Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=O)[C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[N:25][CH:22]=[CH:23][N:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(C(=O)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Reactant: NCCN
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCO
Product: Fc1cc(-c2nccnc2-c2cccc(C(F)(F)F)c2)ccn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Under Ar, a solution of 42 (3.35 g, 11.3 mmol) in EtOH (150 mL) was treated with ethylene diamine (0.9 g, 15 mmol) and heated at 50° C. After 3 h, the reaction was concentrated to dryness and the residue was partitioned between H2O and EtOAc (3×). The combined organic extracts were dried, filtered and concentrated to dryness. The residue was dissolved in toluene (230 mL) and reacted with DDQ (4.0 g, 17.6 mmol). After 18 h at room temperature, the reaction was heated at 60° C. for 2 h then treated with additional DDQ (1.0 g) and heated at 80° C. for 5 h. The reaction was then dry packed with silica gel (70 g) and chromatographed on a Still column (80 mm). The product was eluted with 30% EtOAc-hexanes to yield 2.85 g of 43.
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].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:20].O.C(C(O)=O)(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:20])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl
Yield: 32.8 %

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodo]benzene (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 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: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)cc1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.058 mMol 4-methoxybenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C[O:2][C:3](=[O:47])[C@H:4]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:46])/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=1)[NH:5][C:6](=[O:23])/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH3:22][O:21][C:13]1[CH:12]=[C:11](/[CH:10]=[CH:9]/[CH:8]=[CH:7]/[C:6]([NH:5][C@H:4]([C:3]([OH:47])=[O:2])[CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:46])/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[C:34]2[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=2)=[O:23])[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COC(=O)[C@H](CCCCNC(=O)/C=C/C=C/c1cc(OC)c(OC)c(OC)c1)NC(=O)/C=C/C=C/c1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(/C=C/C=C/C(=O)NCCCC[C@H](NC(=O)/C=C/C=C/c2cc(OC)c(OC)c(OC)c2)C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
Added to a solution of 265 mg (0.40 mmol) of Nα,Nε-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-lysine methyl ester synthesized by the process of Example 9 in methanol-tetrahydrofuran (1 ml-1 ml) was 1.0 ml (5.0 mmol) of a 5N aqueous solution of potassium hydroxide, and the mixture was stirred for 3 hours at room temperature. A saturated saline solution (3 ml) and concentrated hydrochloric acid (0.5 ml) were added to the reaction mixture to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil (234 mg) was purified by column chromatography on silica gel to obtain 203 mg (yield: 80%) of the title compound as a colorless amorphous powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([SH:16])[NH:9][C:10]=1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[F:17][C:18]([F:22])=[C:19]([F:21])[F:20]>>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:10]1[N:9]=[C:8]([S:16][C:19]([F:21])([F:20])[CH:18]([F:22])[F:17])[NH:7][C:6]=1[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)=C(F)F
Reactant: Sc1nc(-c2ccco2)c(-c2ccco2)[nH]1
Product: FC(F)C(F)(F)Sc1nc(-c2ccco2)c(-c2ccco2)[nH]1
Yield: 22.9 %

Procedure:
4,5-bis-(2-Furyl)-1H-2-imidazolethiol (8.1 g; 39.4 mmoles) was reacted with 7.0 g of tetrafluoroethylene and the product purified by chromatography on Silicar CCNo. 7 with chloroform to give 3.0 g of 4,5-bis-(2-furyl)-2-(1,1,2,2-tetrafluoroethylthio)-1H-imidazole, m.p. 166°-167°: (recrystallized from 1-chlorobutane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36].C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:35]#[N:36]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c(C#N)c[nH]c12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c(C#N)c[nH]c12
Reaction time: 1 h
Yield: 94.2 %

