Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[CH2:26][C:27](OC)=[O:28]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:28]=[C:27]([CH2:26][CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CC1Cc2ccccc2C1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CC1Cc2ccccc2C1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78°, 36.0 g (0.20 mole) methyl (2-indanyl)acetate added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of choroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, dimethyl 2-oxo-3-(2-indanyl) propylphosphonate.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[ClH:1].[I:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(I)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1ccc(I)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A suspension of ethyl glycinate hydrochloride (944 mg) in DMF (6.0 mL) was stirred for 5 min. p-Iodobenzyl bromide (2.00 g) was added. The heterogeneous system was warmed to 50° C. and stirred for 5 min, during which time, most solids dissolved. K2CO3 (2.80 g, granular) was added steadily over 5 min. After 2 h, the reaction was cooled to 23° C. Conc. aq. HCl (3.3 mL) was added, followed by H2O (7.0 mL). The heterogeneous mix was stirred for 15 min and filtered (the cake was washed with CH3CN (4×5 mL)). The net filtrate was concentrated until no CH3CN remained. The crude product solution was filtered through a 0.45 micron Teflon filter and loaded directly onto a Teledyne Isco ‘gold’ 100 gram column and flashed (Eluent: 0.05% w/v aq. HCl/CH3CN 95:5→0:100), giving DK (688 mg, 29% yield) as an HCl salt. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.78 (s, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.36 (d, J=7.8 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 4.15 (s, 2H), 3.95 (s, 2H), 1.25 (t, J=7.0 Hz, 3H). LCMS-ESI+: calc'd for C11H15INO2: 320.0 (M+H+). Found: 319.9 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[P:27]([O:34]CC)([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].[I-].[Na+]>C(#N)C>[CH2:29]([O:28][P:27]([CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)([O:31][CH2:32][CH3:33])=[O:34])[CH3:30]
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCOP(OCC)OCC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product from Step C is dissolved in acetonitrile and cooled to 0° C. Triethyl phosphite (1 equivalent) and sodium iodide (1 equivalent) are added, and the reaction stirred at room temperature overnight. The reaction is quenched with ammonium chloride, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:17])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1.C(=O)([O-])[O-].[Na+:27].[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[NH:7][C:8]1[NH:9][C:10](=[O:17])[C:11]([C:14]([O-:16])=[O:15])=[CH:12][N:13]=1.[Na+:27]
Reactant: CC(C)COc1ccccc1Nc1ncc(C(=O)O)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccccc1Nc1ncc(C(=O)[O-])c(=O)[nH]1
Yield: 57.8 %

Procedure:
A mixture of 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylic acid (20 g) and sodium carbonate (7.0 g) in ethanol (100 ml) and water (100 ml) is heated until the solution is completed. After allowing to stand the solution overnight, the precipitate is collected by filtration, washed with water and dried to give sodium 1,6-dihydro-2-[2-(2-methylpropoxy)anilino]-6-oxo-5-pyrimidinecarboxylate (12.4 g). M.p. 231°-233° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=3)[C:22](O)=[O:23])[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:28])[CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC#N>[CH2:26]([NH:28][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([C:10]2[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[N:9]=2)[CH:18]=[N:19][CH:20]=1)[CH3:27]
Reactant: Cc1cccc(-c2nc(-c3cncc(C(=O)O)c3)c3cc[nH]c3n2)n1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCNC(=O)c1cncc(-c2nc(-c3cccc(C)n3)nc3[nH]ccc23)c1

Procedure:
To a solution of 5-[2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-nicotinic acid (Intermediate 5) (1 eq, 0.143 mmol, 50 mg) in MeCN (3 ml), ethylamine (1 eq, 0.143 mmol, 6.6 mg), EDC hydrochloride (1.5 eq, 0.215 mmol, 42 mg), HOBt (1.2 eq, 0.172 mmol, 23 mg), and TEA (5 eq, 0.720 mmol, 0.1 ml) are added. The mixture is heated using microwave radiation at 140° C. for 20 min. The resulting precipitate is filtered off and washed with MeCN. Drying the solid in vacuum affords the title compound; [M+H]+=359; 1H-NMR (400 MHz, CD3OD): δ 9.55 (d, 1H), 9.15 (t, 1H), 9.12 (d, 1H), 8.47 (d, 1H), 7.86 (t, 1H), 7.67 (d, 1H), 7.36 (d, 1H), 6.99 (d, 1H), 3.50 (q, 2H), 2.68 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:11])([F:1])[F:12])=[CH:4][CH:5]=3)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)nc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(C(F)(F)F)nc1
