Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccccc1Oc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1Oc1cccc2cccnc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.54 g of 8-(2-aminophenoxy)quinoline are dissolved in 70 ml of dichloromethane, and a solution of 3.17 g of 4-chlorobenzenesulphonyl chloride in 30 ml of dichloromethane is added at 25° C. After 1 hour, 2.42 ml of pyridine are added, and the mixture is stirred for 15 hours at 25° C. After removal of the solvent by evaporation, the residue is stirred with water. The product is filtered off and recrystallized from ethanol.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1>C(O)C.CN(C=O)C.[H][H].[C].[Pd]>[NH2:18][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 62.3 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-3-quinolinecarboxylic acid (322 mg) in ethanol-DMF (4:1) was added 10% palladium-carbon (25 mg) and the mixture was stirred in hydrogen gas atomosphere for 6 hours at room temperature. The catalyst was filtered off and washed with a solution of chloroform-methanol-concentrated aqueous ammonia (10:10:3). The filtrate and washings were combined and concentrated. The residue was recrystallized from a solution of chloroform-methanol-concentrated aqueous ammonia (20:6:1) to give the title compound (183 mg) as yellow prisms, mp 291°-291.5° C. (decompd.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])/[C:9](/[N+:10]([O-:12])=[O:11])=[CH:16]\[N:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: O=C(C[N+](=O)[O-])c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CN(C)/C=C(\C(=O)c1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-2-nitroethanone (5.38 g, 0.022 mol, Seter J. et al., Isr. J. Chem., 4, 7 (1966)) and N,N-dimethylformamide dimethylacetal (2.9 g, 0.024 mol) and catalitic amount of p-TsOH in THF (100 mL) was refluxed for 10 h. The mixture was cooled to room temperature and concentrated in vacuo. The reaction mixture was purified by flash chromatography eluting with ethyl acetate/hexane (1/1) to give title compound (2.8 g, 43%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Product: COc1ccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)cc1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline-5(6H)-one was reacted with 4-methoxybenzoyl chloride according to the procedure of Part b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(4-methoxybenzoyl)-quinoline5(6H)-one (21) as a yellow waxy solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].Br.N>C(OCC)C>[C:9]1(=[O:10])[N:5]([CH2:4][CH2:3][CH2:2][NH:19][C:18]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=2[CH3:16])[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: Cc1cccc(C)c1N
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: Br
Agent: N
Solvent: CCOCC
Product: Cc1cccc(C)c1NCCCN1C(=O)c2ccccc2C1=O

Procedure:
50 g. N-(3-Bromopropyl)-phthalimide and 50 g. 2,6-dimethylaniline are stirred for 5 hours at 100° C. After adding diethyl ether to the reaction mixture, it is filtered off with suction to give 69 g. of the hydrobromide (m.p. 226°-228° C.). The base is liberated from aqueous solution by adding a concentrated aqueous solution of ammonia. There are obtained 48 g. (83% of theory) of the desired product in the form of colorless crystals; m.p. 97°-98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][CH:41]([NH:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH2:46][CH2:45][CH2:44][NH:43][CH:41]([CH3:42])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: CC(C)NCCCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 64.4 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (14 mg, 64%). LC-MS m/z 604 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 6H), 1.65 (m, 2H), 2.34 (s, 3H), 2.50 (m, 2H), 2.78 (m, 1H), 3.15 (m, 2H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:7][C:5]1[N:6]=[C:2]([O:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1csc(Oc2ccccc2)n1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
3.00 g of 2,4-dibromothiazole, 1.74 g of phenol, and 3.44 g of potassium carbonate were added to 75 ml of N,N-dimethylformamide, and the obtained mixture was then stirred at 140° C. for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 100 ml of water was then added thereto, followed by extraction with 100 ml of ethyl acetate twice. The organic layer was washed with 100 ml of water twice and then with 50 ml of a saturated brine once. The resultant was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=9:1), so as to obtain 2.86 g of an ether compound.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CO.CCO[CH2:18][CH3:19].O=O>N1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:18][CH3:19]
Reactant: CCOCC
Reactant: C#CCCCCCCCCCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCCCCCC#CC#CCCCCCCCCCC
Reaction time: 72 h

Procedure:
Dodec-1-yne (EGA 24,440-6) (1.2 g) was heated in the presence of copper acetate (4 g) in a mixture of pyridine (100 cm3) , methanol 300 cm3) and ether (400 cm3), for 72 h, at 30°-32° C., in the presence of a gentle stream of pure oxygen. The ether and methanol were then evaporated off under reduced pressure after the excess dissolved oxygen had been removed by the passage of argon, in the presence of 1 g of CuCl. The solution was taken up by fresh anhydrous pyridine (400 cm3) for 72 h at 47° C. (reflux). Part of the pyridine was then evaporated off under reduced pressure, after which the mixture was acidified with a 10% aqueous solution of HCl. After extraction with ether and evaporation, an oily liquid was obtained which crystallized in the cold. The oil was chromatographed in CHCl3 on SiO2 to give an oil which was transparent at room temperature (0.877 g, y=73%). The product was checked by NMR, gas chromatography (purity 97%) and mass spectroscopy (peak 330).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.N.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][N:23]2[C:27]3[CH:28]([CH2:31][C:32](O)=[O:33])[CH2:29][CH2:30][C:26]=3[N:25]=[C:24]2[CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][C:20]=1[Cl:21]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:22][N:23]2[C:27]3[CH:28]([CH2:31][C:32]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:33])[CH2:29][CH2:30][C:26]=3[N:25]=[C:24]2[CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)O)CC2
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)OCc1ccccc1)CC2
Temperature: 0 °C

