Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:9][CH:8]=1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1.O>O1CCCC1.C(OCC)(=O)C>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:10]1[S:11][C:7]([CH:23]([C:21]2[S:22][C:18]([CH3:17])=[CH:19][CH:20]=2)[OH:24])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=O)s1
Reactant: Brc1ccc(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O)c2ccc(C3OCCO3)s2)s1
Reaction time: 0.17 h
Yield: 41.7 %

Procedure:
n-Butyl lithium (2.44N hexane solution, 7.4 mL, 17.9 mmol) was added dropwise to a solution of 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (4.0 g, 17 mmol) in tetrahydrofuran (50 mL) at from −75° C. to −70° C., and the solution was stirred for 10 minutes. 5-Methylthiophene-2-carbaldehyde (2.4 g, 18.7 mmol) was further added dropwise to the reaction solution at from −75° C. to −70° C. After dropwise addition was completed, the reaction solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction mixture, which was then partitioned, and the solvent was evaporated. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1, then 2:1), and the title compound (2.0 g, 7.09 mmol, 41.7%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10].C1(C)C(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=CC=1.CC([O-])(C)C.[K+]>CC1OCCC1.CO>[CH3:1][N:2]1[C:7]2=[CH:20][NH:21][CH:22]=[C:6]2[C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC1CCCO1
Product: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,3-Dimethylpyrimidine-2,4(1H,3H)-dione (commercially available, 40 g, 285 mmol) and toluenesulfonylmethyl isocyanide (commercially available, 84 g, 428 mmol) were dissolved in 2-MeTHF (1000 mL) under nitrogen at 30° C. and held for 5 mins. The vessel was cooled to 0° C. (internal). A solution of KOtBu (commercially available, 64.1 g, 571 mmol) in 2-MeTHF (500 mL was then added to the solution via a dropping funnel over 0.5 h, such that the internal temperature remained below 5° C. On addition of the KOtBu solution, an orange precipitate formed. An additional portion of 2-MeTHF (455 mL) was then charged via dropping funnel over 5 mins. After 40 mins, the dark orange suspension was quenched with sat NH4Cl solution (2×400 mL) charged via dropping funnel over 15 mins. The suspension was diluted with EtOAc (1 L), the layers were separated and the aqueous extracted with EtOAc (3×1 L). The combined organics were dried (MgSO4) and filtered under reduced pressure. The solvent was removed under reduced pressure to afford a brown semi-solid. The solids were suspended in MeOH (300 mL), sonicated and stirred at room temperature for 15 mins, filtered by reduced pressure filtration and washed with MeOH (100 mL). The solid was dried under vacuum at 50° C. for 24 h. The title compound was obtained as a pale brown amorphous solid;
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH:12]1([C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[I-].[Na+]>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: c1c[nH]c(C2CCCCC2)n1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1-n1ccnc1C1CCCCC1
Temperature: 160 °C
Reaction time: 15.5 h
Yield: 67.9 %

Procedure:
2,5-Dichloro-3-nitropyridine 1.00 g, 2-cyclohexylimidazole 1.56 g, sodium iodide 500 mg and N,N-dimethylformamide 25 mL were mixed and stirred at 160° C. for 15.5 hours. The reaction liquid was poured in ice water and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (hexane:ethyl acetate=2:1) to provide 1.08 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([CH:29]([OH:34])[C:30]([F:33])([F:32])[F:31])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OC(c1cccc(Br)n1)C(F)(F)F
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(C(O)C(F)(F)F)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethanol (123 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]([C:18](C(OCC)=O)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:34]([CH3:36])[CH3:35])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.CCOCC>[C:19]([OH:21])(=[O:20])[CH3:18].[I:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:34]([CH3:36])[CH3:35])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3cccc(I)c3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O
Product: CC(C)c1nc2c(n1Cc1cccc(I)c1)C(CC(=O)O)CCC2
Temperature: 80 °C
Reaction time: 17 h
Yield: 11.2 %

Procedure:
To a stirred solution of Intermediate 92 (7.67 g) in Methanol (150 mL) was added 2M Aqueous Sodium Hydroxide (25.1 mL). The reaction mixture was then stirred at 80° C. and under nitrogen for 17 hours. The reaction mixture was concentrated in vacuo, taken up in glacial acetic acid (28.8 mL) and allowed to stir at 80° C. and under nitrogen for 24 hours. The reaction mixture was concentrated in vacuo to give an orange oily solid. This was suspended in ether, stirred well for 15 mins and then filtered under vacuum. The white solid from this filtration was suspended in ethyl acetate and stirred well at 80° C. for 1.5 hours then filtered under vacuum to give 350 mg of the desired product as an off-white solid. LCMS of the filtrate from the first filtration showed the presence of the desired product as an ethyl ester and so 2M aqueous sodium hydroxide (5 mL) in methanol (5 mL) was added and the mixture left for 2 days. This sample was then loaded in 1:1 methanol:DMSO and purified by column chromatography, reverse phase (C18), using a 5-50% acetonitrile(+0.1% TFA)-water(+0.1% TFA) gradient and a further 80% acetonitrile(+0.1% TFA)-water(+0.1% TFA) gradient. The appropriate fractions were combined, evaporated in vacuo and added to the previously obtained product to give the required product 2.98 g as an off-white solid. LC/MS MH+439, Rt 1.90 min (5 min run).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(Cl)(=[O:14])CCCC>>[C:5]([OH:6])(=[O:14])[CH2:7][CH2:8][CH2:1][CH3:3].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCCCC(=O)Cl
Agent: Oc1ccc(O)cc1
Product: CCCCC(=O)O

