Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][N:7]([CH3:14])[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[F:15][C:16]([F:46])([F:45])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31](OS(C)(=O)=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C>CC(C)=O.C(=O)([O-])O.[Na+]>[F:15][C:16]([F:45])([F:46])[C:17]1[CH:18]=[C:19]([CH2:27][CH2:28][N:29]([CH3:44])[C:30](=[O:43])[CH:31]([N:11]2[CH2:12][CH2:13][CH:8]([N:7]([CH2:6][CH:3]3[CH2:4][CH2:5]3)[CH3:14])[CH2:9][CH2:10]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=1
Reactant: CN(CC1CC1)C1CCNCC1
Reactant: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(OS(C)(=O)=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)C(c1ccccc1)N1CCC(N(C)CC2CC2)CC1
Yield: 37.3 %

Procedure:
11.9 g of 4-(cyclopropylmethyl-methyl-amino)-piperidine-dihydrochloride are taken up in 400 ml of acetone and combined with 21.7 g of N-[2-(3.5-bis-trifluoromethyl-phenyl)-ethyl]-2-methanesulphonyloxy-N-methyl-2-phenyl-acetamide and 21 ml of triethylamine. The mixture is refluxed for 16 hours, then the solvent is eliminated in vacuo and the residue is taken up in 10% sodium hydrogen carbonate solution. It is extracted with ether, the combined organic phases are dried over sodium sulphate and the solvent is eliminated in vacuo. The residue is filtered with ethyl acetate/methanol/conc. ammonia solution 70:30:1 through silica gel, freed from the solvents in vacuo and crystallised in methanol with fumaric acid. The precipitate is suction filtered, washed with methanol and dried in vacuo. 9.3 g of N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-[4-(cyclopropylmethyl-methyl-amino)-piperidin-1-yl]-N-methyl-2-phenyl-acetamide are obtained as the sesquifumarate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][CH3:12].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:42][C:43]1([CH3:50])[C:47]([CH3:49])([CH3:48])[O:46][BH:45][O:44]1.C(N(CC)CC)C>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[CH2:11]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([F:8])=[CH:7][C:2]=1[B:45]1[O:46][C:47]([CH3:49])([CH3:48])[C:43]([CH3:50])([CH3:42])[O:44]1)[CH3:12]
Reactant: CCc1cc(OC)c(F)cc1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(OC)c(F)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of 1-bromo-2-ethyl-5-fluoro-4-methoxy-benzene (Preparation 12, 18.0 g, 77.2 mmol) in dioxane (100 mL) were added SPhos (4.12 g, 10.0 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (14.8 g, 116 mmol) and triethylamine (10.7 mL, 77.2 mmol). The reaction mixture was degassed with nitrogen prior to the addition of dichlorobis(acetonitrile)palladium (II) (801 mg, 3.09 mmol). The reaction mixture was then heated at 110° C. for 18 hours, cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The solvent was removed in vacuo and the residue was redissolved in EtOAc (30 mL) and washed with water (30 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was triturated with methanol and the resulting solid was collected by filtration to give the title compound as a beige solid (13.8 g) in a 64% yield.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:16][CH2:17]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (3.15 g, 15.8 mmol), 4-piperidinol (1.0 g, 9.88 mmol), and acetic acid (0.8 mL) in methylene chloride (30 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (3.35 g, 15.8 mmol) was added and the mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride and washed with 1N HCl. The aqueous phase was extracted with ether (3×10 mL) and adjusted to pH 9-10 with 1N NaOH. The basic aqueous mixture was extracted with methylene chloride (3×10 mL). The combined organic extracts were concentrated in vacuo to afford 1,1-dimethylethyl 4-hydroxy-1,4′-bipiperidine-1′-carboxylate (1.1 g, 39% yield). This material was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1>[Pd].CO>[NH2:24][C:22]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[C:4]([O:3][CH:2]([F:27])[F:1])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2OC(F)F)CC1
Yield: 63.1 %

Procedure:
The general hydrogenation procedure as described herein was used with tert-butyl 4-(2-(difluoromethoxy)-4-nitrophenoxy)piperidine-1-carboxylate (193 mg, 0.5 mmol), palladium on charcoal (39 mg) and MeOH (5 mL) under atmospheric pressure (H2 balloon) to give the product (113 mg, 63% yield) after purification by column chromatography on silica gel using EtOAc/heptane (2:8 to 6:4) as eluent.