Procedure:
Benzyl alcohol (0.193 mL), DMAP (16.96 mg) and EDC (195 mgl) were successively added to a stirring solution of Example 9 (340 mg) in dichloromethane (5 mL) cooled at 0° C. under nitrogen. The RM was warmed to room temp and left stirring under nitrogen atm. overnight. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous phase was again extracted with DCM (20 ml). The 2 phases were separated; the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (380 mg). LC/MS MH+ 457, 459, Rt 3.55 min (5 minute run).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH:10]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]2([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:13]([N:11]1[CH2:12][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]1[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)CC1N(C(=O)Cl)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1N(C(=O)NCC[C@H](O)CO)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride (0.34 g, 0.7 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.1 g, 0.71 mmol) and triethylamine (0.15 mL, 1 mmol). The reaction mixture was stirred at room temperature for 30 min. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and NaHCO3 (sat.) solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography (EtOAc) to afford rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.11 g, 28%). HRMS (ES+) m/z Calcd for C27H31Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1785.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCCO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-aminoethanol. MS obsd. (ESI+) [(M+H)+] 398, 1H NMR (400 MHz, CD3OD) δ ppm 8.08 (d, J=7.6 Hz, 1 H), 7.91 (s, 1 H), 7.85 (d, J=7.6 Hz, 1 H), 7.74-7.67 (m, 2 H), 7.59-7.56 (m, 2 H), 6.09 (s, 1 H), 5.29 (s, 2 H), 4.51 (s, 2 H), 3.83 (t, J=5.6 Hz, 2 H), 3.74-3.72 (m, 2 H), 3.62 (t, J=5.6 Hz, 2 H), 2.47 (s, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=4)[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)cc3)CC2)c(C)c1
Yield: 91.7 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (1.09 g) described in Preparation Example 133 and 1-acetylimidazolidin-2-one (384 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.00 g) was obtained.
Reaction SMILES: [NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].O>CO.[Pd]>[NH:1]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)O
Reaction time: 8 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:19])=[O:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 4-methyl-1-naphthalenecarboxylic acid (4.14 g, 22.2 mmol) in methanol (50 ml) was added thionyl chloride (3 ml), and the mixture was stirred at 60° C. overnight. The reaction solution was concentrated, water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced ressure to give methyl 4-methyl-1-naphthalenecarboxylate (4.32 g, 97%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C1COCC1>[C:32]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:24])(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(C(F)(F)F)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 1.15 g (3.39 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 50 ml anhydrous THF containing BHT inhibitor (Aldrich). Triethylamine (1.4 ml, 11 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (0.436 g, 4.17 mmol) was added dropwise and the mixture was stirred for 1 hr at −10° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with 100 ml diethyl ether. The filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and then concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in methanol to give 0.35 g product (25%). [M+H+]=408.1. 1H NMR (CDCl3) delta: 10.97 (s, 1H, Ar—OH), 8.30 (s, 1H, Ar—H benzotriazole), 8.07 (d, 1H, Ar—H benzotriazole), 7.91 (s, 1H, Ar—H phenol), 7.69 (d, 1H, Ar—H benzotriazole), 7.10 (s, 1H, Ar—H phenol), 6.21 (s, 1H, C═C—H trans), 5.62 (s, 1H, C═C—H cis), 5.40 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3). Elemental analysis: calculated % C (56.02), % H (3.96), % N (10.32), % F (13.99). found % C (56.11), % H (3.96), % N (10.24), % F (14.37).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:23][C:22]([C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:20]=2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([O:28][C:26]([N:25]1[C:19]2[CH:18]=[CH:17][C:16]([C:3]3[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=3)=[CH:37][C:20]=2[CH:21]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH2:23][CH2:24]1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v. 42.0 ml) were dissolved 4-propoxyphenyl borate (746 mg) and methyl 7-bromo-1-(t-butoxycarbonyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1320 mg). To the solution was added potassium carbonate (1145 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (160 mg), and the mixture was heated to reflux under argon atmosphere for 14.5 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, hexane:ethyl acetate=3:1) to give methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate as yellow amorphous. The obtained methyl 1-(t-butoxycarbonyl)-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate was dissolved in ethyl acetate (80 ml). To the solution was added 6N hydrochloric acid (20 ml) at room temperature, and the mixture was stirred at 100° C. for 30 minutes and neutralized with 1N sodium hydroxide and saturated sodium hydrogen carbonate solution. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (947 mg) as yellow crystals. The mother liquor was concentrated, and the residue was purified with silica gel column chromatography (15 g, hexane:ethyl acetate=4:1) to give desired product (147 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH2:12][CH3:13].[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C(OCC)C.CCCCC>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:19]([OH:21])=[O:20])[CH:3]=2)[NH:7][N:6]=1)[CH2:12][CH3:13]
Reactant: CCCc1n[nH]c2ccc(Br)cc12
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCc1n[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
To 5-bromo-3-propyl-1H-indazole (1.00 g, 4.18 mmol) in diethyl ether (60 mL), 1.3 M t-BuLi (10.9 mL, 14.2 mmol) in pentane was added slowly at −78° C. under N2 atm. After 1 hour, CO2 gas was passed through the reaction mixture at −78° C. for 1 hour and allowed to slowly warm to room temperature. The reaction mixture was quenched with saturated NH4Cl solution and the ether layer was separated. The aqueous layer was acidified with 2 N HCl and extracted with ethyl acetate to afford the title compound (350 mg, 40.8%) as an off white solid. 1H NMR (DMSO-d6): δ 11.8-13.0 (br, 1H), 8.4 (s, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 3.0 (q, 2H), 1.8 (q, 2H), 0.9 (t, 3H). mp: 296-299° C.