Procedure:
According to the same procedure as described in Preparation 1, hydroquinone and valeryl chloride were reacted and the reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water and ethyl acetate was removed. The resulting residue was thoroughly washed with water to remove unreacted hydroquinone and distilled under a reduced pressure to give hydroquinone monovalerate. b.p. 163°-166° C./1 mmHg.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[C:18]=1[CH3:24])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(O)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Br)cccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.7 %

Procedure:
Tert-butyl bromoacetate (1.08 mL, 7.27 mmol) and potassium carbonate (2.01 g, 14.55 mmol) were added to a solution of 3-bromo-2-methylphenol (1.29 g, 6.92 mmol) in acetone (17 mL), and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to dryness to give (3-bromo-2-methylphenoxy)acetic acid tert-butyl ester as a pale yellow oil (2.12 g, 100%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1O.C(N(CC)CC)C>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:20]=[CH:21][C:22]=1[O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9]
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 65.5 %

Procedure:
Trifluoromethanesulphonic anhydride (2.67 mL, 16.29 mmol) was added dropwise to a stirred solution of methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (2 g, 10.86 mmol) in DCM (47.1 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. Triethylamine (4.54 mL, 32.58 mmol) was added dropwise over 5 minutes and the resulting solution stirred at rambient temperature for 4 hours under nitrogen. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (100 mL), saturated NaHCO3 (100 mL), and water (100 mL). The organic layer was dried by passing through a phase seperating cartridge and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl)acetate (2.250 g, 65.5%) as a straw yellow oil.
Reaction SMILES: CON(C)[C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][CH2:24][Mg]Br>C1COCC1.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH2:23][CH3:24])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC[Mg]Br
Reactant: COc1ccc(/C=C/C(=O)N(C)OC)cc1OC1CCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of (E)-N-methoxy-N-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enamide (1.33 g, 4.36 mmol) in 8.0 mL of THF cooled to 0° C. was added CH3CH2MgBr (9 mL of 1.0M THF solution). The resulting solution was stirred for 30 min, diluted with ether and transferred to a separatory funnel. After washing with H2O, 1M H3PO4, and brine, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (4:1, hexanes:ethyl acetate) provided (E)-5-(3-cyclopentoxy-4-methoxyphenyl)-pent-4-en-3-one as a white solid (400 mg, 34%). 1H-NMR (300 MHz): δ 1.17 (t, 3, J=7.6), 2.69 (q, 2, J=7.3), 3.89 (s, 3), 6.59 (d, 1, J=16), 7.50 (d, 1, J=16). Anal. Calcd for C17H22O3 : C, 74.42; H, 8.08. Found: C, 74.52; H, 8.13.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].C([N:15](CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.ClC1C=C(F)C(CN2[C:51]3[N:52]=[CH:53][CH:54]=[CH:55][C:50]=3[S:49](=[O:57])(=[O:56])[N:48]([C:58]3[CH:63]=[CH:62][C:61](OC)=[C:60]([O:66][CH3:67])[CH:59]=3)[C:47]2=[O:68])=C(F)C=1>>[CH3:67][O:66][C:60]1[CH:59]=[C:58]([N:48]2[C:47](=[O:68])[N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=3[F:11])[C:51]3[N:52]=[CH:53][CH:54]=[CH:55][C:50]=3[S:49]2(=[O:56])=[O:57])[CH:63]=[N:15][C:61]=1[CH3:62]
Reactant: COc1ccc(N2C(=O)N(Cc3c(F)cc(Cl)cc3F)c3ncccc3S2(=O)=O)cc1OC
Reactant: NCc1c(F)cc(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cnc1C

