Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C(N(CC)CC)C.CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)=[N:4][C:3]=1[O:9][CH3:10]
Reactant: OC1CCNC1
Reactant: COc1nc(Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1nc(N2CCC(O)C2)ccc1Br
Temperature: 150 °C
Yield: 21.2 %

Procedure:
A vial was charged with 3-bromo-6-chloro-2-methoxypyridine (1.00 g, 4.5 mmol), rac-pyrrolidin-3-ol (0.59 g, 6.7 mmol), triethylamine (0.91 g, 8.9 mmol) and dimethylsulfoxide (4 mL). The mixture was heated to 150° C. for 5 hrs. The mixture was cooled to room temperature and diluted with 20 mL of water. The solution was extracted with ethyl acetate (10 mL×3). The extracts were combined, dried (sodium sulfate) and concentrated. The resulting residue was purified through flash column chromatography (petroleum ether/ethyl acetate=5:1˜2:1) to give the title compound (0.26 g, 25.3%) as light brown gum.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-])=O)=[CH:13][C:14]=2[N+:16]([O-])=O)[C:9]([NH2:22])=[N:8]1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:23]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:19])=[CH:13][C:14]=2[NH2:16])[C:9]([NH2:22])=[N:8]1)[CH3:24]
Reactant: CCN(CC)CCCn1nc(N)c2cc([N+](=O)[O-])cc([N+](=O)[O-])c21
Agent: [Fe]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCN(CC)CCCn1nc(N)c2cc(N)cc(N)c21
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 24.1 %

Procedure:
A mixture consisting of 9.0 g of 1-(3-diethylaminopropyl)-3-amino-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After the reaction mixture was cooled, the mixture was filtered. The pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution and the filtrate was extracted three times with 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 1.78 g of 1-(3-diethylaminopropyl)-3,5,7-triaminoindazole having the following analytical values in a yield of 23%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1.C(O)(C(F)(F)F)=O.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:5][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=2)[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCOc1ccc(Br)cc1C(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCOc1ccc(Cc2cc(C)c(O)c(C)c2)cc1C(C)C

Procedure:
Intermediate 2,6-dimethyl-4-(4′-methoxymethoxy-3′-iso-propyl-benzyl)phenol was prepared from 3,5-dimethyl-4-hydroxy benzaldehyde and bromo-4-methoxymethoxy-3-iso-propylbenzene according to the procedure described in Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000) and transformed into the title compound according to the procedure described for the synthesis of compound 7-17, step b; (0.12 g, 85%); 1H NMR (300 MHz, CD3OD): δ 6.97 (s, 1H), 6.83 (s, 2H), 6.77 (d, J=7.5 Hz, 1H), 6.65 (d, J=7.5 Hz, 1H), 4.0 (d, J=9.9 Hz, 2H), 3.75(s, 2H), 3.20-3.29 (m, 1H), 2.28 (s, 6H), 1.19 (d, J=6.6 Hz, 6H); LC-MS m/z=363 [C20H25O6P−H]+; (94%) HPLC conditions: ODSAQ AQ-303-5 column; mobile phase=CH3OH: 0.05% TFA/H2O (7:3) flow rate=1.0 mL/min; detection=UV @ 254 nm retention time in min: 10.92; Anal Calcd for (C20H25O6P+1.2H2O): C, 59.12; H, 7.15. Found: C, 58.96; H, 6.77.
Reaction SMILES: CN(C)C=O.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:12][C:10]1[N:11]=[C:7]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1csc(Oc2ccccc2)n1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
To 75 ml of N,N-dimethylformamide were added 3.00 g of 2,4-dibromothiazole, 1.74 g of phenol, and 3.44 g of potassium carbonate, and the mixture was stirred at 140° C. for 6 hours. After cooling to room temperature, 100 ml of water was added to the reaction mixture and two extractions were conducted with 100 ml of ethyl acetate. After being washed twice with 100 ml of water and once with 50 ml of saturated brine, the organic layer was dried over magnesium sulfate. After filtering the magnesium sulfate, the organic layer was concentrated and the residue was purified by column chromatography (Wakogel C-200; hexane:ethyl acetate=9:1) to give 2.86 g of an ether compound.
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[C:1]([NH:20][C@@H:21]1[CH2:25][C:24]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH2:22]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C=C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C1=CC[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 40 °C
Reaction time: 19 h

