Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:71]=[CH:70][C:69]([C:72]2[NH:76][N:75]=[CH:74][N:73]=2)=[CH:68][CH:67]=1>C(Cl)Cl>[N:75]1[NH:76][C:72]([C:69]2[CH:70]=[CH:71][C:66]([NH:65][C:28]([CH:9]3[CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:67][CH:68]=2)=[N:73][CH:74]=1
Reactant: Nc1ccc(-c2ncn[nH]2)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(-c3ncn[nH]3)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.32 mmol) in methylene chloride (5 mL), HATU (Aldrich, 152 mg, 0.4 mmol) was added followed by the addition of DIPEA (0.1 mL) and 5-(4-amino-phenyl)-1H-[1,2,4]triazole (made above, 64 mg, 0.4 mmol). The mixture was stirred at rt for 2 hrs. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 70% EtOAc/hexanes) to give a white solid. 140 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][C@@H:10]([O:18]C(=O)[C@@H](OC)C1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[OH:18])[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H](C(=O)O[C@H](CN(C)C(=O)OC(C)(C)C)c1ccc(F)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C[C@@H](O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-methoxyphenyl acetic acid (1S)-2-(t-butoxycarbonyl-methylamino)-1-(4-fluorophenyl)ethyl ester (the compound of Preparation Example 35) (3.6 g) in methanol (17 mL) was added potassium carbonate (1.8 g) on an ice bath. After stirring at room temperature for 30 minutes, the colorless solid that was generated by diluting with water was collected by filtration. After washing with water, and then drying by aeration, the title compound (2.35 g) was obtained as a colorless solid. The NMR data matched the racemic mixture described in Preparation Example 32.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:30]1([CH2:35][C:36](O)=[O:37])[CH:34]=[N:33][CH:32]=[N:31]1>>[N:30]1([CH2:35][C:36]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:37])[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 66 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 149, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide (45 mg, 66%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.26 (br s, 1H), 8.84-8.78 (d, 1H), 8.48 (s, 1H) 7.96 (s, 2H), 7.63-7.59 (d, 2H), 7.32-7.28 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.98 (m, 4H), 5.03 (s, 2H), 4.76-4.69 (m, 1H), 4.54 (s, 2H), 3.69-3.67 (d, 2H). MS (EI) for C26H24FN5O4. found 490.0 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:10](Cl)(=[O:14])[C:11]([Cl:13])=[O:12]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:10](=[O:14])[C:11]([Cl:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCNc1ccccc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)C(=O)Cl)c1ccccc1
Reaction time: 1 h

Procedure:
Similar to Referential Example 1, N-ethylaniline (1.0 g) was dissolved in toluene (10 mL), and oxalyl chloride (4.0 mL) was added thereto under cooling with ice. The temperature of the mixture was then returned to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, to thereby give the title compound (2.05 g) as a brown oil. The compound was used without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([C:16](=[N:21]O)[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(O)(=O)C.[C].[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[N:19]3[C:20]4[C:15]([CH:16]([NH2:21])[CH2:17][CH2:18]3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: NC1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 85.7 %

Procedure:
A portion (4.9 g) of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one oxime obtained in Step 1 was suspended in methanol (50 mL) and acetic acid (25 mL), followed by stirring at room temperature for 18 hrs under a hydrogen atmosphere in the presence of 10% palladium-carbon (0.5 g). The insoluble matter was separated by filtration with Celite® pad and the filtrate was concentrated; thereafter, the residue was dissolved in water and the pH of the solution was adjusted to about 8 with sodium hydrogencarbonate, followed by extraction with dichloromethane. The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate; the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol) to yield the titled compound as pale yellow crystals (4.0 g).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33].C1N2CCN(CC2)C1>CC#N>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][C:2]1[C:7]2=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH:12]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnn2cc(-c3ccnc(N4CCOCC4)c3)cc12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a suspension of the crude 4-chloro-6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine in MeCN (5 mL) were added 2-fluoro-4-nitrophenol (59 mg, 0.37 mmol) and DABCO (45 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (ISCO RediSep® silica gel cartridge) to give the desired compound (54 mg, 33% yield in two steps). MS(ESI) m/z 437.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[CH:23][CH:22]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccc(F)cc2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Fluoroaniline instead of 3-chloroaniline to yield the final compound as a gray solid, MS (ISP): m/e=324.9, 326.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:42]=[CH:41][C:27]([CH2:28][P:29](=[O:40])([O:35][CH2:36][CH2:37][O:38][CH3:39])[O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:26][CH:25]=1>>[CH3:14][NH:13][C:11]([C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][P:29](=[O:40])([O:30][CH2:31][CH2:32][O:33][CH3:34])[O:35][CH2:36][CH2:37][O:38][CH3:39])=[CH:41][CH:42]=2)[N:7]=1)=[O:12]
Reactant: COCCOP(=O)(Cc1ccc(N)cc1)OCCOC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCOC)OCCOC)cc2)ncc1C(F)(F)F

