N hydrochloric acid (6 ml) and ethanol (6 ml), and the mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and water was added thereto, and extracted with ethyl acetate. To the extract was added a saturated aqueous sodium chloride solution, and the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (500 mg).