Procedure:
(±)-tert-butyl 4-((1-(5-chloro-3-cyano-1H-indol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (70 mg, 0.137 mmol) was stirred in TFA (2 mL, 26.0 mmol) at 0° C. for 20 minutes. The solvent was evaporated at a bath temperature of 23° C. The residue was taken up in Ethanol (5 mL), then triethylamine (1 mL), formaldehyde (0.102 mL, 1.367 mmol) and sodium triacetoxyborohydride (87 mg, 0.410 mmol) were added. The reaction was stirred 1 hour, then solvent was evaporated. The residue was taken up in aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (4×10 mL). The organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with 3%-5%% 2M ammonia in methanol/dichloromethane to give (±)-5-chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indole-3-carbonitrile (55 mg, 0.129 mmol, 94% yield) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.27 (bs, 1H), 7.56 (d, J=1.8 Hz, 1H), 7.27 (m, 2H), 7.14 (d, J=2.8 Hz, 1H), 7.08 (t, J=8.5 Hz, 2H), 6.93 (d, J=1.8 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 4.55 (m, 1H), 3.19 (d, J=8.6 Hz, 1H), 2.62 (m, 1H), 2.52 (m, 2H), 2.35 (m, 1H), 1.95-2.20 (m, 2H), 1.86 (m, 1H), 1.48 (m, 1H), 1.41 (d, J=6.5 Hz, 3H). LC/MS (HPLC method 4): tR=2.84 min, 426.14(MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)=[C:24]3[N:23]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccnc(C)c4)c3n2)ccc1C(F)(F)F
Yield: 48.5 %

Procedure:
Reaction of 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (113 mg, 49%). MS (ISP) 467.4 [(M+H)+]; mp 226° C.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C[S+](C)C.[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][C:20]2=O)=[CH:16][CH:15]=1.C1C[O:27][CH2:26]C1>O.C(OCC)C>[CH3:12][O:13][C:14]1[CH:22]=[C:21]2[C:17]([CH2:18][CH2:19][CH:20]2[CH:26]=[O:27])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: C1CCOC1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(C=O)CC2
Temperature: 75 °C
Reaction time: 96 h

