Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13](OS(C(F)(F)F)(=O)=O)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:29][CH2:30][C:31]1[O:35][C:34](=[O:36])[NH:33][N:32]=1.C(NC(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([NH:29][CH2:30][C:31]3[O:35][C:34](=[O:36])[NH:33][N:32]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCc1n[nH]c(=O)o1
Reactant: COc1ccc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc1OC
Solvent: CC(=O)N(C)C
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2cc3ncccc3c(NCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
97 mg Trifluoromethanesulfonic acid 7-(3,4-dimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.2), 30 mg 5-aminomethyl-3H-[1,3,4]oxadiazole-2-one (2.33) and 0.132 mL N,N-diisopropylamine were placed in dimethylacetamide at ambient temperature. The reaction was heated to 70° C. overnight. After this time the reaction was cooled to ambient temperature and additional 0.132 mL N,N-diisopropylamine were added. The reaction was heated to 90° C. for 6 h. After this time, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (×3) and the combined organic fractions were dried over sodium sulfate, filtered and the solvent was concentrated from the filtrate under reduced pressure. Purification by and then by silica gel chromatography (ethyl acetate/methanol: 100:0 to 95:5) provided the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([C:54]3[CH:59]=[CH:58][C:57]([C:60]4[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=4)=[CH:56][CH:55]=3)=[CH:51][CH2:52]O)=[CH:46][CH:45]=2)[CH:39]=1.[CH2:66]([O:68][C:69](=[O:83])[CH2:70][O:71][C:72]1[CH:77]=[CH:76][C:75]([SH:78])=[CH:74][C:73]=1[C:79]([F:82])([F:81])[F:80])[CH3:67]>C1COCC1>[CH2:66]([O:68][C:69](=[O:83])[CH2:70][O:71][C:72]1[CH:77]=[CH:76][C:75]([S:78][CH2:52][CH:51]=[C:50]([C:54]2[CH:59]=[CH:58][C:57]([C:60]3[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=3)=[CH:56][CH:55]=2)[C:47]2[CH:46]=[CH:45][C:44]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)=[CH:49][CH:48]=2)=[CH:74][C:73]=1[C:79]([F:80])([F:81])[F:82])[CH3:67]
Reactant: CCOC(=O)COc1ccc(S)cc1C(F)(F)F
Reactant: OCC=C(c1ccc(-c2cccnc2)cc1)c1ccc(-c2cccnc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCC=C(c2ccc(-c3cccnc3)cc2)c2ccc(-c3cccnc3)cc2)cc1C(F)(F)F
Reaction time: 0.08 h

Procedure:
Triphenylphosphine (138 mg, 0.68 mmol) and ADDP (173 mg, 0.68 mmol) were added to a solution of 3,3-bis-(4-pyridin-3-yl-phenyl)-prop-2-en-1-ol (100 mg, 0.27 mmol) in THF (5 ml) at 0° C. The reaction mixture was stirred for 5 min under nitrogen atmosphere. (4-Mercapto-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester (prepared analogous to procedure in BioOrg. Med. Chem. Lett. 2003, 13, 1517) (92 mg, 0.32 mmol) was slowly added to the reaction mixture and the reaction was stirred for further 2 h at 0° C. The reaction mixture was evaporated and the residue was triturated with ether (2×15 ml). The filtered ether phases were evaporated and purified by column chromatography (eluent: ethyl acetate) to give {4-[3,3-bis-(4-pyridin-3-yl-phenyl)-allylsulfanyl]-2-trifluoromethyl-phenoxy}-acetic acid ethyl ester in 100 mg (60%) yield.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9]Br.[Cl:11][C:12]1[N:13]=[C:14]([Cl:25])[C:15]2[CH:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[NH:18][C:16]=2[N:17]=1>CN(C=O)C>[Cl:25][C:14]1[C:15]2[CH:20]=[C:19]3[N:18]([CH2:8][CH2:9][O:24][C:21]3([CH3:22])[CH3:23])[C:16]=2[N:17]=[C:12]([Cl:11])[N:13]=1
Reactant: CC(C)(O)c1cc2c(Cl)nc(Cl)nc2[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1cc1c(Cl)nc(Cl)nc12
Temperature: 100 °C