Reaction SMILES: [CH3:1][C:2]([CH:9]=O)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:11][C:12]([CH:23]=[CH:24][C:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]=1[CH3:33])=[CH:13][CH2:14]P(=O)(OCC)OCC.CS(C)=O.CC(C)([O-])C.[K+]>O1CCCC1.CCCCC>[CH3:8][CH2:7][O:6][C:4](/[CH:3]=[C:2](\[CH:9]=[CH:14]\[CH:13]=[C:12](/[CH:23]=[CH:24]\[C:25]1[C:30]([CH3:32])([CH3:31])[CH2:29][CH2:28][CH2:27][C:26]=1[CH3:33])\[CH3:11])/[CH3:1])=[O:5]
Reactant: CCOP(=O)(CC=C(C)C=CC1=C(C)CCCC1(C)C)OCC
Reactant: CCOC(=O)C=C(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)\C=C\C=C(C)/C=C\C1=C(C)CCCC1(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
To a solution of 57 mg (0.40 mmole) of ethyl 3-methyl-4-oxobutenoate [prepared according to a procedure described by R. W. Curley, Jr., et al., J. Org. Chem., 51, 256 (1986); an alternate synthesis has been described by A. Guingant, et al., J. Org. Chem., 52, 4788 (1987); the compound is commercially available from Fluka Chemical Corp., Ron Kon Koma, New York 11779.] and 132 mg (0.388 mmole) of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diethyl ester (produced in accordance with Example X) in 3.5 mL of 6:1 (v/v) anhydrous tetrahydrofuran:dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5° C. by use of an ice water bath, was added 43 mg (0.38 mmole) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 10 minutes and then at room temperature for 6 hours. The product was isolated by dilution of the mixture with 30 mL of 1:1 (v/v) pentane:ether and subsequent washing of the organic layer with 30 mL portions of 10% aqueous sodium chloride (3×30 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by filtration through a small column of silica gel (15 mL, 60-200 mesh, elution with 75 mL of hexane-4% ether) to remove any unreacted starting materials, afforded 76 mg (61% yield) of ethyl retinoate shown by high-field (300 MHz) NMR analysis to be predominantly the all trans stereoisomer. The product was characterized by three broad singlets of equal intensity at δ 2.37, 2.02, and 1.73 (3 vinyl methyls). For tables listing spectroscopic properties of retinoids, see: R. S. H. Liu, et al. Tetrahedron, 40, 1931-1969 (1984). Ethyl retinoate was also prepared in a similar manner from ethyl 3-methyl-4-oxo-butenoate and 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diisopropyl ester (produced in accordance with Example XI).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[C:16](=O)[NH:15][CH2:14][CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.B>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(C3C(=O)NCCN3C(=O)OC(C)(C)C)ccc21
Agent: B
Solvent: C1CCOC1
Product: Cn1ncc2cc(C3CNCCN3C(=O)OC(C)(C)C)ccc21
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To the solution of tert-butyl 2-(1-methyl-1H-indazol-5-yl)-3-oxopiperazine-1-carboxylate (10 mg) in THF (0.5 mL) at 0° C. was added borane in THF (1.0 N, 1 mL) slowly. The mixture was heated at 55° C. for 3 hours, and was cooled. The reaction was quenched with methanol (1 mL), and was stirred for 30 minutes. The mixture was diluted with ethyl acetate, and was made basic with 1 N sodium hydroxide solution. The organic phase was separated, and was washed with water and brine, and was dried with sodium sulfate. Concentration gave tert-butyl 2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate. LCMS-ESI+: calc'd for C17H25N4O2: 317.2 (M+H+); Found: 317.0 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[CH:6](O)[CH2:7][CH2:8][O:9][C:4]=2[N:3]=[CH:2]1.CC(C)(O)[C:13]#[N:14].P(CCCC)(CCCC)CCCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OC(C)C)(C)C>[S:1]1[C:5]2[CH:6]([C:13]#[N:14])[CH2:7][CH2:8][O:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(O)C#N
Reactant: OC1CCOc2ncsc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: N#CC1CCOc2ncsc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6,7-dihydro-5H-pyrano[2,3-d]thiazol-7-ol (0.65 g, 4.14 mmol), acetone cyanohydrin (880 mg, 10.3 mmol) and (n-Bu)3P (1.67 g, 8.27 mmol) in THF (79 mL) was added at 0° C. 1,1′-(azodicarbonyl)dipiperidine (2.09 g, 8.27 mmol). The mixture was stirred at 0° C. for 30 min, then, it was allowed to warm to RT and was stirred for 2 h. Subsequently, the reaction mixture was diluted with diisopropyl ether, filtrated and the filtrate was conc. in vacuo. Purification by means of CC (5-70% EtOAc/Hept) provided a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([OH:15])=[CH:13][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.BrCC(OCC)=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][C:11]=1[CH3:16])[CH3:7]
Reactant: Cc1cc(N)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(N)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
