Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](C)=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][C:19]([Cl:22])=[CH:20][N:21]=1.Br[C:24]1C=CC=CC=1>>[Cl:22][C:19]1[S:18][C:17]([NH:16][C:10]([C:4]2([CH3:24])[CH:5]([OH:9])[CH:6]=[CH:7][N:2]([CH3:1])[C:3]2=[O:15])=[O:12])=[N:21][CH:20]=1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Brc1ccccc1
Reactant: Nc1ncc(Cl)s1
Product: CN1C=CC(O)C(C)(C(=O)Nc2ncc(Cl)s2)C1=O
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
223 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 129 mg of 2-amino-5-chlorothiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 8.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 153 mg of N-(5-chlorothiazol-2-yl)-1,3-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 22) represented by the formula:
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]2[NH:8][C:9](=[O:27])[C:10](=[CH2:26])[CH2:11]2)=[CH:19][CH:18]=1
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) (509 mg) is dissolved in dichloromethane (10 ml). Mixture is cooled to 0° C. and trifluoroacetic acid (0.5 ml) is added. The mixture is then stirred for 2 h then extracted with saturated sodium carbonate solution (20 ml). Phases are separated. The organic phase is dried (MgSO4) and concentrated to give (R)-5-biphenyl-4-ylmethyl-3-methylenepyrrolidin-2-one (4-a, R1=H). δH (400 MHz, DMSO) 2.47 (1H), 2.68 (1H), 2.74 (1H), 2.87 (1H), 3.87 (1H), 5.22 (1H), 5.64 (1H), 7.33 (3H), 7.45 (2H), 7.60 (2H), 7.65 (2H), 8.32 (1H); m/z (+) 264 ([MH]+, 100%); m/z (+ESI) 264 ([MH]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[CH:14]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][C:19](=[O:21])[CH2:18]3)[CH:14]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(O)C2)n1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)C2)n1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
156 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyrimidin-4-yl}azetidin-3-ol (Example 72) was dissolved in 1 ml of dimethyl sulfoxide, and 571 μl of triethylamine was added thereto and cooled to 15° C. 0.5 ml of dimethyl sulfoxide suspension including 388 mg of pyridine-trisulfur oxide complex was added thereto, and the mixture was stirred at room temperature overnight. Ice and saturated ammonium chloride aqueous solution were added to the reaction solution, and the mixture was stirred for 15 minutes, and diluted with ethyl acetate, and the organic layer was washed with saturated ammonium chloride aqueous solution and water in turn, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 50 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[F:23][C:24]([F:36])([F:35])[C:25]1[NH:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:34][C:32]4[CH:31]=[CH:30][C:28]5[N:29]=[C:25]([C:24]([F:36])([F:35])[F:23])[NH:26][C:27]=5[CH:33]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)cc1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75 mg, 0.22 mmol) was coupled with 2-trifluoromethyl-3H-benzimidazol-5-ylamine (78 mg, 0.38 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 34 mg (26%) of brown powder; LC/MS: 473 (M+H); HPLC: 95% pure, RT=2.99 min; 1H NMR: (DMSO, δ) 9.73 (s, 1H), 9.09 (s, 1H), 8.51 (d, J=8.4, 2H), 8.40 (s, 1H), 8.13 (br s, 1H), 8.04 (d, J=8.4, 2H), 7.71 (m, 2H), 7.38 (d, J=4.9, 1H), 7.03 (d, J=4.9, 1H), 3.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[CH:37][C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:38]=[CH:37][C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=c1[nH]c2ccc(Oc3cc(Cl)ncn3)cc2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.34 mmol) 6-(6-chloropyrimidin-4-yloxy)benzo[d]oxazol-2(3H)-one and 0.07 mL (0.41 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 4 h at 40° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were partially evaporated down i.vac. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:19][CH:16]2[CH2:18][CH2:17]2)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(trifluoromethyl)benzenesulfonyl chloride (0.2 g, 0.62 mmol) is added to a solution of cyclopropylamine (0.09 μl, 1.3 mmol) in DCM (5 ml), and the resulting solution is stirred at room temperature overnight. The reaction mixture is diluted with DCM (2×10 ml), washed with 0.1M HCl (5 ml), sat. aq. NaHCO3 (5 ml), dried (MgSO4) and concentrated in vacuo to yield the title compound. 1H NMR (400 MHz, d6-DMSO) δ 8.37 (1H, s), 8.23 (1H, s), 8.06 (1H, s), 2.21-2.17 (1H, m), 0.55-0.50 (2H, m) 0.40-0.36 (2H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH2:7][C:8]#[N:9].Br[C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=1.C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1>[Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:11][CH2:12][O:13][CH3:14])=[C:6]([CH:10]=1)[CH:7]([C:17]1[C:22]([O:23][CH2:24][O:25][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8]#[N:9]
Reactant: COCOc1cccnc1Br
Reactant: COCOc1cc(Cl)c(Br)cc1CC#N
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(Cl)c(Br)cc1C(C#N)c1ncccc1OCOC
Temperature: 0 °C
Yield: 71.2 %

