Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:16]1([NH:22]N)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.COC1C=CC(C2C3C4C=CC=CC=4NC=3CC2)=CC=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][C:12]3[NH:22][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:11]=3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Reactant: NNc1ccccc1
Agent: COc1ccc(C2CCc3[nH]c4ccccc4c32)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3[nH]c4ccccc4c3C2)cc1

Procedure:
A mixture of 3-(4-methoxyphenyl)-1-cyclopentanone (15.21 g) and phenylhydrazine hydrochloride (11.56 g) in glacial acetic acid (110 ml) under nitrogen was stirred magnetically and slowly heated to 90° with a heating mantle. A white precipitate, which formed at approximately 60°, dissolved to give a red solution as the temperature rose exothermically to 110°. As soon as the solid had dissolved, the heating mantle was removed and the temperature allowed to return to 90°. The temperature was then maintained at 90° for 1 hour. The cooled solution was poured into water (400 ml). After refrigeration under nitrogen overnight, the supernatant liquid was filtered. The filter pad and residual material were dissolved in dichloromethane and the solution was washed with saturated sodium bicarbonate solution. The dried (MgSO4) solution was evaporated to a syrup which was subjected to an oil pump vacuum; wt. 18.7 g. This material in dichloromethane was chromatographed on a column of silica gel prepacked in dichloromethane. Elution with dichloromethane afforded a mixture of the titled product and 1,2,3,4-tetrahydro-1-(4-methoxyphenyl)cyclopent[b]indole. After solvent removal, the residual yellow syrup was crystallized from ethanol-hexane to give the titled product as pale yellow crystals; wt. 5.14 g (24.4%), mp=108°-110°.
Reaction SMILES: [CH3:1][C@@:2]12[CH:10](C(C([O-])=O)=C)[CH2:9][C@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24].CCCCCCCCCC(C)C.C(C(CCCC)C(OOC(C)(CCC(OOC(=O)C(CC)CCCC)(C)C)C)=O)C>>[C:16]([O:20][CH:10]1[CH2:9][CH:5]2[C:6]([CH3:7])([CH3:8])[C:2]1([CH3:1])[CH2:3][CH2:4]2)(=[O:19])[CH:17]=[CH2:18].[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=C(C(=O)[O-])C1C[C@H]2CC[C@@]1(C)C2(C)C
Agent: C=CC(=O)O
Agent: CCCCC(CC)C(=O)OOC(C)(C)CCC(C)(C)OOC(=O)C(CC)CCCC
Agent: CCCCCCCCCC(C)C
Solvent: C=CC(=O)OC
Product: C=CC(=O)OC1CC2CCC1(C)C2(C)C

Procedure:
18 g of isobornyl acrylate, 71.1 g of methyl acrylate, 0.9 g of acrylic acid, 90 g of isododecane and 1.2 g of 2,5-bis(2-ethylhexanoylperoxy)-2,5-dimethylhexane were then introduced into the above mixture, still at 90° C. and over 1 hour.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].CCCCCCCCCCCCCCCC>C([O-])(=O)C.[Na+].ClCCl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC(=O)CN1C(=O)OC
Reaction time: 31 h

Procedure:
An aqueous solution (5.0 mL) containing 25 mM N-(methoxycarbonyl)-4-keto-Dproline methyl ester and 25 mM N-(methoxycarbonyl)-4-keto-L-proline methyl ester in 0.200M sodium acetate (pH 5.0) was mixed with 2.5 g of immobilized Candida antartica lipase fraction B (Boehringer Mannheim, CHIRAZYME® L-2, c.-f., C2, lyo.) at 25° C. The reaction mixture was analyzed after 31 h by mixing the entire reaction mixture with 5.0 mL of 20 mM hexadecane in dichloromethane for 10 minutes, which resulted in the complete extraction of the unreacted D- and L-isomers. The dichloromethane extract was then analyzed by chiral gas chromatography on a Chiraldex G-TA column (Advanced Separation Technologies, Inc., 50 m×0.32 mm ID) to determine the amounts of the unreacted D- and L-isomers. After 31 h, an 85% enantiomeric excess of N-(methoxycarbonyl)-4-keto-D-proline methyl ester was obtained at 41% conversion of the racemic mixture.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C>O.CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][C:6]([OH:22])=[O:5])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reaction time: 2.5 h

