Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([CH3:1])([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH3:11])=[O:28]
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)cc(Cl)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 0.03 h
Yield: 72.4 %

Procedure:
To a solution of (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (0.10 g; 0.459 mmol) and triethylamine (0.15 ml; 1 mmol) in DCM (3 ml) was added a solution of 2,4-dichloro-6-methyloxybenzoyl chloride (0.13 g; 0.540 mmol) in DCM (2 ml). After 1 h. saturated aqueous sodium hydrogen carbonate (8 ml) was added and the mixture shaken for 2 minutes. The organic layer was passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was dissolved in the minimum of DCM and applied to a 10 g silica gel column. Elution with 0-100% ethyl acetate in pentane gradient and removal of solvent under reduced pressure afforded the title compound as a colourless gum (0.14 g: 72%). 1H NMR (CDCl3) δ: 0.91 (3H, s), 0.96 (3H, s), 1.60-1.80 (4H, m), 2.55-2.75 (4H, m), 3.82 (3H, s), 4.76 (1H, d, J=2.4 Hz), 6.81 (1H, d, J=1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 7.20-7.50 (6H, m). Mass spectrum (Electrospray LC/MS). Found 421 (MH+). C22H2635Cl2N2O2 requires 420. Ret. Time: 1.97 min.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[CH3:19][N:20]([CH:22]([N:26](C)C)[N:23](C)C)C.CO.C(=O)(O)O.NC(N)=N>C1(C)C=CC=CC=1>[NH2:26][C:22]1[N:20]=[CH:19][C:11]2[CH2:10][CH2:9][C@@H:8]3[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@H:3]3[C:2]=2[N:23]=1
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2C(=O)CCC[C@H]21
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2c3nc(N)ncc3CC[C@@H]21

Procedure:
To a refluxing solution, under nitrogen, of 8.89 g (35 mmol) of cis and trans octahydro-5-oxo-1(2H)-quinolinecarboxylic acid, 1,1-dimethylethyl ester, (Example 8), in 400 ml of toluene is added dropwise a solution of 6.37 g (43.8 mmol) of tris-(dimethylamino)methane in 200 ml of toluene. The solution is refluxed for 2 hours. The reaction mixture is concentrated and the residue is dissolved in 500 ml of methanol. To the methanol solution is added 12.64 g (70.1 mmol) of guanidine carbonate, and the reaction mixture is refluxed, under nitrogen, for 12 hours. The mixture is concentrated and partitioned between brine and chloroform. The organic phase is separated, dried over magnesium sulfate, filtered and concentrated to a yellow solid. Medium pressure chromatography (silica gel, ethyl acetate) afforded 4.55 g (51%) of recovered starting ketone, 0.94 g (8.8%) of (±) cis-2-amino-6,6a,8,9,10,10a-hexahydropyrido[2,3-h]quinazoline-7(5H)-carboxylic acid, 1,1-dimethylethyl ester (Rf =0.33 (ethyl acetate)) as a foamy off-white solid, mp 178°-182° C., and 2.47 g (23%) of (±) trans-2-amino-6,6a,8,9,10,10a-hexahydropyrido[2,3-h]quinazoline-7(5H)-carboxylic acid, 1,1-dimethylethyl ester (Rf =0.27 (ethyl acetate)) as a white solid, mp 200°-206° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:15][CH2:16][O:11][N:10]=[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([F:12])([F:13])[F:1]
Reactant: ON=C(c1ccccc1)C(F)(F)F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)C(=NOCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of the above oxime (13.5 g, 71 mmol), 1,2-dibromoethane (65 ml), potassium carbonate (29.4 g, 213 mmol) and acetone (100 ml) was heated at reflux for 16 h and then stirred at room temperature for 7 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo to give 20.7 g of 2,2,2-trifluoroacetophenone O-(2-bromoethyl)oxime.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.[Li+].[OH-].O.C1COCC1.CO>>[Cl:30][C:25]1[CH:24]=[C:23]([C:18]2[CH:19]=[CH:20][C:21]([OH:22])=[C:16]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]3[CH:7]=[CH:8][C:9]([C:38]4[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=4)=[CH:10][CH:11]=3)[C:3]([OH:2])=[O:31])=[O:15])[CH:17]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(-c2cccc(C(F)(F)F)c2)cc1)C(=O)O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reaction time: 4 h
Yield: 44.8 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-2-[(3′-chloro-4′-fluoro -4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.3 mmol) was reacted with 3-trifluoromethyl-phenylboronic acid (285 mg, 1.5 mmol) by following Procedure K. The resulting resin-bound methyl ester was hydrolyzed with LiOH/H2O/THF/methanol, and washed with DMF, MeOH, DCM (three times of each). The title compound was then cleaved from the resin with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by column chromatography to give 75 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([NH2:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:7][CH2:6]2)OCC1.Cl.ClCCl>CC(C)=O>[NH2:19][C:11]([CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: CC(N)(c1ccccc1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(N)(c1ccccc1)C1CCC(=O)CC1
Reaction time: 5 h