Procedure:
Cesium carbonate (1.2 g, 3.7 mmol) and 1,2-dibromoethane (316 μL, 3.7 mmol) were added to a solution of 2-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 1.23 mmol) in DMF (4 mL) and the reaction mixture was heated at 100° C. for 45 min, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene. A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (1.23 mmol), morpholine (236 μL, 2.69 mmol) and triethylamine (342 μL, 2.46 mmol) in IMS (3 mL) was heated at reflux for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (159 mg, 40%). LCMS (method A): RT=3.13 min, [M+H]+=323.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=CN=2)=[CH:6][CH:5]=[CH:4][NH:3]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:36][N:37](C)C=O>>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:36]=[N:37][CH:21]=[CH:22][CH:23]=2)=[CH:6][CH:5]=[CH:4][N:3]1[CH2:25][CH:26]1[CH2:28][CH2:27]1
Reactant: CN(C)C=O
Reactant: O=c1[nH]cccc1CN1CCCCC1CCCc1ccccn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1c(CN2CCCCC2CCCc2cccnc2)cccn1CC1CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
300 mg of 1-[(2-Oxo-1,2-dihydro-3-pyridinyl)methyl]-2-[3-(2-pyridyl)propyl]piperidine obtained in Example 178, 0.2 ml of (bromomethyl)cyclopropane and 610 mg of potassium carbonate were suspended in 5 ml of N,N-dimethylformamide (DMF), and the mixture were stirred at 80° C. for 4 hours. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently 1:1, and subsequently ethyl acetate), to give 150 mg of the objective oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:20])([CH3:19])[CH:6]1O)=S.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1.Cl>N1C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:20])([CH3:19])[CH:6]=1)=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=S)C1c2cc(C(F)(F)F)ccc2OC(C)(C)C1O
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)C1=CC(C)(C)Oc2ccc(C(F)(F)F)cc21
Yield: 29 %

Procedure:
A mixture of 0.17 g of N-methyl-3,4-dihydro-3-hydroxy-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 0.21 g of p-toluenesulfonyl chloride, and 10 ml of pyridine was heated at reflux for 4 hours. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CH2Cl2 :methanol=100:1) and then recrystallized from a mixture of diethyl ether and n-hexane to obtain 44 mg of N-methyl-6-trifluoromethyl-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]([OH:11])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:12]([NH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:12]([NH:18][C:9](=[O:11])[CH2:8][NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCNCC(=O)O
Reactant: CCCCCCN
Solvent: CCO
Product: CCCCCCNCC(=O)NCCCCCC

Procedure:
Into an autoclave, 5.6 gr (0.03 mol) of ethyl ester of 2-(n-hexylamino)acetic acid, 15 ml (0.1125 mol) of n-hexylamine and 1 mml of ethanol were added. The mixture was heated to 120° for 40 hours. The solvent and excess amine were then evaporated. The residue was solidified in pentene at low temperature (-80° C.), recrystallized three times from hexane, then dissolved in ether and added with a saturated HCl solution in ether till acid pH. The hydrochloride was recrystallized from isopropanol.
Reaction SMILES: [C:1](O)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[N:31]=[CH:30][N:29]=[C:28]2[NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Br:53])[CH:48]=1>O1CCCC1.N1C=CC=CC=1>[Br:53][C:49]1[CH:48]=[C:47]([NH:46][C:28]2[C:27]3[C:32](=[CH:33][C:34]([O:35][CH2:36][CH2:37][CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[C:25]([NH:24][C:1](=[O:7])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6])[CH:26]=3)[N:31]=[CH:30][N:29]=2)[CH:52]=[CH:51][CH:50]=1
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1
Reactant: C/C=C/C=C/C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC=CC=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCC1CCN(C)CC1
Reaction time: 0.02 h

Procedure:
To 31 mg of sorbic acid in 1 ml of tetrahydrofuran are added 40 μl of isobutyl chloroformate followed by 45 μl of N-methylmorpholine whilst cooling with an ice bath. The white suspension is stirred for one minute, then a solution of 100 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 1.5 ml of pyridine is added. The ice bath is removed and the reaction mixture is stirred overnight. For working up, it is poured onto 20 ml of ice water, stirred for 30 minutes and adjusted to pH 9-10 with a few drops of 2 N sodium hydroxide solution. The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over an aluminium oxide column (activity III) with methylene chloride/methanol (99.5:0.5). Yield: 62 mg (52% of theory); Rf value: 0.29 (aluminium oxide, activity III; methylene chloride/methanol=98:2); mass spectrum (EI): m/z=563, 565 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[C:12]3[NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:5]=[CH:6][C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][C:13]([C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[C:12]3[NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1NCCN1CCNCC1)C1CC1
Yield: 69.9 %