Procedure:
A reactor was charged with a solution of methyl (1S,4R)-4-(tritylamino)cyclopent-2-ene-1-carboxylate (4.75 kg, 12.4 mol) in methylene chloride. The reactor was charged with additional methylene chloride (15 L) to bring the total volume to 23.8 L. To the stirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.82 L, 32.2 mol). The reaction mixture was warmed to 40° C., with stirring for 16 to 22 h. 1H NMR (CDCl3) analysis of a small sample of the reaction mixture confirmed the formation of the product. The reaction was washed with 10% aqueous citric acid solution (2×7 L). The organic phase was concentrated under reduced pressure to afford the title compound as an oil. The oil was diluted with anhydrous toluene and concentrated to remove residual water and used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.60-7.54 (m, 5H), 7.34-7.17 (m, 10H), 6.53-6.50 (m, 1H), 3.70 (s, 3H), 3.50-3.40 (m, 1H), 2.60-2.52 (dd, J=16.6, 8.3 Hz, 1H), 2.24-2.20 (m, 1H), 2.16-2.05 (m, 1H) and 1.91-1.80 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[ClH:13].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[S:12][CH:11]=[CH:10][C:5]1=2
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CN1CCC(O)c2ccsc2C1
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2ccsc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 22) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([C:13]1[CH:38]=[CH:37][C:16]([CH2:17][NH:18][C:19]2[C:29]3[CH2:28][CH2:27][N:26]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][C:20]=2[Cl:36])=[CH:15][CH:14]=1)(=O)[CH3:11]>C(O)C>[Cl:36][C:20]1[CH:21]=[CH:22][C:23]2[CH2:24][CH2:25][N:26]([C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])[CH2:27][CH2:28][C:29]=2[C:19]=1[NH:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10](=[N:2][OH:3])[CH3:11])=[CH:38][CH:37]=1
Reactant: NO
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 10.1 %

Procedure:
Add hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04 mL, 0.54 mmol) to a solution of 6-(4-acetylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (115 mg, 0.27 mmol) in ethanol (10 mL). Heat the mixture to reflux for 2 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate. Dissolve the oil into the minimum amount of ether and add hexane to precipitate the solid. Filter to obtain 7-chloro-6-[4-(1-hydroxyiminoethyl)-benzylamino]3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a solid (12 mg, 94%) that was used without further purification. MS (ES+) m/z: 440 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:14])[C:10]([N+:11]([O-])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(O)C.O>[Zn].C(O)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:14])[C:10]([NH2:11])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn2c(Br)cccc2c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a Suspension of 7-bromo-2-methyl-3-nitropyrazolo[1,5-a]pyridine (890 mg) in a mixed solution of ethanol (20 mL), water (10 mL) and acetic acid (2 mL) was added zinc powder (890 mg) at room temperature, and the reaction mixture was heated and stirred for 30 minutes at 60° C. After filtering off the insoluble residue, the filtrate was extracted with ethyl acetate and the organic extract was washed with saturated aqueous sodium bicarbonate and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and [7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl]amine (371 mg) was obtained as an brown oil from the n-hexane:ethyl acetate (1:1) fraction.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][CH:16]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13]>C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>[N:6]1([C:12]([O:14][CH2:15][CH:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[C:28]2=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:13])[CH2:7][CH:8]([OH:10])[CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:11]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CC(O)CN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
L-hydroxyproline methylester hydrochloride is reacted with Fmoc-OSu in aqueous 1.0 N sodium carbonate/THF at room temperature. After completion of the reaction, Fmoc-Pro(4-OH)—OMe is isolated by precipitation. Fmoc-Pro(4-OH)—OMe is then added dropwise into a solution of trisphosgene (0.6 eq.) in THF to give a chlorocarbonate intermediate. After 1 h dimethylaminopyridine (1.0 eq.) and N-Boc-diaminoethane (6.0 eq.) are added and the reaction is stirred at room temperature. After completion of the reaction, the solvent is removed in vacuo and the resulting Fmoc-Pro(4-OCO—NH—CH2—CH2—NH-Boc)-OMe is extracted from a two phase system of ethyl acetate/0.1 M HCl to give crude product (MH+=554) which is purified by crystallization from ethyl acetate. The methyl ester is then cleaved to the free acid by treatment with 1N NaOH in dioxane/water and the product Fmoc-Pro(4-OCO—NH—CH2—CH2—NH-Boc)-OH is purified on silica gel, [(M+Na)]+=562).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].N[CH2:11]C1(C(O)=O)CC1>>[ClH:1].[NH2:2][CH2:3][C:4]1([C:5]([O:7][CH3:8])=[O:6])[CH2:11][CH2:9]1
Reactant: COC(=O)C(C)CN
Reactant: NCC1(C(=O)O)CC1
Agent: Cl
Product: COC(=O)C1(CN)CC1

Procedure:
The title compound was prepared in analogy to Compound W in Example 20 by using 1-(aminomethyl)cyclopropanecarboxylic acid (CAS number: 139132-50-6, J&K; for its synthesis, please refer to: Mertin A., et al. Synlett, 1991, 2, 87-9) instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=[CH2:14])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)Oc1cncc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1cncc(OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
After dissolving 5.25 g of 2-tert-butoxy-6-chloropyrazine in 80 ml of N,N-dimethylformamide, 9.66 g of tributyl(vinyl)tin and 0.97 g of dichlorobis(triphenylphosphine) palladium (II) were added and the mixture was stirred for 8 hours and 30 minutes at 80° C. under a nitrogen atmosphere. Saturated brine and ethyl acetate were added to the reaction solution, and the insoluble portion was filtered off. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (4.24 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:34]4[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc3C2=O)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-(trifluoromethyl)phenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (47%).
Reaction SMILES: Cl[CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4].[C:22]([OH:27])(=[O:26])[CH:23]([CH3:25])[CH3:24]>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[C:22]([O:27][CH:2]([O:6][C:7]([NH:9][CH2:10][C:11]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:8])[CH:3]([CH3:5])[CH3:4])(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC1(CNC(=O)OC(Cl)C(C)C)CCCCC1
Reactant: CC(C)C(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)C(C)C)C(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.3 %

