Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.122 g; 0.302 mmol) in methanol (6.2 mL) and ethanol (3.1 mL) was added a 5% sodium hydroxide solution (8 mL; 10.00 mmol). The reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.031 g (26%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:28][CH:29]([F:33])[C:30](Cl)=[O:31]>>[Cl:28][CH:29]([F:33])[C:30]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31]
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=C(Cl)C(F)Cl
Product: C[C@H](NC(=O)C(F)Cl)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and chlorofluoroacetyl chloride (19 mg, 150 μmol). Yield 16 mg (70%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([O:13][CH2:14][CH3:15])=[N:11][CH:12]=1.[B:20]([O-])([O-:22])[O-:21]>CCOCC>[CH2:14]([O:13][C:10]1[C:9]([C:16]([F:19])([F:18])[F:17])=[CH:8][C:7]([B:20]([OH:22])[OH:21])=[CH:12][N:11]=1)[CH3:15]
Reactant: CCOc1ncc(Br)cc1C(F)(F)F
Reactant: [O-]B([O-])[O-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOc1ncc(B(O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Alternatively, n-butyl lithium (1.6 M solution in hexane, 0.9 mL, 1.43 mmol) was slowly added to a solution of 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (352 mg, 1.3 mmol) in 2.6 mL anhydrous Et2O at −78° C. under nitrogen. The mixture was kept at −78° C. for 1 hr, and then to this mixture was added triisoporpyl borate (489 mg, 2.6 mmol). The mixture was allowed to warm to ambient temperature overnight. The reaction was quenched by water and the pH was adjusted to 5 by carefully addition of 1N aqueous HCl. Two layers were separated and the aqueous layer was extracted with ethyl acatate three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-ethoxy-3-trifluoromethylpyridine-5-boronic acid as a brown oil (240 mg, 67% yield). The product was used for the next step without purification.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([CH:11]1[CH2:15][S:14][CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]>O>[CH2:7]([CH:11]1[CH2:15][S:14](=[O:2])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC1CCSC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCC1CCS(=O)C1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Sodium metaperiodate (4.1 g, 0.019 mole) was dissolved in 40 ml of water and cooled in an ice bath. 3-Butyltetramethylene sulfide (2.62 g, 0.018 mole) was added and the reaction mixture was stirred at 0° overnight. The NaIO3 which precipitated during the reaction was removed by filtration, and the filtrate was extracted with two 40-ml portions of chloroform. The extract was dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. Vacuum distillation yielded 1.8 g (62%) of 3-butyltetramethylene sulfoxide: b.p. 95° C. C/0.52 mm. Anal. Calcd. for C8H16SO; C, 59.95, H, 10.06; S, 20.00. Found: C, 59.78; H, 10.05, S, 1972%. The NMR spectrum is consistent with the structure for 3-butyltetramethylene sulfoxide.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C(Cl)Cl.CO>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:5]([C@H:14]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:44][CH2:43]1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)nc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(CCCc4ccccn4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 96.8 %