Procedure:
Crude 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-phenyl-ethylamine (26, 2.5 g) was dissolved in acetone (40 mL) and treated with 6M aqueous hydrochloric acid (21.1 mL). After 5 hours stirring the mixture was evaporated at less than 20° C. to give a residue which was treated with dichloromethane, washed with saturated sodium bicarbonate solution, dried and filtered to give a solution of crude product which was used immediately. Rt=0.7 min (Method 5). Detected mass: 218.3 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[CH:34](=[O:39])/[CH:35]=[CH:36]/[CH2:37][CH3:38].O>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:36]([CH2:37][CH3:38])[CH2:35][CH:34]=[O:39])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC/C=C/C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (100 mg, 0.0003 mol) in ACN (2 mL, 0.04 mol) and DBU (50 μL, 0.0003 mol), the (2E)-pent-2-enal (4.0E1 mg, 0.00048 mol) in 1 ml ACN was added drop wise. The reaction was stirred for 1 h, and then water was added and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the crude as the hydrated product form. LC/MS (M+H)+: m/z=400.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([C:12]#[N:13])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][C:7]=1[C:12]#[N:13]
Reactant: CON=Cc1ccc(F)c(C#N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(F)c(C#N)c1

Procedure:
Reduction of 3-cyano-4-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (73% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.46 (3H, s, OCH3), 4.02 (2H, s, NCH2), 7.18 (1H, t, aromatic), 7.58–7.66 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 152–158° C. Anal. calcd for C9H9FN2O—HCl: C, 49.89; H, 4.65; N, 12.93. Found: C, 50.04; H, 4.64; N, 12.84.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:36])(=[O:35])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:33][CH:32]=1
Reactant: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{4-[(4-fluoro-benzyl)-isobutyl-sulfamoyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester (208 mg) in DCM (9 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2 M NH3 in MeOH to give N-(4-fluoro-benzyl)-N-isobutyl-4-(piperidin-4-ylamino)-benzenesulfonamide. A solution of the crude product (149 mg) in DCM (5 mL) was added DIPEA (124 μL, 711 μmol) followed by methane sulfonylchloride (28 μL, 356 μmol) and the reaction stirred at room temperature for 30 minutes. Water was then added, passed through a phase separator, extracted once more through a phase separator, concentrated and purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) to give the title compound (139 mg). 1H NMR (400 MHz, DMSO): δ 7.51 (d, J=8.7 Hz, 2H), 7.4 (dd, J=8.5, 5.6 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 6.71 (d, J=8.7 Hz, 2H), 6.55 (d, J=7.8 Hz, 1H), 4.15 (s, 2H), 3.48-3.53 (m, 3H), 2.93 (d, J=11.6 Hz, 2H), 2.89 (s, 3H), 2.76 (d, J=7.4 Hz, 2H), 1.99 (m, 2H), 1.44-1.49 (m, 3H), 0.65 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 498.0 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([S:10][CH3:11])=[C:7]([CH3:9])[CH:8]=1.[C-:13]#[N:14].[Na+].[Cl-].[Na+]>>[C:13]([CH2:2][C:3]1[C:4]([F:12])=[CH:5][C:6]([S:10][CH3:11])=[C:7]([CH3:9])[CH:8]=1)#[N:14]
Reactant: [C-]#N
Reactant: CSc1cc(F)c(CCl)cc1C
Agent: [Cl-]
Agent: [Na+]
Product: CSc1cc(F)c(CC#N)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-Chloromethyl-4-fluoro-2-methylthiotoluene (21 g) is dissolved in N,N-dimemthylformamide (90 ml), and thereto is added finely divided sodium cyanide (6.03 g), and the mixture is stirred at room temperature for 18 hours. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-cyanomethyl-4-fluoro-2-methylthiotoluene.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1C=CC=CC=1.[B:15](OCC)(OCC)OCC.[B]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1>C(O)C>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:15]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[O:26]1
Reactant: CC1(C)O[B]OC1(C)C
Reactant: CCOB(OCC)OCC
Reactant: Oc1ccc(I)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