Procedure:
Following general procedure A-2, tert-butyl 4-{2-[6-(3-Chloro-4-hydroxyphenyl)-3-(cyclopropanecarbonyl)quinolin-4-ylamino]ethyl}piperazine-1-carboxylate (40 mg, 0.073 mmol) was reacted with TFA (2 mL) to afford the desired product (23 mg, 35%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.09 (s, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.7, 1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 7.61 (dd, J=8.5, 2.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.82 (d, J=5.2 Hz, 2H), 2.95-2.82 (m, 1H), 2.68 (t, J=4.7 Hz, 4H), 2.55 (t, J=6.0 Hz, 2H), 2.35 (s, 4H), 1.11-0.97 (m, 4H); ESI MS m/z 451 [C25H27ClN4O2+H]+; HPLC>99% (AUC), tR=9.32 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].[C:20]1(=[O:31])[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[CH2:21]1.O1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:31])[CH2:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24]([OH:26])=[O:25])[CH:16]=[CH:17][CH:18]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(/C=C/c2cccc(N)c2)n1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: C1CCOCC1
Product: CCOC(=O)c1csc(/C=C/c2cccc(NC(=O)Cc3ccccc3C(=O)O)c2)n1
Yield: 100.6 %

Procedure:
A solution of 0.5 g of (E)-2-[2-(3-aminophenyl)ethenyl]-4-thiazolecarboxylic acid ethyl ester, 0.3 g of homophthalic anhydride, 15 ml of toluene and 5 ml of tetrahydropyran was heated to reflux for 0.5 hr. Upon cooling, a solid formed which was filtered to yield 0.8 g of (E)-2-[2-[3-[2-[4-(ethoxycarbonyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 221°-223° C. from ethanol.
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[CH3:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:28]=1[C:29](Cl)=[O:30].[Al+3].[Cl-].[Cl-].[Cl-].[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:29](=[O:30])[C:28]3[C:27]([CH3:26])=[CH:35][C:34]([CH3:36])=[CH:33][C:32]=3[CH3:37])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:42](=[O:44])[CH3:43])[CH:10]=2)[CH3:2]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(=O)Cl
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccc(C(C)=O)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 11-(2-ethylhexyl)-11H-benzo[a]carbazole (0.42 g; 1.27 mmol) in CH2Cl2 (20 mL) are added 2,4,6-trimethylbenzoyl chloride (0.23 g; 1.27 mmol) and AlCl3 (0.17 g; 1.27 mmol) at 0° C. After stirring at room temperature for 2.5 hours, acetyl chloride (0.17 g; 1.31 mmol) and AlCl3 (0.19; 1.40 mmol) are added at 0° C., and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated to give a beige solid (0.45 g; 75%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.82 (t, 3H), 0.90 (t, 3H), 1.18-1.45 (m, 6H), 2.20 (s, 6H), 2.29-2.30 (m, 1H), 2.41 (s, 3H), 2.72 (s, 3H), 4.74-4.77 (m, 2H), 6.98 (s, 2H), 7.58 (d, 1H), 7.70-7.79 (m, 2H), 8.10 (dd, 1H), 8.39 (s, 1H), 8.60 (d, 1H), 8.64 (d, 1H), 9.53 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH2:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45]C)=O)#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:68](CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:32]([C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([CH2:35][CH2:34][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([NH2:68])=[O:45])[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=1)[CH3:33]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CCN(CC)CC
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 120 °C
Yield: 104.1 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate (I41) (283 mg, 0.584 mmol), methyl 2-(2-ethynylphenyl)acetate (I4) (122 mg, 0.700 mmol), copper(I) iodide (17 mg, 15 mol %), triphenylphosphine (23 mg, 15 mol %), bis(triphenylphosphine)palladium(II) chloride (41 mg, 10 mol %), triethylamine (0.33 mL, 2.3 mmol) and DMF (3 mL) was degassed with a nitrogen then heated under microwave irradiation (120° C./15 min). The cooled mixture was poured into water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over sodium sulfate and evaporated. Chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I42) (311 mg, 86% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.73-7.65 (m, 2H), 7.46-7.28 (m), 7.15-7.08 (m), 4.25 (s, 2H), 3.95 (s, J=9.6 Hz, 2H), 3.70 (s, 3H), 2.80 (t, J=12.1 Hz, 2H), 2.70-2.59 (m, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.65 (td, J=12.8, 4.1 Hz, 2H), 1.49 (s, 9H), 1.25 (t, J=7.6 Hz, 3H). LCMS: rt 7.01 min; m/z 623.1 [M+H]+; 567.1 [M-tBu+2H]+, 523.1 [M-Boc+2H]+; m/z 621.2 [M−H]−.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])=[CH:42][C:41]=1[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To a solution of L-pyroglutamic acid (49 mg, 0.38 mmol) in 5 mL of DMF was added 3-hydroxy,1,2,3-benzotriazin-4(3H)-one (62 mg, 0.38 mmol), (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) and [4-amino-2-phenylbenzoyl-L-methionine methyl ester (90 mg, 0.38 mmol), prepared as in Example 192B, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with 10 mL 1N HCl, 5 mL satd aqueous NaHCO3 and brine (3×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. Purification by radial chromatography (2-5% methanol-ethyl acetate gradient) to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester (92 mg, 79%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:14]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10](=[O:25])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=1
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)[nH]c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC(=O)O)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 0.42 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone in 10 ml of methanol was added 10 ml of a 1 N aqueous sodium hydroxide solution. After stirred at room temperature for 6 hours, the solvent was distilled off under reduced pressure, this was acidified with 1 N hydrochloric acid, and precipitated crystals were filtered, washed with water, washed with tetrahydrofuran, and then dried to obtain 0.31 g of 4-hydroxy-3-[3-[3-(carboxymethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (9a)] as a yellow crystal.
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:3].[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[N:18]=[CH:17]1>>[CH2:2]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][N:6]([S:21]([C:19]2[N:18]=[CH:17][N:16]([CH3:15])[CH:20]=2)(=[O:23])=[O:22])[CH2:5]1)[CH3:3]
Reactant: CCOC(=O)C1(CC)CCCNC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Product: CCC1(C(=O)O)CCCN(S(=O)(=O)c2cn(C)cn2)C1

