Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:29])[C:16]3[C:21]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:20][N:19]([CH3:28])[C:17]=3[N:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1.[C:32](=[O:34])=[O:33].[OH-].[Na+]>O1CCCC1>[CH:22]1([C:21]2[C:16]3[C:15](=[O:29])[NH:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([C:32]([OH:34])=[O:33])=[CH:8][C:9]=4[O:30][CH3:31])=[N:18][C:17]=3[N:19]([CH3:28])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
In a stream of nitrogen, 1.6 ml of n-butyl lithium (1.56M hexane solution 2.5 mmol) was added dropwise at −78° C. to a 10 ml tetrahydrofuran solution of 500 mg (1.20 mmol) of the compound obtained in Example 26. The mixture was stirred at the same temperature for 30 minutes, and then a carbon dioxide gas was blown into the reaction mixture for 45 minutes. Further, the reaction mixture was stirred at −78° C. for 2 hours, and then brought to room temperature. The reaction mixture was alkalinized by addition of a 1M aqueous solution of sodium hydroxide, and washed with dichloromethane. The aqueous layer was acidified with a 6M aqueous solution of hydrochloric acid, and precipitated solids were collected by filtration, obtaining 200 mg (44%) of the captioned compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH:19]=O)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][N:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:46]2[CH2:47][CH2:48][CH:43]([N:35]([CH2:34][C:31]3[N:30]=[CH:29][C:28]4[O:27][CH2:26][CH2:25][O:24][C:33]=4[CH:32]=3)[C:36]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:42])[CH2:44][CH2:45]2)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=CCn1c(=O)cc(OS(=O)(=O)C(F)(F)F)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc32)CC1
Reaction time: 18 h

Procedure:
The crude 7-fluoro-2-oxo-1-(2-oxoethyl)-1,2-dihydro-4-quinolinyl trifluoromethanesulfonate (5.6 g, 15.9 mmol assumed 100% from previous step) was dissolved in THF (50 ml) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (5.60 g, 15.9 mmol) added followed by sodium sulphate (˜15 g). After 2 h sodium triacetoxyborohydride (12.3 g, 58 mmol) was added portionwise over 1 h and the solution stirred for 18 h. The solution was diluted with ethyl acetate and washed with sodium bicarbonate solution, dried and concentrated. Chromatography (70 g silica SPE, eluting with ethyl acetate) provided product (4.88 g) contaminated with an impurity. Further chromatography (70 g silica SPE gradient elution with 2:1 ethyl acetate/hexane to ethyl acetate to ethyl acetate/10% methanol) provided the title compound as a clear oil (2.81 g, 26%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[NH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[CH:55]1([N:61]=[C:62]=[O:63])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1.O>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]1=[N:17][C:62](=[O:63])[NH:61][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=c1sc2ccccc2n1Cc1ccccc1
Reactant: O=C=NC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: O
Solvent: CC(C)=O
Product: O=C(N=c1sc2ccccc2n1Cc1ccccc1)NC1CCCCC1
Reaction time: 7 h
Yield: 73.1 %

Procedure:
To a solution of 1.8 g of 3-benzyl-2-iminobenzothiazole and a catalytic amount of dibutyltin dilaurate in 30 ml of acetone was added 0.95 g of cyclohexyl isocyanate dropwise. After seven hours, the reaction mixture was poured into approximately 100 ml of water. The crystals precipitated were collected by filtering to thereby obtain 2.0 g of the objective compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH3:13])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1cc2c(Cl)ccnc2cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Cl)ccnc2cc1SCc1ccccc1
Temperature: 110 °C

Procedure:
To a flask charged with 7-bromo-4-chloro-6-methylquinoline (0.240 g, 0.936 mmol) was added Xantphos (0.108 g, 0.187 mmol), Pd2(dba)3 (0.086 g, 0.094 mmol), dioxane (3.74 ml), DIEA (0.327 ml, 1.871 mmol) and benzyl mercaptan (0.111 ml, 0.936 mmol). The vessel was heated at 110° C. for 2 hr affording conversion to desired product. The mixture was cooled to room temperature, filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product as a yellow solid with minor impurities, 7-(benzylthio)-4-chloro-6-methylquinoline (0.287 g, 0.957 mmol, 102% yield). m/z (ESI) 300.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[N:8][CH:7]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].N12CCN(CC1)CC2>O1CCCC1>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][CH:7]=1)=[O:13]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)CNC(=O)c1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: CN(C(=O)Oc1ccc(C(=O)NCC(C)(C)C)cn1)c1ccccc1
Yield: 52.5 %