Procedure:
A solution of KOH (86%, 0.42 g, 6.4 mmol) in water (1.5 mL) was added to a solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid ethyl ester in 95% EtOH (15 mL) at rt. After 2.5 h, the mixture was partitioned between EtOAc (50 mL) and 2 N aq. HCl (50 mL). After extraction of the aqueous layer with EtOAc (50 mL), the organic layers were washed with sat'd NaCl (25 mL), dried (Na2SO4), decanted, and evaporated to give 1.06 g of the title compound as a crystalline solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=O.CC(C[AlH]CC(C)C)C>C1COCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:9]=[CH:10][C:5]([CH2:3][OH:2])=[N:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.585 g (2.07 mmol) of the above synthesized 5-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid methyl ester in 10 ml of abs. THF was cooled down to −30° C. and reacted with 5.18 ml of DIBAL-H-solution (1.2 M in toluene, 3 eq.) for 10 min. The reaction was warmed up during 2.5 h to 10° C. and stirred 1 h at RT. Careful quenching at 0° C. with saturated NaCl solution, twofold extraction with ether, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, heptane/AcOEt=4/1) to deliver finally 0.325 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].[CH:28]([CH:30]1[CH2:32][CH:31]1[C:33]([O:35][CH2:36][CH3:37])=[O:34])=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH2:36]([O:35][C:33]([CH:31]1[CH2:32][CH:30]1[CH2:28][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=2[Cl:1])=[O:12])[CH2:14][CH2:15]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CC1C=O
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: CCOC(=O)C1CC1CN1CCN(C(=O)c2cnccc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 150 °C
Yield: 45.6 %

Procedure:
To a solution of 0.10 g (0.25 mmol) [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3) were added 0.036 g (0.25 mmol) ethyl 2-formyl-1-cyclopropane-carboxylate (commercially available, CAS RN 20417-61-2), 0.008 g (0.026 mmol) dibutyltin dichloride and 0.06 mL (0.50 mmol) phenylsilane. The resulting solution was heated for 10 min. in a microwave oven at 150° C. The light yellow solution was evaporated and dissolved in acetonitrile containing a few drops of N,N-dimethylformamide. The suspension was filtered using a syringe micro filter and purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 60 mg (46%) of the desired compound as a light brown foam. MS (ESI): m/z=526.13 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.[CH2:21]([NH2:24])[CH:22]=[CH2:23]>O1CCCC1>[CH2:21]([NH:24][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Br:1])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCNC(=O)c1cc([N+](=O)[O-])ccc1Br