A solution of ethyl bromoacetate (7.19 ml, 63 mmol) and 4-amino-o-cresol (7.39 g, 60 mmol) in dry acetonitrile (420 ml) was treated at 15° C. with Cs2CO3 (42.03 g, 129 mmol) and stirred at RT for 2 h. Additional ethyl bromoacetate (0.33 ml, 3 mmol) was added and after 4 h, the mixture was filtered, washed with acetonitrile and evaporated. The residue was suspended in CH2Cl2, filtered and evaporated to give 13.34 g (quantitative) of (4-amino-2-methyl-phenoxy)-acetic acid ethyl ester as a green oil, MS: 210 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1>CN(C=O)C.CCOCC.Cl>[CH3:30][C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:40][C:39]3[CH:38]=[CH:37][C:36]([C:35]([F:34])([F:44])[F:45])=[CH:43][CH:42]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:31]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
To a mixture of 54 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester in 2 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 10 mg of NaH (0.253 mmol) is added. The resulting solution is allowed to stand at ambient temperature for 20 min. Then 61 mg of 4-trifluoromethylbenzyl bromide is added and resulting mixture is allowed to stand at ambient temperature for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.3 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 mL). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 35 mg (49%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.35 (d, 2H, J=8.0 Hz), 7.28-7.18 (m, 4H), 7.05 (t, 1H, J=7.2 Hz), 6.91 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.0 Hz), 5.49 (bs, 1H), 4.45, 4.39 (ABq, 2H, J=15.4 Hz), 3.98 (t, 2H, J=5.8 Hz), 3.77-3.65 (m, 1H), 3.42 (t, 1H, J=8.5 Hz), 3.28, 3.14 (ABq, 2H, J=14.0 Hz), 3.05 (t, 1H, J=8.5 Hz), 2.86 (s, 3H), 2.28-2.20 (m, 1H), 1.95-1.85 (m, 1H), 1.43 (s, 3H). HRMS (ES+) m/z exact mass calcd for C30H32N2O5F3 (m+1) 557.2263, found 557.2257.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: c1cncc(-c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c1

Procedure:
The product of Example 1B (80 mg, 0.28 mmol) and pyridine-3-boronic acid (36 mg, 0.29 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.00-2.14 (m, 4 H), 3.01-3.15 (m, 3 H), 3.20-3.28 (m, 2 H), 4.27 (s, 2 H), 7.04-7.09 (m, 1 H), 7.12 (t, J=7.3 Hz, 1 H), 7.37 (dd, J=7.5, 1.4 Hz, 1 H), 7.56 (dd, J=7.8, 5.1 Hz, 1 H), 8.05-8.12 (m, 1 H), 8.55 (dd, J=4.9, 1.5 Hz, 1H), 8.77-8.79 (m, 1 H); MS (ESI+) m/z 290 (M+H)+.
Reaction SMILES: [C:1](=[N:10][OH:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:11][N:10]=[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3])#[N:18]
Reactant: CCC(=NO)c1ccccc1
Reactant: N#Cc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=NOc1ccccc1C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
A solution of 5.0 g of propiophenone oxime in 35 ml of dimethylformamide is added dropwise to a solution of 1.55 g of 62.5% sodium hydride in 80 ml of dimethylformamide under ice-colling, and the mixture is stirred at the same temperature for 20 minutes. A solution of 4.24 g of 2-chlorobenzonitrile in 20 ml of dimethylformamide is added dropwise to the mixture and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=6:1) to give 2.19 g of propiophenone O-(2-cyanophenyl)oxime as oil.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH:12]=[O:13].[BH4-].[Na+].Cl>CO>[CH2:1]1[C:5]2([CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:12][OH:13]
Reactant: O=CC1CCC2(CCC=CCC2)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1CCC2(CCC=CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of spiro[4.6]undec-8-ene-2-carbaldehyde (44 mg) obtained in Step 5 in methanol (1 mL) was added sodium borohydride (9 mg), followed by stirring at room temperature overnight. Then, after addition of aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated to give spiro[4.6]undec-8-ene-2-methanol (44 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[C:17](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17](=[O:25])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)c1cn2c3ccc(Br)cc3c3cc(OC)cc(c1=O)c32
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(=O)c(C(=O)O)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
10-bromo-5-ethoxycarbonyl-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 98 was suspended in ethanol (10 ml), and 1N sodium hydroxide (3 ml) was added. The mixture was stirred at room temperature for 12 hours, and the solvent was evaporated under reduced pressure. To tne residue was added IN hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration, and washed with ethanol and ether to obtain the title compound (310 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1>>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1cc(Br)cc(Br)c1
Reactant: Nc1cccnc1
Product: NC(=O)c1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3,5-Dibromo-benzamide and pyridin-3-ylamine were coupled to give 3-bromo-5-(pyridin-3-ylamino)-benzamide as described for Example 44. 3-Bromo-5-(pyridin-3-ylamino)-benzamide was converted to 3-(1H-indol-4-yl)-5-(pyridin-3-ylamino)-benzamide as described in Example 75. 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.65 (d, J=7.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6.62 (d, J=2.9 Hz, 1H).