Procedure:
A solution of N-(2,2-dimethyl-propyl)-6-hydroxy-nicotinamide (0.50 g, 2.40 mmol), N-methyl-N-phenylcarbamoyl chloride (0.41 g, 2.40 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.27 g, 2.40 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (first column: SiO2, dichloromethane:ethyl acetate 95:5, second column: SiO2, ethyl acetate), yielding the title compound (0.43 g, 52% yield).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:24]=O)=[CH:18][NH:19]2.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:24][NH:6][CH3:5])=[CH:18][NH:19]2
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: O=Cc1c[nH]c2cccc(F)c12
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2cccc(F)c12

Procedure:
According to the procedure of Preparation 13 (c), except substituting 4-fluoro-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:24][CH:23]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-bromoaniline (67 mg, 0.39 mmol). The title compound was obtained as a solid (55 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.63 (1H, s), 9.01 (2H, s), 8.71 (1H, s), 7.63 (2H, m), 7.56 (2H, m). MS m/z: 502.01, 503.94, 505.92 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: ClCc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg), 5-chloromethyl-2-phenylpyridine (350 mg), potassium carbonate (460 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (710 mg, yield: 85%). This was recrystallized from acetone-hexane. Melting point: 155–156° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([F:31])[C:23]=1[CH3:32]>>[F:31][C:24]1[C:23]([CH3:32])=[C:22]([NH:11][C:10]2[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: Cc1c(F)cc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])cc(F)c1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.5 g (5.43 mmol) of the compound of Example 4A and 1.4 g (5.97 mmol) of 1-bromo-3-fluoro-2-methyl-5-nitrobenzene gave 1.19 g (50% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].Cl.CN.[C:15]([BH3-])#[N:16].[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:16][CH3:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(NC)CCC1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with methylamine hydrochloride (1.296 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-methylamino-cyclopent-1-enecarboxylic acid ethyl ester, as a light yellow oil. LC-MS (ESI) calcd for C9H15NO2 169.11, found 170.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[Sn](Cl)Cl.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCOc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1ncc(Br)cc1N
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of 5-bromo-2-ethoxy-3-nitropyridine (75.2 mg, 0.304 mmol) in ethyl acetate (3 mL) was added tin(II) chloride (289 mg, 1.52 mmol), and the mixture was heated to reflux for 2 h. After cooling to rt, 50% aqueous sodium hydroxide was added dropwise until a sticky brown solid completely formed. Sodium sulfate was then added, and the mixture was stirred for several minutes. The solids were then removed by filtration. The filtrate was dried over sodium sulfate, filtered, and concentrated in vacuo to provide 5-bromo-2-ethoxypyridin-3-amine (53 mg, 0.25 mmol, 80% yield) as a dark blue film. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, 1H), 6.97 (d, 1H), 4.37 (q, 2H), 3.85 (br s, 2H), 1.40 (dd, 3H); MS (EI) for C7H9BrN2O: 217, 219 (Br isotopes, MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]([CH2:12][CH3:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=[CH:4]1)[CH3:2].[CH:14]([N:17]=[C:18]=[S:19])([CH3:16])[CH3:15]>CC#N>[CH2:1]([N:3]1[C:7]2[CH:8]([CH2:12][CH3:13])[N:9]([C:18](=[S:19])[NH:17][CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11][C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCC1NCCc2ncn(CC)c21
Reactant: CC(C)N=C=S
Solvent: CC#N
Product: CCC1c2c(ncn2CC)CCN1C(=S)NC(C)C
Reaction time: 8 h

Procedure:
A solution of 9.3 g of 3,4-diethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.59 g of isopropyl isothiocyanate in 75 ml of anhydrous CH3CN is refluxed for 7.5 hours. The solution is allowed to stand overnight at -15° C., then is filtered. 5.59 g of the crude title compound are collected; m.p. 195° C. (recrystallized from CH3CN).
Reaction SMILES: C(O[N:6]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([S:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:15]=1)=[O:12])[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([S:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:24]3[CH2:25][CH2:26][CH:21]([C:16]4[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][NH:6][CH3:7])[CH:19]=[CH:18][C:17]=4[CH3:20])[CH2:22][CH2:23]3)=[CH:33][CH:32]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)CN(OC(C)(C)C)C(C)=O)ccc4C)CC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Sc4ccc(OC)cc4)cc3)CC2)c1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
2-[(tert-butoxy)-N-methylcarbonylamino]-N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl} (4-piperidyl))-4-methylphenyl]acetamide was dissolved in CH2Cl2 (1.00 mL) and trifluoroacetic acid (0.160 mL) was added to the stirred solution. Stirring was continued for 10 min then the reaction mixture was concentrated in vacuo to give a gum. The crude product was dissolved in saturated NaHCO3 solution (10 mL to pH 10) and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl]2-(methylamino)acetamide (68.6 mg, 99.2% yield) as a yellow solid.
Reaction SMILES: [O-]CC.[Na+].[Cl:5][C:6]1[C:7](=[N:12][NH2:13])[NH:8][CH:9]=[CH:10][CH:11]=1.[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C>O.C(O)C>[Cl:5][C:6]1[C:7]([N:12]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NN=c1[nH]cccc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 83 °C
Reaction time: 2 h

