Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:10]N)[CH:5]=[C:6]([I:9])[C:7]=1[I:8].[CH3:12][CH:13]([C:22](=O)[CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>C(O)(=O)C>[I:1][C:2]1[C:7]([I:8])=[C:6]([I:9])[CH:5]=[C:4]2[C:3]=1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([CH3:12])[C:22]([CH3:23])=[N:10]2
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: NNc1cc(I)c(I)c(I)c1
Solvent: CC(=O)O
Product: CC1=Nc2cc(I)c(I)c(I)c2C1(C)CCCCCC(=O)O
Yield: 23.5 %

Procedure:
A mixture of 3,4,5-triiodophenylhydrazine 2 g (4 mmol) and 1 g (5 mmol) of 7-methyl-8-oxononanoic acid was refluxed in 15 mL of acetic acid for 16 hours. The acetic acid was evaporated, and the residue was dissolved in CHCl3, and washed by aqueous NaHCO3 and water. The organic layer was dried with CaCl2 and solvent was removed under reduced pressure by a rotary evaporator. The residue was column purified (Silica gel 60, 0-4% methanol-chloroform) to give 0.6 g of 6-(4,5,6-triiodo-2,3-dimethyl-3H-3-indolyl)hexanoic acid. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 8.02 (1H, s, arom.), 2.16 (3H, s, 2-CH3), 2.07 (2H, t, CH2COOH), 1.65-1.05 (6H, m, CH2), 1.26 (3H, s, CH3), 0.58-0.20 (2H, m, CH2).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[CH2:31][CH2:30]1)[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CI.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[C:13]([O:17][C:18]([NH:20][C@H:21]([C@H:29]1[O:33][C:32](=[O:34])[C@H:31]([CH3:1])[CH2:30]1)[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
2.83 ml (7.07 mmole) of butyllithium (as a 2.5M solution in hexane) were added, at -78° C. and under an atmosphere of nitrogen, to a solution of 0.99 ml (7.07 mmole) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran. The resulting mixture was then stirred at the same temperature for 30 minutes, after which a solution of 1.0 g (3.2 mmole) of (5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]dihydrofuran-2(3H)-one in 10 ml of anhydrous tetrahydrofuran was added to it. The mixture was then stirred at -78° C. for 30 minutes, after which 0.44 ml (7.07 mmole) of methyl iodide was added dropwise. The mixture was then allowed to stand at the same temperature for 1.5 hour, after which it was mixed with a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel (using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent) to afford a colorless oil. This oil was triturated with hexane to crystallize the product, and then the solvent was removed by distillation, to afford 0.69 g of the title compound as white crystals, melting at 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH3:20].C(OC(=O)C)(=O)C.[CH3:28][C:29]1[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=1>O.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:34][C:32]1[N:33]=[C:29]([CH3:28])[S:30][CH:31]=1
Reactant: Cc1nc(C=O)cs1
Reactant: Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1nc(C=Cc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Br)cs1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Anhydrous zinc chloride (0.150 g, 1.1 mmol) was fused with a nitrogen purge in a round bottom flask with an open flame. The reaction vessel was allowed to return to ambient temperature, then dioxane (5 mL) was added. To this mixture was added 3-(2-bromo-phenyl)-6-fluoro-2-methyl-3H-quinazolin-4-one (0.182 g, 0.55 mmol), acetic anhydride (0.156 mL, 1.65 mmol), and 2-methythiazole-4-carboxaldehyde (0.209g, 1.65 mmol in 3 mL of dioxane). The reaction was refluxed 3 h, cooled to ambient temperature, and diluted with water. The mixture was repeatedly extracted with chloroform. The combined chloroform layer was washed with water and brine and finally dried over magnesium sulfate and concentrated to leave a dark residue. This residue was triturated with ether, filtered and dried to afford 0.116 g (52%) of 3-(2-bromo-phenyl)-6-fluoro-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one as tan solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[C:15]1(B(O)O)[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20][C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Reactant: OB(O)c1cccc2sc3ccccc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1cc(-c2cccc3sc4ccccc4c23)oc(N2CCOCC2)c1
Temperature: 90 °C
Yield: 6.4 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (3)(740 mg, 3.43 mmol), dibenzothiophene-1-boronic acid (860 mg, 3.77 mmol), and ground potassium carbonate (964 mg, 6.86 mmol) were suspended in dioxane (10 ml) and degassed (sonication for 5 minutes then saturated with N2). Pd(PPh3)4 (200 mg, 0.17 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hours under a vigorous stirring and a N2 atmosphere. The solvent were removed in vacuo and the residue was then suspended in water (50 ml) and extracted with ethyl acetate (3×50 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica; ethyl acetate:ethanol; 9:1) to give the title compound as a white solid (80 mg, 6%). 1H-NMR (300 MHz, DMSO-d6): δH=3.49 (4H, t, J 5 Hz); 3.76 (4H, t, J 5 Hz); 5.53 (1H, d, J 2 Hz); 6.63 (1H, d, J 2 Hz); 7.59 (2H, m); 7.69 (1H, t, J 8 Hz); 7.96 (1H, dd, J 1 and 7.5 Hz); 8.11 (1H, m); 8.47 (1H, m); 8.57 (1H, dd, J 1 and 8 Hz). m/z (LC-MS, ESP): 364 (M++1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[N:4][N:3]=1.[Cl:14]N1C(=O)CCC1=O>CN(C=O)C>[Cl:14][C:12]1[CH:13]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: Cc1nnc(-c2ccc(N)cc2)o1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(N)c(Cl)c2)o1
Temperature: 40 °C
Yield: 49.2 %