Procedure:
A dimethylsulfoxide (8 mL) solution containing sodium hydride (60%, 0.14 g, 3.5 mmol) was heated at 75° C. for ca. 45 minutes. The solution was cooled to room temperature and diluted with THF (8 mL). The solution was cooled to 0° C. and trimethylsulfonium iodide (0.7 g, 3.4 mmol) was added in portions. After 15 minutes a THF solution of 6-methoxyindan-1-one (0.5 g, 3.1 mmol) was added. The solution was then stirred at room temperature for 4 days. The solution was diluted with water and ethyl ether. The organic phase was washed with water (3×) and brine. The solution was then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. 1H NMR (500 MHz, CDCl3): δ 9.68 (d, J=2.9 Hz, 1H); 7.29 (s, 1H); 7.21 (d, J=8.0 Hz, 1H); 6.86-6.82 (m, 1H); 3.95-3.93 (m, 1H); 3.82 (s, 3H); 3.03-2.93 (m, 2H); 2.48-2.44 (m, 1H); 2.41-2.37 (m, 1H). LCMS1 2.90 min. (M+H)=177
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:31]5[C:27]=4[CH:28]=[N:29][N:30]5[CH3:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[N:29][N:30]4[CH3:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A solution of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.025 g, 0.05 mmol) in tetrahydrofuran (5 mL) was treated with 1M aqueous hydrochloric acid (1 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was partioned between ethyl acetate and water. The aqueous phase was made basic with 1N aqueous sodium hydroxide and extracted with ethyl acetate twice. The combined organic phase was concentrated in vacuo and the residue purified by flash column chromatography (silica gel, 0% to 40% tetrahydrofuran/ethyl acetate) which afforded (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.013 g, 56%) as a white solid: HR-ES-MS m/z calculated for C24H30N6O5 [M+H]+ 483.2351, observed 483.235; 1H NMR (300 MHz, CDCl3) δ ppm 0.97 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 1.59 (br. s., 1H), 1.69-1.97 (m, 2H), 2.72 (br. s., 2H), 3.56 (dd, J=11.8, 4.8 Hz, 1H), 3.68 (dd, J=11.8, 3.3 Hz, 1H), 4.06-4.16 (m, 5H), 4.20 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.88 (t, J=7.8 Hz, 1H), 5.03 (s, 1H), 6.66 (d, J=2.1 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 7.29-7.43 (m, 4H), 7.96 (s, 1H), 9.39 (br. s., 1H).
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:23](=[O:24])[N:22]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[CH2:21][CH:20]([C:33]([O:35][CH3:36])=[O:34])[C:11]3[N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]4=[C:9]([OH:8])[C:10]=3[C:23]2=[O:24])=[CH:31][CH:30]=1
Reactant: COC(=O)C1CN(Cc2ccc(F)cc2)C(=O)c2c(OCc3ccccc3)c3n(c21)CCN(C)C3=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c3n(c21)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 10-(benzyloxy)-2-(4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,3,4,6,7,8,9-octahydropyrido[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (50 mg, 0.10 mmol) and Pearlman's catalyst (5 mg, 20% Pd(OH)2 on carbon) in ethanol (4 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 1 hr. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue subjected to reverse phase HPLC purification. Collection and lyophilization of appropriate fractions provided the title product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[CH3:17][C:11]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][CH3:1])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CSc1ccccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)Oc1ccccc1SC
Temperature: 105 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
2-Methylsulfanyl-phenol (2.00 g, 14.29 mmol), 2-bromo-2-methyl-propionic acid, ethyl ester (28 g, 142.8 mmol) and powdered K2CO3 (4.93 g, 35.7 mmol) were mixed (no solvent) and stirred at 105° C. for 8 hrs. After cooling, water and CHCl3 were added. The CHCl3 was separated, dried (MgSO4) and concentrated. Xylene was added and concentrated in vacuo (4 times) to remove the bromo ester. The resulting oil was chromatographed on silica, eluting with CH2Cl2 to obtain the title compound (2.30 g, 63% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]([CH3:12])[C:10]2[CH:13]=[C:14]([Br:20])[C:15](=[O:19])[C:16]([OH:18])=[CH:17][C:9]=2[C:8](=[O:21])[CH:7]=1)=[O:5])C>Cl>[Br:20][C:14]1[C:15](=[O:19])[C:16]([OH:18])=[CH:17][C:9]2[C:8](=[O:21])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]([CH3:12])[C:10]=2[CH:13]=1
Reactant: CCOC(=O)c1cc(=O)c2cc(O)c(=O)c(Br)cc2n1C
Agent: Cl
Product: Cn1c(C(=O)O)cc(=O)c2cc(O)c(=O)c(Br)cc21
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-8-bromo-4,7-dioxo-6-hydroxy-1-methyl-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (3.6 g, described in Example 9) and concentrated hydrochloric acid (300 ml) is refluxed for 30 min and cooled to room temperature. The precipitate is collected and washed with water to give the title compound, mp > 250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CO.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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc(Cl)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 2-bromo-4-chloro-toluene (20.5 g) in toluene (100 mL) was added Pd(PPh3)4 (1 g) and the mixture was stirred at room temperature under N2 for 0.25 hours. A 2M solution of Na2CO3 (100 mL) was then added, followed by the dropwise addition of 4-trifluoromethylphenyl boronic acid (19 g) in MeOH (100 mL). The resulting mixture was heated under reflux for 48 hours. The mixture was then cooled to room temperature and the phases were separated. The organic layer was then dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with petroleum ether/AcOEt (90/10) to give the title compound (25.3 g) as a colorless liquid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].O.[CH3:19][NH:20][C:21](=[O:24])[CH2:22]Cl>CC(C)=O>[CH3:19][NH:20][C:21](=[O:24])[CH2:22][O:11][C:4]1[CH:3]=[C:2]([C:12]([F:13])([F:14])[F:15])[CH:1]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:5]=1
Reactant: CNC(=O)CCl
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a stirred solution containing 5 g (0.022 mole) of 3,5-ditrifluoromethylphenol, 1.6 g (0.024 mole) of 85% potassium hydroxide, 10 ml of water and 200 ml of acetone, 0.024 mole of N-methyl chloroacetamide was added in one portion. The stirred reaction mixture was heated at 56°-60° C. for 22 hours. After cooling to 0° C., 600 g of ice water was added and stirring continued at 0°-10° C. for 30 minutes. The resulting solid was collected by filtration, washed with water until neutral to litmus and air-dried at 25°-30° C. A product with a melting point of 98°-99° C. (determined after recrystallization from heptane) was obtained with a 24% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][CH:16]=1.II.[OH-].[Na+]>CCOCC.CCCCCC.C(Cl)Cl.O>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Clc1ccnc2ccccc12
Agent: II
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a solution of 4.3 g (25 mmol) of p-bromotoluene in 75 ml of ether cooled to 5° was dropwise added 15 ml of a 1.6M solution of butyl lithium in hexane, while maintaining the temperature below 5°. This mixture was stirred at 5° for 10 min. and at 30° for 10 min., and then cooled to -20°. A solution of 3.4 g (20 mmol) of 4-chloroquinoline in 15 ml of ether was added while maintaining the temperature at -20°. It was allowed to warm to room temperature during 15 min. To the reaction mixture was then added 10 ml of water and 5 g of iodine, and 60 ml of 3N sodium hydroxide. After 20 min. of stirring the organic layer was separated. The aqueous phase was extracted with an equal volume of ether in three portions. The organic phases were combined, washed with water, dried over sodium sulfate, and concentrated in vacuo to leave an oil. This oil was dissolved in methylene chloride and the solution filtered through a plug of alumina. The filtrate was concentrated in vacuo to give 2.6 g of product mp 75°-77°, as off-white needles.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:3])=[O:12])([O-:7])=[O:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1