Yield: 38 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (6-(trifluoromethyl)pyridin-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 38% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.89 (t, J=5.6 Hz, 1H), 8.69 (br s, 1H), 8.61 (d, J=8.1 Hz 1H), 7.98-7.96 (m, 1H), 7.87-7.84 (m, 1H), 7.45-7.33 (m, 5H), 6.39 (dd, J=8.1, 2.6 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 5.16 (s, 2H), 4.50 (d, J=5.6 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 501.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C.O>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:37])=[O:36]
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2c(F)cccc2F)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,6-difluorobenzenesulfonyl chloride (24.0 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,6-difluorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6.6 mg, 0.013 mmol ) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (6.8 mg). MS m/z 409 [M+H]+.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:30][C:29]=2[C:39]([O:41][CH3:42])=[O:40])[C:19]([CH:21]2[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C=O>CO.CC(O)=O.[Pd]>[CH3:42][O:41][C:39]([C:29]1[S:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:32][C:28]=1[N:18]([C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH3:9])[CH2:12][CH2:13]1)=[O:40]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)C1CCC(C)CC1
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C)CC1)C(=O)C1CCC(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
4-{[(2-Methoxycarbonyl-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (190 mg, 0.32 mmol) was dissolved in MeOH (3.2 mL) and treated with formaldehyde (37% solution, 0.36 mL, 3.2 mmol), AcOH (1 drop) and 10% Pd/C (97 mg) under H2 (30 psi). The reaction was stirred at room temperature for 48 h and the mixture was filtered on celite. The solution was evaporated to a residue that was purified by silica gel column chromatography using CH2Cl2:MeOH as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (46.5 mg, 31% yield). 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.43 (m, 3H), 7.10 (s, 1H), 3.97 (m, 1H), 3.85 (s, 3H), 3.20 (m, 3H), 2.48 (s, 3H), 2.42 (m, 1H), 2.10 (m, 1H), 1.85 (m, 3H), 1.70-1.40 (m, 8H), 1.30 (m, 2H), 0.78 (d, 3H), 0.68 (m, 2H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:7][CH:8]1[CH2:25][CH2:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[CH:5]=C.CSC>CO>[O:1]=[CH:5][CH2:4][O:7][CH:8]1[CH2:9][CH2:10][C:11]2([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH2:24][CH2:25]1
Reactant: O=[O+][O-]
Reactant: C=CCOC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CO
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCC=O)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
O3 gas was passed through a stirred solution of tert-butyl 9-(allyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (6.47 mmol, 1.0 eq.) in MeOH (40 ml) for 45 min at −78° C. Dimethylsulfide (77.64 mmol, 12.0 eq.) was added dropwise to the reaction mixture at 0° C. and it was stirred for 30 min at 25° C. The reaction mixture was concentrated under reduced pressure to yield the crude product as a light yellow oil which was used in next step without further purification. Yield: 99%
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Z-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (2.0 g, 0.0051 mol) (prepared as described in Method A) was dissolved in ethanol (8 ml) and 12N sodium hydroxide solution (1.3 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 1.8 ml) was added with cooling, followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtratiion and dried in vacuo to give the title compound (0.70 g, 34%), m.p. 206°-211° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.[Br:23]Br.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:23][CH:13]([C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([F:1])=[CH:3][CH:4]=1)=[O:22])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: BrBr
Reactant: CCOC(=O)CCCCC(=O)c1ccc(F)c2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)c2ccccc12
Temperature: 25 °C

Procedure:
Ethyl 6-(4-fluoro-1-naphthyl)-6-oxohexanoate (27.7 g) was dissolved in methylene chloride (100 ml), and bromine (14.6 g) was added dropwise with stirring at room temperature. After an hour of stirring at room temperature, a 10% aqueous solution of sodium sulfite was carefully added until disappearance of the red color of bromine, which was extracted with diethyl ether (300 ml×2). The organic layer was washed with a 10% aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous magnesium sulfate, and concentrated to give ethyl 5-bromo-6-(4-fluoro-1-naphthyl)-6-oxohexanoate as an oil (34.9 g, quantitative).