Procedure:
The title compound was prepared from 42 mg (0.096 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, (4-methoxy)benzyl ester (from EXAMPLE 33, Step E) and 36 mg (0.18 mmol) of 4-(2-pyridylpropyl)piperidine.2 TFA (from EXAMPLE 72, Step B) using a procedure analogous to that described in EXAMPLE 71, Step A. Flash chromatography using 25:1 v/v CH2Cl2/MeOH provided 58 mg (97%) of the title compound: 1H NMR (500 MHz) δ 0.94-3.28(35H), 3.82 (s, 3H), 5.11 (ABq, J=11.9, 2H), 6.88-7.35 (11H), 7.58-7.61 (m, 1H), 8.52 (d, J=4.1, 1H); ESI-MS 624 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O
Yield: 88.9 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) was dissolved in tetrahydrofurane (5 ml). Sodium hydrogencarbonate (0.053 g; 0.631 mmole) was added and the mixture was stirred for a little while. 4-tert-Butylbenzoyl chloride (0.118 g; 0.6 mmole) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane:heptane (1:1), dichloromethane and finally methanol:dichloromethane (1:99) as eluants gave 0.238 g (89% yield) of 3-{4-[2-{4-(4-[tert-butyl]benzoyl)aminophenyl}ethoxy]phenyl}-2-(S)-ethoxypropanoic acid.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:38])[F:37])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:37])[F:38])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28][CH3:29])=[O:27])=[O:21])[CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)ccc2C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of methyl 3-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2(trifluoromethyl)benzoyl]amino]-2,4-dimethyl-benzoate (180 mg, 0.32 mmol) in THF (10.0 ml) is added Bu4NF 1.0 M in THF (2.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 8 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (neutral alumina) over a gradient using 100% ethyl acetate in hexane to afford the title compound as a white solid (0.11 g, 76%). Mass spectrum (m/z): 451.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O)([CH3:4])[CH3:3].[Br:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[NH:33][C:32]2=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:9][N:33]1[C:32](=[O:39])[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=2)[C:34]1=[O:38])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(Br)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
325 mg of 2-(R)-[1-(S)-(benzylamino)carbonyl-3-methyl-butylamino]-4-hydroxy-butanoic acid-1,1-dimethylethyl ester, prepared as described for Example N, was added to 10 mL DMF, followed by 226 mg 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole. 231 mg of triphenylphosphine was added and the mixture was cooled to 0° C. 0.14 mL diethyl azodicarboxylate was added and the mixture was warmed to RT with stirring for 16 h. The solvents were removed by evaporation and the resulting residue was purified by reverse phase H.P.L.C. to give the title compound; 53 mg.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH2:13]C)=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.C(N(CC)CC)C.[CH2:22]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH2:3]1
Reactant: CCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1(N)CCCN(C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OC)CCCN(C)C2)cc1
Reaction time: 8 h

Procedure:
A solution of ethyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (52 mg, 0.28 mmol) and triethylamine (0.2 mL, 1.44 mmol) in dichlormethane (15 mL) was treated with 4-n-pentylbenzenesulfonly chloride (120 mg, 0.487 mmol). The resulting mixture was stirred overnight. After removal of the volatiles, the residue was redissolved in dichloromethane, washed with sat. NaHCO3, dried (Na2SO4), evaporated and purified by flash chromatography (eluent: EtOAc/hex 1:1 to EtOAc) to give the title compound. (95 mg, 86%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 5.67 (brs, 1H), 3.55 (s, 3H), 2.84 (d, 1H, J=11.6 Hz), 2.73-2.60 (m, 4H), 2.47 (brs, 1H), 2.20-1.92 (m, 6H; NCH3 and 3H), 1.70-1.57 (m, 3H), 1.48-1.27 (m, 6H), 0.88 (t, 3H, J=7.2 Hz); MS 397.2 ESI [M+H]+, calcd for [C20H32N2O4S+H]+ 397.22
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[N:10]1[C:18]2[C:13]3[C:14](=[CH:19][CH:20]=[CH:21][C:12]=3[C:11]=1S)[CH:15]=[CH:16][CH:17]=2.C(O)C.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>CC(C)=O>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:11]2[C:12]3[CH:21]=[CH:20][CH:19]=[C:14]4[C:13]=3[C:18](=[CH:17][CH:16]=[CH:15]4)[N:10]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: NCCCn1cccn1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCn1cccn1)=N2