Procedure:
Thionyl chloride (25 mL) was added to 3-nitrobenzoic acid (3 g, 18 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried to obtain 3-nitrobenzoyl chloride as a yellow solid. 3-Hydroxyanthranilic acid (0.92 g, 6.0 mmol) and pyridine (1.45 mL, 18.0 mmol) were added to toluene (30 mL) and the mixture was stirred at room temperature for 30 min. Then 3-nitrobenzoyl chloride prepared above (3.34 g, 18 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The solvents was evaporated under reduced pressure and the residue was washed with 5% aqueous hydrochloric acid (100 mL×3), filtered, the solid was washed with water (100 mL×3), dried in vacuum at 50° C. to obtain 3-hydroxy-2-(3-nitrobenzeneamido)benzoic acid as a yellow solid (1.8 g, yield 100%). LC-MS (ESI) m/z 303 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[CH2:26]([Mg]Br)[CH3:27].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:26][CH3:27]
Reactant: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1ccc(OC)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(6,7-Dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml), and a 1 M tetrahydrofuran solution of ethylmagnesium bromide (0.5 ml) was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxyphenyl}-1-propanol.
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][C@H:6]1[OH:21].[H][H].C(OCC)C>CO.[Pd]>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@H:6]1[OH:21]
Reactant: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: Cc1cccc(O[C@@H]2CCNC[C@H]2O)c1C
Yield: 46.6 %

Procedure:
A solution of trans-benzyl 4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate (3.5 g, 9.8 mmol) in methanol (50 ml) was added to 5% palladium on charcoal (350 mg) under an atmosphere of nitrogen. The vessel was placed under an atmosphere of hydrogen and stirred vigorously until hydrogen uptake ceased. The resulting suspension was filtered over a short pad of celite (pre-washed with methanol) and the pad washed with a further portion of methanol (100 ml). Concentration of the methanolic solution in vacuo gave a yellow oil. Dilution with diethyl ether (100 ml) yielded trans-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine as a white solid (1.01 g, 50%).