Procedure:
A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol), and isobutyric acid (442 μL, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) was added, and the resulting mixture was stirred for another 24 h. After filtration, the filtrate was concentrated and the resulting residue purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane, to afford 560 mg (63%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 0.94 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H), 1.17 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 10H), 2.01 (m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33 (t, 1H), 6.56 (d, J=4.8 Hz, 1H). MS (ESI) m/z 372.38 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:33]=[CH:32][C:31]([CH2:34][N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=1
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1ccc(CBr)c(C(=O)OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(C(=O)OC)c1

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine, 4-bromomethyl-isophthalic acid dimethyl ester (Egbertson, M. S. et al. Bioorg. Med. Chem. Lett. 1996, 6, 2519-2524), DIPEA and KI in CH3CN gave 4-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-isophthalic acid dimethyl ester as a tan oily foam. 1H NMR (CDCl3) δ 1.64 (m, 1H), 2.01 (m, 2H), 2.14 (s+m, 4H), 2.27 (s, 3H), 2.68 (m, 1H), 2.79 (m, 1H), 3.89 (s, 6H), 3.92 (s, 2H), 4.09 (t, 1H, J=6.0 Hz), 4.26 (m, 2H), 6.97 (s, 1H), 7.03 (m, 1H), 7.30 (d, 1H, J=9.0 Hz), 7.89 (dd, 2H, J=7.5, 4.5 Hz), 8.02 (s, 1H), 8.25 (s, 1H), 8.50 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.1, 18.7, 22.2, 26.8, 29.7, 52.5, 54.7, 57.1, 63.3, 121.9, 128.0, 130.7, 131.4, 131.9, 133.3, 134.5, 136.7, 138.8, 146.3, 148.5, 166.8, 168.1. HPLC: 96%. ES-MS m/z 474 [M+H]+, 496 [M+Na]+. Anal. Calcd. for C28H31N3O4.1.1H2O: C, 68.30; H, 6.59; N, 8.53. Found: C, 68.23; H, 6.41; N, 8.60.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.Cl.[CH2:28]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH2:41][C@@H:40]([NH:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[C:50]([C:55]([F:58])([F:57])[F:56])[CH:49]=2)=[O:47])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:20])[N:44]([C@@H:40]2[CH2:41][CH2:42][CH2:43][N:38]([C:36]([O:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:39]2)[CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([F:54])=[C:50]([C:55]([F:56])([F:57])[F:58])[CH:49]=2)=[O:47])[CH2:16][CH2:17]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: O=C(CN[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC(=O)c2ccc(F)c(C(F)(F)F)c2)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reaction time: 1.5 h
Yield: 63 %

Procedure:
Add thionyl chloride (1.2 equiv; 10.5 mmol; 765 μL) dropwise over 3 min at 20° C. to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 equiv; 8.75 mmol; 2.03 g) and pyridine (5 equiv; 43.74 mmol; 3.54 mL) in DCM (60 mL). Stir 90 min. Add (R)-3-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylamino]-piperidine-1-carboxylic acid benzyl ester hydrochloride (0.80 equiv; 7.00 mmol; 3.32 g) followed by TEA (3.5 equiv; 30.62 mmol; 4.3 mL) dropwise over 3 min and stir 18 h. Wash the organic phase 3× with 1N HCl, water, brine, dry over MgSO4, filter and evaporate. Purify the residue on 150 g silica gel with 20-50% EA/DCM to provide the title compound (2.86 g; 4.41 mmol; 50%). MS (ES+): m/z=672 (M+Na).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O>C1C=CC=CC=1>[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=1.[CH:1]1([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCCC(=O)O
Solvent: c1ccccc1
Product: C1=CCCCC1
Product: OC1CCCCC1

Procedure:
The preparation of adipic acid is also carried out commercially by the selective hydrogenation of benzene to form cyclohexene, separation of the cyclohexene from the unconverted benzene and the over-hydrogenated cyclohexane by extractive distillation, then hydration of cyclohexene to form cyclohexanol, and the nitric acid oxidation of the cyclohexanol to adipic acid. See for example Kagaku Kogaku (Chemical Technology), vol. 55, No. 5, pp 382-385 (1991); "Technology for Manufacturing Cyclohexanol using Cyclohexene Technique" by Shikazo Senoo and Koji Nakagawa.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH2:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH:39]1[C:30]2[CH2:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:4](=[O:5])[C:3]4[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=4[Cl:11])=[CH:44][CH:43]=3)=[O:27])[C:29]=2[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg of N,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of 5-(4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. The reactants are refluxed in an oil bath at 110° C. for 18 hours. The xylene is eyaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated, washed with 1N HCl, 1M NaHCO3, and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 370 mg of the desired product as a crystalline solid, m.p. 257°-259° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH3:25])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: COC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, methyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-methoxycarbonyl-quinoline (compound 6, 100 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.