440 mg (2 mmol) of p-iodophenol were placed in a Schlenk flask with 10 ml of dry benzene and 0.17 ml of triethyl borate (1 mmol). The solution was heated for 1.5 h under an inert atmosphere (argon) at 80° C. and then the benzene and ethanol formed were distilled off the product after raising the oil bath temperature to 100° C. To the liquid in the Schlenk was then added 10 ml of activated catalyst (PdCl2[dppf].CH2Cl2) solution, prepared as described in Example 26, followed by 0.35 ml (2.4 mmol) of pinacolborane. No frothing indicating H2 evolution, which would suggest free phenol groups, was observed. The reaction solution was then heated at 80° C. for 7.5 h before removal of an aliquot for gc analysis. This sample was washed in ethyl acetate with 10% brine as described elsewhere. Only two peaks were observed in the gc with retention time longer than 2 minutes and these corresponded to phenylboronic acid pinacol ester (area approx. 7.5%) and with the desired product contributing the remaining area (92.5%).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Cl.CN.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([O-:10])=[O:9].Cl>CO.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH2:14][NH:2][CH3:1])[CH:16]=[CH:17][CH:18]=1)([O-:10])=[O:9]
Reactant: [BH3-]C#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CNCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a mixture of sodium cyanoborohydride (2.52 g), triethylamine (18.7 ml), methylamine hydrochloride (5.42 g) and methanol (660 ml), m-nitrobenzaldehyde (10.10 g) was added dropwise over 20 minutes at room temperature and the resulting mixture was stirred at room temperature for 20 h. The pH of the reaction mixture was adjusted to 2 by addition of 10% HCl and the methanol was distilled off under reduced pressure. The residue was washed with chloroform and a 10% aqueous potassium hydroxide solution was added to the aqueous layer for pH adjustment to 12, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=95:5) to give 3.0 g of the titled compound (yield, 27%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][N:12]=1.[H-].[Na+]>C(#N)C>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([CH2:17][N:7]2[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]2=[O:9])=[CH:15][CH:16]=1
Reactant: CCCC1CNC(=O)C1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2ccc(Cl)nc2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 4-propylpyrrolidin-2-one x1 (0.50 g, 3.93 mmol, 1 eq) and 2-chloro-5-(chloromethyl)pyridine x37 (0.64 g, 3.93 mmol, 1 eq) in acetonitrile (3 ml) is heated at 50° C. NaH (60% dispersion in oil, 158 mg, 3.93 mmol, 1 eq) and acetonitrile (5 ml) are added and the solution is stirred for 8 h at 50° C. The mixture is then poured on ice/water and the aqueous phase is extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 99/1/0.1 (v/v/v)) to afford 790 mg of 1-[(6-chloropyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 228.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>C(O)(=O)C>[ClH:30].[ClH:30].[N:11]1([CH:14]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:28][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(c2ccccc2)c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
Compound 78 (150 mg, 0.38 mmol) was treated with excess HCl in acetic acid 1 h. Acid removed in vacuo and residue dissolved in methanol and precipitated by addition of ether. The precipitate was dried in vacuum at 100° C. Mp: 172-80° C. IR (KBr) (cm−1): 3000(br), 1700, 1606, 1454. 1H NMR: (DMSO-d6): δ=12.85 (s, 1H, CO2H), 8.95 (s, 2H, NH), 7.92-7.20 (m, 9H, Ar—H), 4.56 (s, 1H, Ar2CH), 3.33 (s, 8H, piperazne-H). Anal. calc. for C18H20N2O2×2HCl, C,58.54; H, 6.00; N, 7.59. Found: C, 59.9; H, 6.47; N, 7.88.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:24]([C:26]1[CH:27]=[C:28]([C:32]([OH:34])=O)[NH:29][C:30]=1[CH3:31])#[N:25].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=2)[C:46]([NH2:48])=[O:47])[CH2:39][CH2:38]1>CN(C=O)C>[Cl:52][C:50]1[CH:49]=[C:45]([CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][CH:37]([NH:36][C:32]([C:28]3[NH:29][C:30]([CH3:31])=[C:26]([C:24]#[N:25])[CH:27]=3)=[O:34])[CH2:38][CH2:39]2)[N:51]=1)[C:46]([NH2:48])=[O:47]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)cc1C#N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1C#N
Reaction time: 8 h
Yield: 7.2 %