Procedure:
To a solution of 2.5 g (0.01 mol) of 2-bromo-5-nitro-benzoic acid in 70 ml tetrahydrofuran are added dropwise 3.2 g (0.01 mol) of O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium-tetrafluoroborate, 5 ml triethylamine and a solution of 570 mg (0.01 mol) of allylamine in 5 ml tetrahydrofuran. After 60 minutes at ambient temperature the mixture is poured onto ice water, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:13])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6].[BH4-].[Na+]>C(COC)OC>[Br:1][CH2:2][CH:3]([OH:13])[CH2:4][C:5]([NH:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:6]
Reactant: COC(=O)CNC(=O)CC(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CNC(=O)CC(O)CBr
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1.5 g Methyl 2-(4-bromo-3-oxobutanamido)acetate is dissolved in 15 ml dimethoxyethane. The solution is cooled to 0° C. and 60 mg NaBH4 is added. After 5 min, the solvent is evaporated in vacuo and the residue is chromatographed on silica, eluting with ethyl acetate. The title compound is obtained as a white powder, m.p. 60°-61° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)CCC>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCCCO
Product: FC(F)(F)c1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
A solution of 2-chloro-3-trifluoromethylpyridine (6.57 g, 36.2 mmol) and piperazine (31.48 g, 365.5 mmol) in n-butanol was heated to 115° C. After 48 hours, the mixture was cooled to room temperature, the solvent removed under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 15% methanol:dichloromethane) to provide 3.35 g (40% yield) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H), 3.10 (m, 4H), 7.15 (ddd, 1H, J=7.8, 4.7, 1.0 Hz), 8.03 (dd, 1H, J=7.8, 1.7 Hz), 8.50 (ddd, 1H, J=4.8, 2.0, 0.7 Hz); MS (DCI/NH3) m/e 232 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:3]=1.CN(C1C=CC=CN=1)C.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:37]2[CH2:36][CH2:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:39][CH2:38]2)=[O:7])=[C:4]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(NC(=O)C(F)(F)F)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(NC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
1.12 g (0.00453 mol) of 4-methyl-2-trifluoroaceta-mido-benzoic acid were dissolved in 23 ml of dimethylformamide, treated with 0.277 g (0.00227 mol) of dimethylaminopyridine and cooled to 00. 0.867 g (0.00453 mol) of 1-benzyl-4-hydroxy-piperidine and 0.955 g (0.005 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the mixture was stirred at 0° for 2 hrs. Thereafter, the mixture was warmed to room temperature. The mixture was stirred at room temperature for 48 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate and washed with semi-sat. sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 1.27 g (77%) of 1-benzyl-piperidin-4-yl 4-methyl-2-trifluoroacetamido-benzoate were obtained as a yellow oil. MS: me/e=421 (C22H24F3N2 O3 +).
Reaction SMILES: [C:1]1([C@H:7](NC[C@H](CCC)CC(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:22][CH2:23][CH3:24])(=O)C.Cl>CO>[CH:1]1[CH:6]=[C:5]2[CH:4]=[CH:24][C:23]([OH:22])=[C:7]([C:1]3[C:2]4[C:3](=[CH:8][CH:7]=[CH:23][CH:24]=4)[CH:4]=[CH:5][C:6]=3[OH:22])[C:8]2=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](CN[C@H](C)c1ccccc1)CC(=O)O
Agent: Cl
Solvent: CO
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in methanol (20 mL) and (RS)-1,1′-bi-2-naphthol (5.75 g) is added to it at room temperature. The mixture is stirred at 50° C. for 1 hour, during which time solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under reduced pressure to obtain 3.6 g of solid complex. Complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1N hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to obtain optically pure (R)-1,1′-bi-2-naphthol (1.5 g) having 99% ee.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.I.CS[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>C(Cl)Cl>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: CSC1=NCCN1
Agent: I
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2c(c1)CCCC2CNC1=NCCN1)c1ccccc1
Temperature: 150 °C

Procedure:
N-(5-Aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide and 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide were added to methylene chloride and the reaction mixture was heated to reflux until all of the solvent evaporates. The reaction mixture is heated to 150° C. and then cooled. The resulting mixture is basified by dropwise addition of aqueous NaOH solution, and then purified by preparative liquid chromatography to give N-{5-[(4,5-Dihydro-1H-imidazol-2-ylamino)-methyl]-5,6,7,8-tetrahydro-naphthalen-2-yl}-benzenesulfonamide. 5-[(4,5-Dihydro-1H-imidazol-2-ylamino)-methyl]-5,6,7,8-tetrahydro-napthalene-2-sulfonic acid phenylamide may be similarly prepared.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: C1CCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 56 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and pyrrolidine according to the procedure of example 25. Yield: 56%; MS: m/z=385 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCn1cc(CN2CCCC2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (18 g, 36.6 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (4.53 mL, 54.9 mmol), sodium triacetoxyborohydride (15.52 g, 73.2 mmol) and AcOH (0.105 mL, 1.831 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS indicated completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combinflash RF), using a 40 g gold column and eluting with MeOH/DCM (0-20%). The product was further purified by reverse phase automatic chromatography (Combinflash RF), using a 150 g gold C18 column and eluting with acetonitrile/Water (0%-60%) to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (9.4 g, 17.20 mmol, 47.0% yield) as a pale yellow solid. LCMS: (M+H)+: 547.3.
Reaction SMILES: [C:1]1([C:7]2[N:15]([CH3:16])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:12](=[O:23])[C:8]=2[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:25]>CO>[C:1]1([C:7]2[N:15]([CH3:16])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:12](=[O:23])[C:8]=2[C:9]([O-:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:25]
Reactant: Cn1c(-c2ccccc2)cc(=O)c(C(=O)O)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccccc2)cc(=O)c(C(=O)[O-])c1-c1ccccc1
Yield: 94.4 %