Procedure:
A mixture consisting of 2.8 grams of 3-(1H-pyrazol-1-yl)propanamine, 3.7 grams of benz(cd)indol-2-thiol, 7.0 grams of mercuric acetate, and 400 ml of ethanol was stirred and heated under reflux, by the conditions of Example 55. The isolated crude free base, weight 4.0 grams, was dissolved in 150 ml of acetone and added to stirred boiling solution of 3.5 grams of fumaric acid in 800 ml of acetone. After cooling, the precipitate of the title compound was collected, washed with acetone, and dried. The yield was 4.1 grams; mp 178° C.-180° C. was decomposition.
Reaction SMILES: [C:1]1([NH:7]/[N:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[N+]([C:24]([CH2:51][CH2:52][CH2:53][CH3:54])=[CH:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][C:27]=1[C:39]([N:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42]1)=[O:40])([O-])=O.C(O)(C(F)(F)F)=O>C1COCC1>[C:33]([O:32][C:30]([C:29]1[CH:37]=[CH:38][C:26]([C:25]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:24]=2[CH2:51][CH2:52][CH2:53][CH3:54])=[C:27]([C:39]([N:41]2[CH2:50][CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)=[O:40])[CH:28]=1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CCOC(=O)/C=N/Nc1ccccc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of (E)-ethyl 2-(2-phenylhydrazono)acetate (31 mg, 0.16 mmol) in THF (1 mL) at −78° C. was added potassium tert-butoxide (0.161 mL, 0.161 mmol). After stirring at −78° C. for 15 min, a solution of tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (75 mg, 0.161 mmol) in THF (1.0 mL) was added. After stirring at −78° C. for 15 min, TFA (0.024 mL, 0.323 mmol) was added and the reaction mixture became colorless. The reaction mixture was stirred at −78° C. for 2 h and was then allowed to warm to room temperature and stirred at room temperature for 30 min. The reaction mixture was quenched with sat. aq. sodium bicarbonate solution and then extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-40% EtOAc/hexanes) to give the title compound (33 mg, 34%) as a colorless oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.49-7.37 (m, 6H), 7.26-6.81 (m, 4H), 5.02-4.98 (m, 1H), 4.47-4.38 (m, 1H), 4.32-4.27 (m, 2H), 4.16-3.98 (m, 1H), 3.58-3.40 (m, 1H), 2.82-2.51 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.20 (t, J=8 Hz, 1.5H), 1.47-0.91 (m, 4H), 0.60-0.56 (m, 3H); MS(ESI+) m/z 608.3 (M+H)+.
Reaction SMILES: C(O[CH2:4][CH2:5]O)C.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24]C=[CH:22][N:21]=2)[CH:15]=1>O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:4]([CH3:5])=[CH:22][N:21]=2)[CH:15]=1
Reactant: CCOCCO
Reactant: Cc1ccccc1-c1cccc(-c2ccccn2)c1
Solvent: O
Product: Cc1ccc(-c2cccc(-c3ccccc3C)c2)nc1

Procedure:
To a mixture of 2-ethoxyethanol (95 mL) and water (25 mL) were added 11.0 g (42.4 mmol) of 2-(2′-methylbiphenyl-3-yl)pyridine and 7.9 g (21.2 mmol) of IrCl3. The reaction mixture was heated under a nitrogen atmosphere at reflux for 50 h and cooled. The yellow precipitate that formed was collected by vacuum filtration and washed with methanol and ethyl acetate to give 11.0 g (70%) of chloro-bridged dimer
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=1.CO.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:14]1[CH:13]=[N+:12]([O-:9])[CH:17]=[CH:16][CH:15]=1)[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)Cc1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 124.9 %

Procedure:
m-Chloro perbenzoic acid (6.2 g, 36.06 mmol) in CHCl3 (30 mL) was added drop wise to a solution of ethyl 2-(pyridin-3-yl)acetate (3.5 g, 21.21 mmol) in CHCl3 (30 mL) at room temperature under nitrogen atmosphere and the resulting reaction mass was stirred at room temperature for 5 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mass was basified using aqueous NaHCO3 solution to pH 7 and extracted using CHCl3. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4.8 g of the crude product. LCMS: 60.09%, m/z=182.0 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:2].O[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CO)cc1
Reactant: O=Cc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C=O)c2)cc1