Procedure:
The title product was prepared according to the procedure for Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 0.050 g, 0.15 mmol) and bis(2-methoxyethyl) (4-aminobenzyl)phosphonate (Compound 185A, 0.0917 g, 0.302 mmol) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=4.80 Hz, 1H), 8.44 (s, 1H), 7.69-7.74 (m, 1H), 7.57 (d, J=7.58 Hz, 2H), 7.50 (t, J=7.96 Hz, 1H), 7.13-7.21 (m, 3H), 3.94-4.05 (m, 4H), 3.46 (t, J=4.55 Hz, 4H), 3.21-3.26 (m, 6H), 3.18 (s, 2H), 2.78 (d, J=4.55 Hz, 3H); MS (ES+): m/z: 598.1695 [MH+]. HPLC: tR=1.32 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=[C:3]([Cl:10])[CH:2]=1.C1(C)C=CC=CC=1.S(Br)([Br:20])=O>N1C=CC=CC=1>[Cl:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][Br:20])=[CH:1][CH:2]=1
Reactant: O=S(Br)Br
Reactant: OCCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccc(CCBr)cc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A 500 ml. 3 neck round bottomed flask under nitrogen was charged 15.65 g. of 4-chlorophenethanol (1.0 eq., 0.10 moles) in 60 ml. toluene. To the reaction was added dropwise 41.6 g of thionyl bromide (2.0 eq., 0.20 moles) in 15 ml. of toluene maintaining the temp. below 25 C. Finally, 8.7 g. pyridine (1.1 eq., 0.11 moles) in 20 ml. toluene was added dropwise again keeping the temperature below 30° C. with an external ice bath. The reaction was monitored by GLC and after 1 hr. an additional 14.0 g of thionyl bromide (0.67 eq. 0.067 moles) was added followed three hours later by 9.7 gms. (1.1 eq., 0.11 moles). Subsequently 4.3 g. of pyridine was added (0.55 eq., 0.055 moles) after which GLC indicated all the alcohol was consumed. The reaction was quenched by the addition of 300 ml of water while cooling with an ice bath after which 400 ml. of ether was added. The ether was washed water three times with 250 ml.), dried over MgSO4 and concentrated to give 14.4 g of product as an oil (65.2% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with acetonitrile (150 mL), 189a (3.0 g, 8.8 mmol), and N-bromosuccinimide (1.56 g, 8.8 mmol). The mixture was stirred at room temperature overnight. It was then concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 10:1 petroleum ether/ethyl acetate to afford 189b as a yellow solid (2.85 g, 73.4%). MS: [M+H]+ 343.3. 1H NMR (500 MHz, (CD3)2CO) δ 8.03 (s, 1H), 7.94 (s, 1H), 3.48-3.46 (m, 4H), 3.42-3.40 (m, 4H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH:14]C(OC(C)(C)C)=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(N)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
The mixture of 2-ethanoyloxy-5-tert-butoxycarbonylaminobenzoic acid (1.01 g, 3.42 mmole) in TFA/CH2Cl2 (20.0 ml. 1:1 v/v) was stirred for 30 min at room temperature. After the reaction mixture was concentrated, the residue was dissolved in ether. The resulting residue was recrystallized from ethyl acetate/hexane to give 0.65 g (97% yield) of 2-ethanoyloxy-5-aminobenzoic acid as a white solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:13])[CH3:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2ccccc2C1

Procedure:
A mixture of 100 g. (0.75 mole) 1,2,3,4-tetrahydroisoquinoline and 150 ml. acetic anhydride was stirred at ambient temperature for 24 hours and then concentrated to dryness at reduced pressure. The residual liquid was dissolved in methylene chloride and solid potassium carbonate was added to neutralize the solution. The excess potassium carbonate was removed by filtration and the filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-1,2,3,4-tetrahydroisoquinoline as a yellow liquid.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:30])[N:16]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH:17]2[CH2:20][C:21](OCC)=[O:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[CH:19]=[C:18]2[C:14]([C:15](=[O:30])[N:16]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH:17]2[CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cc(C(C)(C)C)ccc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2ccc(C(C)(C)C)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 68.1 %