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)=[O:4].[OH-:21].[Na+]>>[CH:16]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:21])=[CH:6]1)([CH3:18])[CH3:17]
Reactant: [OH-]
Reactant: COc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Agent: [Na+]
Product: COc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-methoxy-1H-indol-3-yl)-ethanone (950 mg, 3.33 mmol) in a 20% aqueous sodium hydroxide solution (12 mL) was heated at 105° C. for 18 h. At this time, the reaction was cooled to 25° C., partitioned between water (50 mL) and ethyl acetate (50 mL), and treated with a 1N aqueous hydrochloric acid solution (35 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solids were collected by filtration, washed with petroleum ether, and dried in vacuo to afford 1-isopropyl-6-methoxy-1H-indole-3-carboxylic acid (553 mg, 71%) as orange needles: mp 162-163° C.; EI-HRMS m/e calcd for C13H15NO3 (M+) 233.1052, found 233.1056.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:16]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]Cl)[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl>CN(C)C=O.CCOCC.O>[CH:20]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][N:11]3[CH2:10][CH2:9][N:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:14][CH3:15])[CH2:13][CH2:12]3)[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Reactant: COc1ccc(F)cc1N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc(F)cc1N1CCN(CCC(C(=O)N2C3CCCC2CC3)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of the 4-(5-fluoro-2-methoxyphenyl)-piperazine (2.1 g, 10.0 mmole, prepared by method disclosed in U.S. Pat. No. 4,585,773), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (3.40 g, 10.0 mmole), diisopropylethylamine (1.4 g, 11.0 mmole) and potassium iodide (1.66 g, 10.0 mmole) was heated in dimethylformamide (35 mL) to 80° C. for 5 hours. After cooling to ambient temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give crude product. Purification of this material by column chromatoghaphy (silica gel with 2% methanol in ethyl acetate as eluant) followed by the treatment with 1.1 equivalent of 1N hydrogen chloride in ether gave 1.3 g of the title compound as the hydrochloride quarter hydrate, m.p. 203°-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:25]=[C:26]([O:32][CH3:33])[C:27]([O:30][CH3:31])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: COc1ccc(Br)cc1OC
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC)c(OC)c3)cc12
Temperature: 110 °C
Yield: 84 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.31 mmol), 4-bromoveratrole (83 mg, 0.37 mmol), and aqueous potassium carbonate solution (2M, 0.62 mL, 1.24 mmol) in toluene (1.8 mL) and ethanol (0.6 mL) was degassed with nitrogen for 5 minutes then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.8 mg, 0.016 mmol). The reaction mixture was heated to 110° C. for 2.5 h. The reaction was cooled to room temperature and poured into water and ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash column chromatography was performed on the crude product using heptanes/ethyl acetate (4:1 to 1:1) to give the title compound (90 mg 84%). MS (ES+) 346.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (br. s., 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.04 (d, J=8.29 Hz, 1H), 6.98 (s, 1H), 6.93 (d, J=8.29 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:22][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:28][CH:29]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCCO)cc1
Reactant: FC(F)(F)c1cc(Cl)cc(-c2cccc(Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 14.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.120 g, 0.41 mmol), 4-aminophenpropyl alcohol (0.093 g, 0.61 mmol), palladium acetate (0.005 g, 0.021 mmol), rac-BINAP (0.019 g, 0.031 mmol) and cesium carbonate (0.335 g, 1.02 mmol) in dioxane (5 mL) under argon. The reaction mixture was heated to 120° C. under microwave irradiation for 4 h. After this time, the reaction mixture was cooled and diluted with water (5 mL) and ethyl acetate (100 mL). The organic layer was washed with saturated sodium chloride (2×5 mL), dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.024 g, 15%) as an off-white solid. MW=406.83. M.p. 46-48° C. 1H NMR (DMSO-d6, 500 MHz) δ 9.28 (s, 1H), 7.98-7.96 (m, 1H), 7.91-7.86 (m, 1H), 7.56-7.51 (m, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.17 (d, J=2.0 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 3.43 (q, J=6.0 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 1.77-1.59 (m, 2H); APCI MS m/z 407 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH2:31])[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH:31][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCOc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(N)c1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 92.7 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-ethoxyphenyl 3-nitrophenyl ketone, 1.16 g of 1-(3,5-difluorophenyl)ethylamine, 2.01 ml of triethylamine, 0.49 ml of titanium tetrachloride, 975 mg of sodium cyanoborohydride and 0.32 ml of acetic acid were reacted, to obtain 1.41 g of the title compound as a yellow oil.