Reaction SMILES: C(NC(C1C=C(S(OC[C@](O)(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC2C=CC=CC=2)NC(=O)CN2CCOCC2)(=O)=O)C=CC=1)=O)C#C.[CH3:69][O:70][C:71]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH2:80][C:81]#[CH:82])[C:72]=1[S:83](Cl)(=[O:85])=[O:84].[OH:87][CH2:88][C@:89]([OH:139])([CH3:138])[C:90](=[O:137])[C@@H:91]([NH:96][C:97](=[O:136])[C@@H:98]([NH:106][C:107](=[O:135])[C@@H:108]([NH:113][C:114](=[O:134])[C@@H:115]([NH:124][C:125](=[O:133])[CH2:126][N:127]1[CH2:132][CH2:131][O:130][CH2:129][CH2:128]1)[CH2:116][CH2:117][C:118]1[CH:123]=[CH:122][CH:121]=[CH:120][CH:119]=1)[CH2:109][CH:110]([CH3:112])[CH3:111])[CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[CH2:92][CH:93]([CH3:95])[CH3:94]>>[CH3:69][O:70][C:71]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH2:80][C:81]#[CH:82])[C:72]=1[S:83]([O:87][CH2:88][C:89]([OH:139])([CH3:138])[C:90](=[O:137])[C@H:91]([CH2:92][CH:93]([CH3:94])[CH3:95])[NH:96][C:97](=[O:136])[C@H:98]([CH2:99][C:100]1[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=1)[NH:106][C:107](=[O:135])[C@H:108]([CH2:109][CH:110]([CH3:112])[CH3:111])[NH:113][C:114](=[O:134])[C@H:115]([CH2:116][CH2:117][C:118]1[CH:119]=[CH:120][CH:121]=[CH:122][CH:123]=1)[NH:124][C:125](=[O:133])[CH2:126][N:127]1[CH2:132][CH2:131][O:130][CH2:129][CH2:128]1)(=[O:84])=[O:85]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CO
Reactant: C#CCOc1cc(OC)cc(OC)c1S(=O)(=O)Cl
Agent: C#CCNC(=O)c1cccc(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc2ccccc2)NC(=O)CN2CCOCC2)c1
Product: C#CCOc1cc(OC)cc(OC)c1S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1

Procedure:
Prepared in a similar manner to compound 13, except from 2,4-dimethoxy-6-(prop-2-yn-1-yloxy)benzene-1-sulfonyl chloride and (S)—N—((S)-1-(((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)amino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:58][NH:59][O:60][CH3:61].C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[CH3:61][O:60][N:59]([CH3:58])[C:21]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[O:23]
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
4-Phenyl-8-(trifluoromethyl)quinoline-3-carboxylic acid (6.19 g, 19.51 mmol) was taken into DMF (75 mL) and cooled to 0° C. Then PyBOP (10.66 g, 20.49 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (2.09 g, 21.46 mmol) and diisopropylethylamine (8.50 mL, 48.78 mmol). The reaction was stirred for 3 hours allowing to warm to room temperature during that time. The reaction was poured into water and extracted with ethyl acetate. The combined organics was washed with water, half-saturated brine and then dried over magnesium sulfate. Purification was carried out via column chromatography using 30% ethyl acetate in hexane as the eluent to yield the desired compound as a white solid (6.37 g, 90.6%). MS (ESI) m/z 361 ([M+H]+); Anal. Calcd for C19H15F3N2O2.0.15H2O: C, 62.86; H, 4.25; N, 7.72. Found: C, 62.89; H, 4.14; N, 7.55.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1)([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:29][CH:30]=1
Reactant: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)O)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
3.0 mL of methanol, 2.0 mL of ethyl acetate and 4.0 mg of 5% palladium-carbon were added to 20 mg of 2-(4-nitrobenzamido)-4-phenoxybenzoic acid at room temperature and stirred under hydrogen atmosphere at 40° C. for 8 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 20 mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid as white solid.