Procedure:
N-[(6-tert-Butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.37 g of sodium, 1.56 g of guanidinium chloride and 3.53 g of ethyl (6-tert-butyl-2-isobutyl-3oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 15 cm3 of water and 45 cm3 of diethyl ether and then stirred at a temperature in the region of 0° C. for 2 hours. The precipitate obtained is filtered off, washed with twice 10 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 2.5 g of N-[(6-tert-butyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a brown powder melting at 214-215° C. Mass spectrum: DCI: m/e 345 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:6][C:5]2[CH:37]=[CH:38][C:2]([O:1][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Product: COCCN(C)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 69.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (15 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18][CH2:17]2.Cl>CCOCC>[CH3:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:18][CH2:17]2
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1ccc2c(c1)CCCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 6.1 h
Yield: 85.1 %

Procedure:
Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in mechanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). The reaction was stirred at room temperature for 6.1 hours then treated with 3N HCl (20 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (8.09 g) that was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19]Br>>[Cl:16][C:17]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:18]=1[CH2:19][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1Cc1cc(F)ccc1Cl

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:34])=[C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([CH3:34])=[C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:11]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of 1,1-dimethylethyl 4-(6-{5-[(ethylamino)carbonyl]-2-methylphenyl}-1H-indazol-3-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (Intermediate 14, 550 mg) in dichloromethane (10 ml) under nitrogen was treated dropwise with trifluoroacetic acid (0.89 ml) then stirred at room temperature for 2 h. More trifluoroacetic acid (0.89 ml) was added and stirring was continued for a further 1 h. The solvent was evaporated and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. Elution with a solution of aqueous ammonia (0.88) in methanol (10%) gave the title compound as a white solid (432 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:14](Cl)(=[O:16])[CH3:15].Cl>ClCCl>[CH3:15][C:14]([C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])=[O:16]
Reactant: COc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 8.55 g (64.2 mmol) of aluminum chloride in 75 mL of dichloromethane cooled to 0° C. (under a blanket of argon) was added dropwise a solution of 10.0 g (53.5 mmol) of 4-bromoanisole and 4.6 mL (64.2 mmol) of acetyl chloride in 25 mL of dichloromethane. After the addition was complete, the clear yellow solution was stirred at 0° C. for 15 minutes, poured into 200 mL of 10% HCl (aq.) solution, cooled to 0° C. in an ice bath and then extracted with dichloromethane (3×200-mL portions). The organic phases were combined and then washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give a yellow semi-solid. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].N1C=CC=CC=1.[C:19](O)(=[O:21])[CH3:20]>C1COCC1>[C:19]([O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: COc1cc(C(C)=O)ccc1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(C(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As shown in the above-described reaction formula, acetovanillone (500 mg, 3 mM) dissolved in 20 ml of THF was mixed with 0.5 ml of pyridine and 0.6 ml of anhydrous acetic acid. The mixture was stirred for 3 hours at room temperature. The resulting product was recovered with the extraction with diethylether and dried with anhydrous magnesium sulfate to remove remaining solvent. The remaining residue was performed to Silica gel column chromatography with a mobile phase (n-hexane:ethylacetate=4:1) to obtain white solid type of 4-acetyl-2-methoxyphenyl acetate (1; 625 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=O.[K+].CO>C(#N)C>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CCCC2=NCCN2)cc1)OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: O=C(Nc1ccc(CCCc2ncc[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 40.5 %

Procedure:
Compound 56 (274 mg, 0.81 mmol) was first dissolved in acetonitrile (10 mL), with potassium permanganate (192 mg, 1.22 mol) and alumina (567 mg, 0.3 mol) added into the solution in batch. After stirring the resulting mixture at room temperature for 40 min, CH3OH (1 mL) was added to reduce excess oxidant. The mixture was filtered and the solid material was washed with DCM:CH3OH=10:1. The filtrate was evaporated and the resulting crude material was purified with silica gel column chromatography (PE:EtOAc:TEA=3:1:0.2) to give compound 57 (110 mg, 41%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ7.32-7.43 (m, 6H), 7.28 (d, 2H, J=8.3 Hz), 7.09 (d, 2H, J=8.3 Hz), 6.90-9.95 (m, 2H), 6.70 (br s, 1H), 5.19 (s, 2H), 2.65 (t, 2H, J=7.4 Hz), 2.62 (d, 2H, J=7.4 Hz), 1.98-2.07 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C@@H:27]([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: OCc1ccc(Oc2cccc(F)c2)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cccc(F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-(3-fluorophenoxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.