Procedure:
To a mixture of 4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (0.220 g, 1.26 mmol) and anhydrous DMF (1.9 mL) was added N-chlorosuccinimide (0.168 g, 1.26 mmol). The reaction mixture was heated at 40° C. for 1.5 hours under argon before being allowed to cool to room temperature and partitioned between EtOAc (90 mL) and saturated aqueous NaHCO3 (15 mL). The organic layer was washed with saturated aqueous NaHCO3 (15 mL), dried (Na2SO4) and concentrated in vacuo. The brown residue was absorbed on silica gel (1.4 g), and purified using silica gel column chromatography eluting with a gradient of 0-30% EtOAc in CH2Cl2 to afford the title compound as a white solid (0.130 g, 49%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C@H:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[C:28](Cl)(=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>C(Cl)Cl>[CH3:31][CH:30]([CH3:32])[CH2:29][C:28]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([CH2:14][O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=2[C:7]#[N:8])[CH2:16]1)=[O:33]
Reactant: N#Cc1c(OC[C@H]2CCCNC2)cccc1[N+](=O)[O-]
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104 %

Procedure:
To a suspension of (S)-2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 1d, 35.84 g, 120.41 mmol) in DCM (600 mL) cooled to 0° C. in an ice bath was added triethylamine (42 mL, 300.94 mmol) followed by dropwise addition of isovaleryl chloride (2.77 mL, 132.35 mmol). The reaction mixture was stirred under N2 for 30 minutes at 0° C., then at room temperature overnight. The solution was diluted with DCM and successively washed with 10% citric acid, saturated NaHCO3 solution, water, brine, dried over Na2SO4, filtered and concentrated to afford crude (S)-2-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)-6-nitrobenzonitrile as a golden brown oil (43.26 g). MS 346 (MH+). This material was used without purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH:45]1[CH2:49][CH2:48][N:47]=[C:46]1[C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][NH2:58])=[CH:52][CH:51]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([NH:58][CH2:57][CH2:56][C:53]3[CH:54]=[CH:55][C:50]([C:46]4[NH:47][CH2:48][CH2:49][N:45]=4)=[CH:51][CH:52]=3)=[O:22])[CH:16]=2)[CH3:13])(=[O:10])=[O:11])=[C:4]([Cl:23])[CH:3]=1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cc(C(=O)NCCc2ccc(C3=NCCN3)cc2)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl

Procedure:
5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.14 mmol)), EDCI (40 mg, 0.21 mmol) and HOAt (28 mg, 0.21 mmol) were dissolved in DMF (1 mL) and the mixture was stirred until acid activation was complete. 2-[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]ethanamine.HCl (114 mg, 0.50 mmol) and DIPEA (0.174 mL, 1.00 mmol) were sonicated in 1 mL DMF for 5 min. The activated acid solution was added to 0.25 mL of amine solution and the reaction was stirred at ambient temperature for 3 h. The reaction was diluted with DCM (15 mL) and washed with saturated aqueous NH4Cl (2×3 mL). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9](CC2C=CC(OC)=CC=2)[NH:8][C:7](=[O:21])[CH:6]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[NH:9][NH:8][C:7](=[O:21])[CH:6]=1
Reactant: COc1ccc(Cn2[nH]c(=O)cc(CCCO)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1cc(CCCO)c(=O)[nH][nH]1
Temperature: 40 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
5-(3-Hydroxypropyl)-1-{[4-(methyloxy)phenyl]methyl}-1,2-dihydro-3,6-pyridazinedione (2.734 g) was treated with anisole (10 ml) and TFA (100 ml) and stirred at 40° C. overnight. The solution was cooled, evaporated to dryness and kept under high vacuum for 30 minutes. The residue was taken up in methanol (150 ml), refluxed for 12 hours, cooled and evaporated. The residue was kept for 1 hour under high vacuum, triturated under ether and the solid was filtered off. Drying under vacuum gave the product as a solid (1.48 g, 92%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.O.[OH-].[Na+]>C1COCC1>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:13][CH:14]=1
Reactant: COC(=O)COc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled suspension of lithium aluminum hydride (0.972 g; 25.622 mmol) in anhydrous THF (60 ml) was added dropwise a solution of (4-trifluoromethyl-phenoxy)-acetic acid methyl ester (3.000 g; 12.811 mmol) in anhydrous THF (40 ml). The resulting reaction mixture was further stirred at 0° C. for 20 min. Water (1 ml), 15% aq. NaOH (1 ml), and water (3 ml) were then successively added dropwise. Filtration, concentration to dryness under reduced pressure, and purification by FC (DCM/MeOH, 19/1) afforded 2-(4-trifluoromethyl-phenoxy)-ethanol as a colorless solid (2.370 g; 90%). LC-MS: tR=0.84 min.; [M+H]+: no ionisation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)=[CH:4][C:3]=1[F:25].Br>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)=[CH:4][C:3]=1[F:25]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(Cl)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3cc(F)c(Cl)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
Trans-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (157 mg, 0.42 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3.32 mL, 18.95 mmol) and stirred at room temperature for 16 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-chloro-3,5-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (26 mg, 19%). 1H NMR (600 MHz, dmso) δ 1.75-2.11 (m, 4H), 2.66-2.77 (m, 1H), 2.81-2.95 (m, 1H), 3.14 (s, br., 1H), 3.86 (s, br., 1H), 6.03 (s, 1H), 7.32-7.42 (m, 2H). HRMS Calculated for [C14H13ClF2N2O2+H]+: 315.0712. Found: 315.0715
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cnc3ccccc3c2)cc1
Agent: O=[Pt]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: Fc1ccc(C2CNc3ccccc3C2)cc1
Yield: 24.6 %