Procedure:
A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 mL) and an ethanolic solution of sodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83° C. It was then treated with 3-chloro-2(1H)-pyridinone hydrazone (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65° C., the reaction mixture was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28° C. The slurry was held at about 2° C. for 2 hours. The product was isolated via filtration, washed with aqueous ethanol (40%, 3×50 mL), and then air-dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline, light orange powder (70.3 g, 55% yield). No significant impurities were observed by 1H NMR.
Reaction SMILES: C(OC(=O)[CH:5]([C:14]#[N:15])[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C>CS(C)=O.O>[CH:8]1([C:6](=[O:7])[CH2:5][C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(C#N)C(=O)C1CCCCC1
Solvent: CS(C)=O
Solvent: O
Product: N#CCC(=O)C1CCCCC1

Procedure:
A solution of 2-cyano-3-cyclohexyl-3-oxo-propionic acid ethyl ester in DMSO:water (10:1) was stirred at 120° C. for 2 hours. The reaction mixture was partitioned between ether and 1N HCl, the organic phase was dried with MgSO4 and the solvent removed under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH2:49].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH:49][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH2:13][CH2:12][N:11]([CH3:23])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: CN(CCN1CCCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCCN1CCN(C)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-1-(2-(((benzyloxy)carbonyl)(methyl)amino)ethyl)piperidine-2-carboxylic acid (0.145 mmol, 46.4 mg), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (0.145 mmol, 55.6 mg), DIEA (0.725 mmol, 94 mg) in DMF (0.3 mL) was added HATU (0.16 mmol, 61 mg). The mixture was stirred at 60° C. for 1 h. The crude mixture was used in next step without purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:33])[C@H:4]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C:7]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:9]([O:11]CC1C=CC=CC=1)=[O:10].C1CCCCC=1>C(O)C.[Pd]>[CH3:1][NH:2][C:3](=[O:33])[C@H:4]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[NH:5][C:6](=[O:23])[C:7]([CH2:19][CH:20]([CH3:21])[CH3:22])=[CH:8][C:9]([OH:11])=[O:10]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)OCc1ccccc1)CC(C)C
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(=CC(=O)O)CC(C)C

Procedure:
E and Z N-[3-(benzyloxycarbonyl)-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide (3.0 g.) was heated under reflux for 2 hours in ethanol (60 mls.) and cyclohexene (30 mls.) in the presence of 10% palladium on charcoal (0.75 g.). The resultant reaction mixture was filtered through Celite and the solvent removed by evaporation in vacuo to yield a gum. This gum was crystallized from methanol/water to yield E and Z N-[3-carboxy-2-(2-methylpropyl)propenoyl]-O-methyl-L-tyrosine N-methylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12]C)[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1cc(Cl)cc(C(=O)O)c1O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)cc(O)c1O

Procedure:
step a) 2-hydroxy-3-methoxy-benzoic acid (13) is chlorinated for example with N-chlorosuccinimide in acetic acid to yield 5-chloro-2-hydroxy-3-methoxy benzoic acid (14); step b) the methoxy group of compound (14) is reacted with hydrobromic acid in acetic acid to yield 5-chloro-2,3-dihydroxybenzoic acid (15);
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C@@H:7]([CH3:27])[CH2:6]1)=[O:4].[OH-].[Li+].CO.Cl>O1CCCC1.O>[CH3:27][CH:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[C:15](=[O:26])[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(F)(F)F)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CC(C(=O)O)c2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 96.5 %

Procedure:
A round bottom flask with magnetic stirrer was charged with cis-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (980 mg, 2.60 mmol) in tetrahydrofuran (10.0 mL). To the reaction was added a solution of lithium hydroxide (179 mg, 7.47 mmol) in water (10 mL), followed by methanol (10 mL). The reaction was stirred at room temperature for 18-20 hours under an argon atmosphere. The reaction was transferred to a separatory funnel and the pH adjusted to 2 via addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate (3×35 mL) and the combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to yield 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (mixture of cis and trans isomers) as an off-white solid (912 mg, 97%). The mixture was used without purification in subsequent reactions.