Procedure:
The title compound was synthesized as in Production Example 1, using the compound synthesized in (1) and 1-methyl-1H-imidazole-4-sulfonyl chloride as the raw material.
Reaction SMILES: [CH3:1][O:2][C:3]([NH2:5])=[NH:4].Cl.[Br:7][C:8]1[CH:9]=[C:10]2NC(=O)O[C:12](=[O:13])[C:11]2=[CH:18][CH:19]=1.[O-]CC.[Na+].O>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:11]([C:12](=[O:13])[NH:4][C:3]([O:2][CH3:1])=[N:5]2)=[CH:18][CH:19]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reactant: COC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of o-methylisourea hydrochloride (1.256 g, 11.36 mmol) and 4-bromoisatoic anhydride (2.500 g, 10.33 mmol) in 10 mL DMF was treated with sodium ethoxide (1.476 g, 21.69 mmol) and was allowed to stir at room temperature overnight. LC/MS showed mostly product, so the reaction mixture was poured into water and the resulting solid was filtered and dried yielding 7-bromo-2-methoxyquinazolin-4(3H)-one (2.57 g, 10.08 mmol, 98% yield) with impurities. (M+H)+=255.0.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:33]([OH:35])=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:36][C:37]([NH:48][CH2:49][CH:50]([OH:66])[CH2:51][O:52][C:53]1[C:58]2[C:59]3[C:64]([NH:65][C:57]=2[CH:56]=[CH:55][CH:54]=1)=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[N+:46]=[N-:47])=[CH:41][CH:40]=1)[CH3:38].C1(OC)C=CC=CC=1.ClCC(O)=O.C(OCC)(=O)C>C(Cl)Cl>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:33]([OH:35])=[O:34])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38][C:37]([NH:48][CH2:49][CH:50]([OH:66])[CH2:51][O:52][C:53]1[C:58]2[C:59]3[C:64]([NH:65][C:57]=2[CH:56]=[CH:55][CH:54]=1)=[CH:63][CH:62]=[CH:61][CH:60]=3)([C:39]1[CH:44]=[CH:43][C:42]([N:45]=[N+:46]=[N-:47])=[CH:41][CH:40]=1)[CH3:36]
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](N)Cc2ccccc2)C(=O)O)c(C)c1C
Agent: CC(C)(NCC(O)COc1cccc2[nH]c3ccccc3c12)c1ccc(N=[N+]=[N-])cc1
Agent: O=C(O)CCl
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: NCCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
A solution of MEt-IDA-(Phe-Lys(Mtr)-PABC-MMC)2 30 (134.6 mg, 0.0590 mmol) in methylene chloride (3 mL) at rt was treated with anisole (1.28 mL, 200 equiv) and 1 M chloroacetic acid in methylene chloride (1.18 mL, 20 equiv). After 3.5 h ethyl acetate (30 mL) was added. The resulting purple solid was collected by filtration, washed with ethyl acetate and air-dried (97.8 mg, 82%). The product appeared to decompose in solution to one product by HPLC. 1H-NMR (CDCl3/CH3OD) δ 1.33 (m, 4H), 1.63 (s and M, 12H), 1.77 (m, 2H), 2.52 (m, 2H), 2.82 (m, 6H), 3.03 (m, 2H), 3.10 (s and brs, 10H), 3.27 (m, 2H), 3.53 (ABq, 2H), 3.96 (brs, 4H), 4.11 (m, 2H), 4.35 (d and m, 3H), 4.53 (m, 2H), 4.78 (ABq, 2H), 4.94 (m, 4H), 6.62 (s, 2H), 7.10 (m, 10H), 7.19 (d, 4H), 7.41 (d, 4H). MS (FAB) 1738.3 (M+Na)+, 1776.4 (M+K)+.