Procedure:
The title compound (52 mg, 0.11 mmol) was prepared in two steps from (IntC14) (88 mg, 0.28 mmol), 2,4,6-trifluorobenzyl amine (58 mg, 0.36 mmol) and N,N-diisopropylethylamine (100 uL, 0.57 mmol); followed by 1,1′-carbonyldiimidazole (110 mg, 0.68 mmol) and triethylamine (45 uL, 0.32 mmol) using the methods of (97).
Reaction SMILES: CO[C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9].C(N(CC)CC)C.ClC(OCC)=O.[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH2:49])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:25]1([CH2:31][O:32][C:33]2[C:34]([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH2:59][C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[CH:53]=3)=[C:35]([CH2:47][CH2:48][NH:49][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:36]=[CH:37][C:38]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCC(=O)NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of monomethyladipate (0.74 ml) and triethylamine (0.69 ml) in dry dichloromethane (50 ml) was stirred at 0° during the dropwise addition of a solution of ethyl chloroformate (0.48 ml) in dry dichloromethane (20 ml). The mixture was stirred under an atmosphere of nitrogen at 0° for 30 minutes and a solution of 3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl]benzeneethanamine (2.70 g) in dry dichloromethane (50 ml) was then added. The mixture was stirred at 20° for 18 hours.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=2)=[CH:40][C:39]=1[CH3:51].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[O:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=4)=[CH:40][C:39]=3[CH3:51])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: Cc1cc(-c2ccc(C=O)o2)ccc1O
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(-c4ccc(C=O)o4)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
DIAD (107 μL, 0.54 mmol) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (135 mg, 0.45 mmol), 5-(4-hydroxy-3-methylphenyl)-2-furanecarboxaldehyde (110 mg, 0.54 mmol) and PPh3 (143 mg, 0.54 mmol) in THF (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 3:2) to give the title compound (147 mg, 67% yield) as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:13])[C:6](=[O:12])[NH:7]2.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>C(OCC)(=O)C>[OH:13][CH:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])[NH:7][C:6]1=[O:12]
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c1CC(O)C(=O)N2
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c1CC(O)C(=O)N2
Temperature: 0 °C

Procedure:
5-Amino-3-hydroxy-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.68 mmol) is dissolved in ethyl acetate and cooled to 0° C. 4-Trifluoromethylbenzylisocyanate (339 mg, 1.68 mmol) is added slowly with stirring. The reaction mixture is stirred for 1 h at room temperature. The insoluble product is filtered and dried in vacuo. Yield: 103 mg (16%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:10]([CH2:21][N:22]([CH:39]([CH3:41])[CH3:40])[C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:25]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:39]([N:22]([CH2:21][C@H:10]1[C@H:11]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][NH:8][CH2:9]1)[C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:25]=1)([CH3:41])[CH3:40]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNc2ccccc2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3R*,4R*)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-phenylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (65 mg, 0.12 mmol) in 2 mL CH2Cl2, TFA (139 μL, 1.8 mmol) is added. The mixture is stirred 2 h at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on an Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 97:3) to give the title product. TLC, Rf (SiO2—NH2, CH2Cl2/MeOH 95:5)=0.6. MS (LC-MS): 470.0 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.37 min.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.O.NN>C(O)C.C(Cl)Cl>[NH2:3][O:12][CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCCON)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of tert-butyl 4-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethoxy}piperidine-1-carboxylate 70 (0.57 g, 1.46 mmol) in a mixture of ethanol (1 mL) and DCM (6 mL) was added hydrazine hydrate (0.086 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h. Precipitate was filtered off. The filtrate was evaporated and the residue was subjected to chromatography to give 71 (0.327 g, 86%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:34][CH2:35]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
91 mg (64%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(2,4-dimethylphenyl)piperazine (55 mg, 0.289 mmol), DIPEA (76 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19].[CH3:20][C:21](=O)[C:22]#[CH:23]>C(O)C>[CH3:20][C:21]1[CH:22]=[CH:23][C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[N:19]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: C#CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc2c(n1)CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
To a mixture of 5-phenylcyclohexane-1,3-dione (1.2 g) and ammonium acetate (0.49 g) in ethanol (30 ml) was added 3-butyn-2-one (0.44 g), and the mixture was stirred at room temperature for 1.5 hours and refluxed for 18 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 2-methyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.88 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Zn]>[Br:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Cc1cccc(Br)c1O
Reactant: ClCc1ccccc1
Agent: [Zn]
Product: Cc1cc(Cc2ccccc2)cc(Br)c1O
Temperature: 150 °C
Yield: 41.2 %

Procedure:
500 g of the so-obtained 6-bromo-2-methylphenol, together with 10 g zinc shavings, are heated to about 100° C. Within 20 minutes 453 g benzyl chloride are added dropwise with stirring and under moisture exclusion. For a further 12 minutes the reaction mixture is heated to 150° C. It is then held a total of 5 hours at the temperature of 150° C. After cooling, the zinc is separated. The reaction product is distilled in a vacuum at 0.03 up to 0.04 Torr. 305 g 6-bromo-2-methyl-4-benzylphenol are obtained as a weakly yellowish, oily liquid, which is nearly odorless.