Procedure:
3-(4-Fluorophenyl) quinoline (1 g, 0.00448 mol) was dissolved in ethanol (25 mL), and to this was added platinum oxide (0.4 g) under nitrogen atmosphere. The reaction mixture was hydrogenated at 45 Psi for 10 h. After completion of reaction (monitored by TLC), the catalyst was removed by filtration, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (silica 100-200 mesh, diameter of column—2.5 cm, height of silica—approx. 5 inch) to provide the desired compound (0.25 g, 25% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:47]=[CH:46][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[C:48]([NH:51][NH2:52])([NH2:50])=[NH:49].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1.O>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[CH:23]=[CH:24]/[CH:25]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:52][NH:51][C:48](=[NH:49])[NH2:50])=[O:32])=[CH:29][CH:28]=2)=[CH:46][CH:47]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: N=C(N)NN
Reactant: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)O)cc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(COc2ccccc2/C=C/C(CCc2ccc(C#N)cc2)Cc2ccc(C(=O)NNC(=N)N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
210 mg (1.66 mmol) of oxalyl chloride are slowly added dropwise to a solution of 150 mg (0.28 mmol) of 4-{(3E)-4-{2-[(4-tert-butylbenzyl)oxy]phenyl}-2-[2-(4-cyanophenyl)ethyl]but-3-en-1-yl}benzoic acid from Example 105A in 1.5 ml of dry toluene with 2 drops of DMF while cooling in ice. The reaction mixture is stirred at RT for 5 minutes and then heated to reflux for 1 hour. After cooling, the mixture is concentrated in vacuo, and the residue is coevaporated twice with toluene and then taken up in 3 ml of THF. This solution is added to a previously prepared solution of 33.5 mg (0.30 mmol) of aminoguanidine hydrochloride and 22 mg (0.55 mmol) of sodium hydroxide in 1 ml of THF and 0.25 ml of water at 0° C. The mixture is stirred at 0° C. for 2 hours and then concentrated, and the residue is reacted without further purification in the next stage.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].O.C(C(O)=[O:23])(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:23])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: Fc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 0.247 g of 6-fluoro-8-piperazino-quinoline (Step 3) in 10 mL of dichloroethane, was added 0.226 g of 1-quinolin-8-yl-piperidin-4-one (Example A, Step 6, above) followed by 0.274 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product crystallized and filtered to give 0.200 g of the desired product. Mp: 211° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH2:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[CH2:35][CH3:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:40]3[CH:41]=[CH:42][C:37]([CH2:34][CH2:35][CH3:36])=[CH:38][CH:39]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CCCc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (1.8 g, 3.3 mmol) was coupled with 4-n-propyl-phenyl boronic acid (659 m g, 4.0 mmol) according to general procedure G to give {4-[4-(2,4-dichloro-phenyl)-2-(4′-propyl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[C:27]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C1(O)C=CC=CC=1>>[C:27]1([O:37][N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH2:12])=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Reactant: Oc1cccc2ccccc12
Solvent: Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1CCCN1Oc1cccc2ccccc12

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 1-naphthol for the phenol used therein, the 1-naphthyloxy proline amide was produced.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.[CH2:29](O)[CH3:30]>>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH2:29][CH3:30])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCO
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Product: CCN(c1ccc(OCCCCN(C)C)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 14.1, reaction of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide 69-2511 with ethanol yielded N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide, MS: 445 (MH+).