Procedure:
Mix 4-ethoxybenzyl alcohol (3.35 g. 22 mmol), 3-hydroxy-benzaldehyde (2.69 g, 22 mmol), triphenylphosphine (5.8 g, 22 mmol) and diethylazadicarboxylate (3.83 g, 22 mmol) in tetrahydrofuran (25 mL). Stirat room temperature under anhydrous atmosphere until the reaction is done. Concentrate the solution in vacuo and dilute with a small quantity of ethyl ether. Filter any precipitate and concentrate the filtrat in vacuo. Purify by silica gel chromatography to give 3-(4-ethoxybenzyloxy)benzaldehyde.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH:6]1([CH2:9][O:10][C:11]2[C:12]([O:23][CH3:24])=[CH:13][CH:14]=[C:15]3[C:20]=2[NH:19][C:18](=[O:21])[CH:17]=[C:16]3O)[CH2:8][CH2:7]1.C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:5][C:16]1[C:15]2[C:20](=[C:11]([O:10][CH2:9][CH:6]3[CH2:8][CH2:7]3)[C:12]([O:23][CH3:24])=[CH:13][CH:14]=2)[NH:19][C:18](=[O:21])[CH:17]=1
Reactant: COc1ccc2c(O)cc(=O)[nH]c2c1OCC1CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2c(N)cc(=O)[nH]c2c1OCC1CC1
Yield: 72 %

Procedure:
Ammonium acetate (620 g, 8.0 mol) was added to a solution of 8-(cyclopropylmethoxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (105 g, 0.40 mol), acetic acid (400 mL), and toluene (200 mL). The reaction was refluxed with a Dean-Stark apparatus for 2 h, and then the mixture was concentrated to remove the toluene. The reaction was then refluxed overnight. Water/ice (200 mL) was added, and with external cooling, the pH was adjusted to 14 using 40% KOH. The resulting solids were collected by filtration and then purified by silica gel chromatography (100:1→30:1; dichloromethane/methanol) to give 75 g of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.59 (d, 1H), 6.88 (d, 1H), 6.53 (s, 2H), 5.29 (s, 1H), 3.86 (s, 3H), 3.81 (d, 2H), 1.22 (m, 1H), 0.44 (m, 2H), 0.22 (m, 2H); MS (ESI): 261.1.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.Cl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Temperature: 0 °C

Procedure:
Into a 250-mL round-bottom flask was placed a solution of tetraethylene glycol (50 g, 257.47 mmol, 9.81 equiv) in DCM (150 mL) and triethylamine (8 g, 79.05 mmol, 3.01 equiv). This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (5.0 g, 26.23 mmol, 1.00 equiv) in DCM (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature, at which time it was diluted with 200 ml of hydrogen chloride (3N aq.). The resulting solution was extracted with 2×150 mL of DCM and the combined organic layers were washed with 3×150 mL of saturated sodium bicarbonate. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜ethyl acetate). This resulted in 7.0 g (77%) of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[C:10]([CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)[N:11]=1.[Br:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[CH2:44][CH2:43]2>C1COCC1>[Br:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45]([CH2:6][C:7]1[N:8]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[C:10]([CH2:12][C:13]3([C:16]([F:17])([F:18])[F:19])[CH2:14][CH2:15]3)[N:11]=1)([OH:49])[CH2:44][CH2:43]2
Reactant: Cc1nc(CC2(C(F)(F)F)CC2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(Cc2nc(CC3(C(F)(F)F)CC3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyl lithium (14.8 mL, 23.7 mmol) was added to a solution of 2-methyl-4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazole (7.05 g, 15.8 mmol) in THF (30 mL) at −78° C. After 5 min, a solution of 5-bromoindan-1-one (5 g, 23.7 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The solution was stirred at −78° C. for 2 h. The reaction was quenched with the addition of saturated aqueous NH4Cl. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to give 5-bromo-1-[(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1-trityl-1H-imidazol-2-yl)methyl]indan-1-ol.