Procedure:
Diisopropylethylamine (0.1 ml, 0.56 mmol), EDC (0.09 g, 0.46 mmol) and HOAT (0.064 g, 0.46 mmol) were added to a stirred solution of 4-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 13, 0.07 g, 0.47 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.16 g, 0.56 mmol) in 1 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=4)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CNCCO2)CC1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CN(CCc3ccccc3)CCO2)CC1

Procedure:
To a stirred solution of N-(3,4-dichlorophenyl)-4-(morpholin-2-ylcarbonyl)piperazine-1-carboxamide (350 mg) in dichloromethane (10 ml) under an argon atmosphere was added phenacetaldehyde (0.16 mL) then NaBH(OAc)3 (383 mg) and the reaction was stirred for 3.5 h. The solvent was then removed under reduced pressure and dissolved in dichloromethane (40 ml) and 1M NaOH (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. Purification by column chromatography 3-7% MeOH:DCM afforded the title compound (170 mg) as a white foam
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1I.[F:15][CH:16]([F:22])[C:17](OCC)=[O:18].Cl>C1COCC1>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:17](=[O:18])[CH:16]([F:22])[F:15]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: CCOC(=O)C(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1Br)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Add n-BuLi (8.86 mL, 14.18 mmol) slowly to a solution of 2-bromo-4-fluoro-1-iodobenzene (4.27 g, 14.2 mmol) in THF (50 mL) at −100° C. over 15 min under N2. Stir the solution for 30 min. Add ethyl difluoroacetate (2.81 mL, 26.9 mmol) and stir for 3 h. Add an HCl (50 mL, 2 N) solution and warm the solution up to RT. Separate the organic layer, dry the organic layer over magnesium sulfate, and remove the solvent. Purify the residue by column chromatography (hexane:ethyl acetate/10:1) to give the title compound (2.3 g, 64%). MS (GC) m/z 252 [M]+.
Reaction SMILES: [N+:1]([C:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]3)[CH:17]=2)[CH:12]=1)([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O-:3])=[O:2].COC(=O)CCC([N+]([O-])=O)(C1C=CC2C(=CC=C(O[C@H]3CC[C@@H](C(F)(F)F)CC3)C=2)C=1)C>>[N+:1]([C:4]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][C@H:22]3[CH2:23][CH2:24][C@@H:25]([C:28]([F:29])([F:30])[F:31])[CH2:26][CH2:27]3)[CH:17]=2)[CH:12]=1)([CH3:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Product: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Yield: 97 %

Procedure:
4-Nitro-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-Nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 280) in 97% yield, using 4-Nitro-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester as starting material.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:19][C:20]=1[CH3:21])[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH2:3][CH:4]([C:16]1[S:17][C:18]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=2)=[CH:19][C:20]=1[CH3:21])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OC(CC(C)C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(CC(C)C)Oc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butan-1-ol (525 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (365 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.8 mL) and 1,1′-(azodicarbonyl)dipiperidine (807 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butoxy)benzoate as an amorphous compound. The obtained methyl 4-(3-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}butoxy)benzoate was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (371 mg, 52%).