Procedure:
1.73 gms of 2,6-diphenyl-1-methyl-4-oxonicotinic acid was suspended in 50 mls of dry methanol. 0.25 gms of NaOH was added. After the carboxylic acid and the NaOH dissolved the solvent was removed yielding 1.75 gms of sodium 2,6-diphenyl-1-methyl-4-oxonicotinate as a glassy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N+:3]=1[O-:11].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N+:3]([O-:11])=[CH:4][C:5]([C:6]([N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)[n+]([O-])c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClC(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Cl)[n+]([O-])c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
6-Chloronicotinic acid 1-oxide (0.347 g, 2.0 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.544 g, 2.2 mmol) were mixed in chloroform (8 mL) at 0° C. 1-Methylpiperazine (0.30 g, 3.0 mmol) was added after 5 min and the reaction mixture was stirred for 16 h at room temperature. The solvent was removed in vacuo and the residual oil was purified on a silica gel column using chloroform/methanol/triethylamine, (100:20:1), as the eluent to give 0.18 g, (35% yield) of the title compound as a brownish solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.56 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 3.63 (br s, 2H), 3.39 (br s, 2H), 2.43 (br s, 2H), 2.34 (br s, 2H), 2.25 (s, 3H); MS (EI) m/z 256 and 258 (M++1).
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N1C2C(=CC=CC=2)C(=O)C1=O)CCC>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Reactant: CCCCN1C(=O)C(=O)c2ccccc21
Product: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was prepared in a method analogous to 2-oxo-1-propylindolin-3-yl benzoate using 1-butylindoline-2,3-dione. 1H-NMR δ 8.11 (d, 2H), 7.58 (m, 1H), 7.49-7.34 (m, 4H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.19 (s, 1H), 3.75 (m, 2H), 1.73 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH2:1]([O:9][C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14]CCCCC=C)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(CCO)C=CC=CC=1.C(O)(=O)CCCCCCCCC=C>>[CH2:1]([O:9][C:10](=[O:21])[CH2:11][CH2:12][CH:13]=[CH2:14])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCCCCCCCCC(=O)OCCc1ccccc1
Agent: C=CCCCCCCCCC(=O)O
Solvent: OCCc1ccccc1
Product: C=CCCC(=O)OCCc1ccccc1

Procedure:
According to the same procedure, undec-10-enoic acid phenethyl ester was prepared from phenylethyl alcohol and 10-undecenoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][C:10]([I:17])=[C:11]([CH3:16])[C:12]=1[CH2:13][CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1[NH:9][C:10]([I:17])=[C:11]([CH3:16])[C:12]=1[CH2:13][CH:14]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(I)[nH]c(C(=O)OC(C)(C)C)c1CCO
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(I)[nH]c(C(=O)OC(C)(C)C)c1CC=O
Reaction time: 3 h
Yield: 70.8 %

Procedure:
3-(2-Hydroxy-ethyl)-5-iodo-4-methyl-1H-pyrrole-2-carboxylic acid tert-butyl ester (0.34 mmol, 114 mg) in DMSO (2 mL) was treated with o-iodoxybenzoic acid (IBX, 0.51 mmol, 148 mg), then held at room temperature for 3h. The mixture was diluted with ethyl acetate (50 mL), washed with brine (10 mL), then concentrated under reduced pressure to provide 84 mg (75%) of 5-iodo-4-methyl-3-(2-oxo-ethyl)-1H-pyrrole-2-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) δ 9.63 (1H, s), 8.91 (1H, br s), 4.09 (2H, s), 2.62 (3H, s), 1.52 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:49]([O:56][C:57]([CH2:59][CH2:60][C@H:61]([NH2:72])[C:62]1[NH:66][C:65]2[CH:67]=[CH:68][C:69]([Cl:71])=[CH:70][C:64]=2[N:63]=1)=[O:58])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH2:49]([O:56][C:57]([CH2:59][CH2:60][C@H:61]([NH:72][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:62]1[NH:66][C:65]2[CH:67]=[CH:68][C:69]([Cl:71])=[CH:70][C:64]=2[N:63]=1)=[O:58])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)OCc2ccccc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 71 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-3-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in tetrahydrofuran. Yield: 71%; Rf value: 0.24 (silica gel; ethyl acetate/ethanol=95:5); C31H31ClN4O4 (559.06); mass spectrum: (M+H)+=559/561 (chlorine isotope).