Procedure:
To a suspension of 5-bromo-4-chloro-2-methoxymethoxybenzyl cyanide (10.4 g), 2-bromo-3-methoxymethoxy pyridine (7.81 g) and sodium p-toluenesulfinate (12.7 g) in THF (150 ml) was added, at room temperature, sodium hydride (3.63 g). The mixture was heated for 2 hours under reflux under argon atmosphere. The reaction mixture was cooled by aeration, which was poured into ice-water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous magnesium sulfate) and concentrated. The crystal obtained was washed with cyclohexane/isopropyl ether (5:1) to give 2-(5-bromo-4-chloro-α-cyano-2-methoxymethoxybenzyl)-3-methoxymethoxypyridine (10.9 g) (Compound C-15). The physical properties and spectrum data are shown in Table 9 and Table 12.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[N:26][C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])[CH3:25])[CH2:20]2)=[O:17])[N:13]([C:40]([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=2)=[O:45])=[C:41]([CH3:43])[CH3:42])[C:12]1=[O:57])[CH3:10])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(#N)C.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24](=[N:26][C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=3)=[O:28])[CH3:25])[CH2:20]2)=[O:17])[N:13]([C:40]([C:44]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=2)=[O:45])=[C:41]([CH3:42])[CH3:43])[C:12]1=[O:57])[CH3:10]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N2C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(C)C)C1
Reaction time: 2.5 h
Yield: 104.7 %

Procedure:
511 mg (0.62 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-1 -[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-2-azetidinone were dissolved in 20 ml of acetonitrile. To this solution were added 176 mg (1.24 mmole) of boron trifluoride etherate, with stirring and ice-cooling. The reaction mixture was then left to stand at room temperature for 2.5 hours, after which it was diluted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and dried. The solvent was distilled off, to afford 462 mg of the title product.
Reaction SMILES: ClC1C=CC(C[N:7]2[C:19]3[CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[C:11]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=2)[C:12]=3CC=C)=CC=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:48][C:49]1C=CC2C(=CC=CC=2)N=1.Cl>CN(C=O)C.O>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:27][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:19]1[CH:18]([CH2:20][C:21]([O:23][CH2:48][CH3:49])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: C=CCc1c(OCc2ccc3ccccc3n2)ccc2c1c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCc2c1[nH]c1ccc(OCc3ccc4ccccc4n3)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the phenol ester of Example 9, Step 2 (8.86 g, 32.4 mmol) in anhydrous DMF (50 ml) was added K2CO3 (6.72 g, 48.6 mmol) followed by 2-(chloromethyl)quinoline (7.49 g, 42.1 mmol). The mixture was stirred for 48 hours at room temperature. 2N HCl was added carefully until neutral to litmus paper. H2O (300 ml) was added and the mixture was extracted with EtOAc (6×100 ml). The combined organic layers were washed with water (400 ml) and dried over MgSO4. Evaporation and flash chromatography (20% EtOAc in hexane) afforded ethyl 6-(quinolin-2-ylmethoxy)-1,2,3,4-tetrahydrocarbazol-1-ylacetate.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[CH:13][S:12][C:11]=2[C:22]=1[Cl:23])C.[OH-].[Na+]>C(O)C>[Cl:23][C:22]1[C:11]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3F)csc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccccc3F)csc2c1Cl

Procedure:
A mixture of 7.2 g of ethyl{[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetate, 150 ml of 20% sodium hydroxide solution and 150 ml of 95% ethanol is stirred under reflux for 90 minutes. The reaction mixture is evaporated under reduced pressure, 200 ml of water is added and the solution is acidified with concentrated hydrocloric acid. The mixture is extracted with four 200 ml portions of ether. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to give a crystalline material. Recrystallization from acetone-hexane provides {[7-chloro-3-(2-fluorophenyl)benzo[b]thien-6-yl]oxy}acetic acid as needles, mp 163°-164° C.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[F:18][C:19]1[C:24]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: OB(O)c1cccnc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15 g), (2-fluoropyridin-3-yl)boronic acid (2.83 g), sodium hydrogen carbonate (2.53 g) and tetrakis(triphenylphosphine)palladium (870 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (80 mL) and water (20 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to give the title compound as a colorless oil (yield 2.25 g, 68%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:9]1[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:33][CH:34]=1)#[N:8]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 80 °C

Procedure:
Methyl bromoacetate (0.023 ml) was added to a suspension of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-hydroxybenzamide (0.06 g) and potassium carbonate (0.045 g) in DMF (3 ml) and the mixture was stirred and heated to 80° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether. The resultant solid was dried under vacuum at 55° C. to give the title compound as a solid (0.024 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.71 (s, 3H), 4.9 (s, 2H), 7.05 (d, 2H), 7.23 (d, 1H), 7.56 (d, 1H), 7.81 (s, 1H), 7.97 (m, 4H), 8.1 (d, 2H), 9.75 (s, 1H), 10.44 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][S:3]1.[OH-:14].[Na+]>C1COCC1>[SH:3][CH2:4][CH2:5][CH:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[C:2]([OH:1])=[O:14]
Reactant: [OH-]
Reactant: CCOC(=O)CCC1CCSC1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCC(CCS)C(=O)O
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of ethyl 3-(2-oxotetrahydro-3-thiophenyl)propanoate (0.77 g, 3.81 mmol) in THF (5 ml) was added sodium hydroxide (1 M in water, 5 ml). The mixture was allowed to stir for two days, then the THF was removed under reduced pressure, the aqueous layer was washed with ether, then acidified to pH 1 with HCl and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography yielding a 150 mg of clear oil (20%). 1H NMR (d6-DMSO) δ 1.7 (m, 3H), 1.8 (m, 1H), 2.2 (m, 2H), 2.3-2.5 (m, 4H). Analysis calculated for C7H12SO4: C, 43.74; H, 6.29; S, 16.68. Found: C, 43.61; H, 6.39; S, 16.55.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.Cl>O.CC(C)=O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:3]2[CH2:10][CH2:9][CH2:8][C@H:4]2[C:5]([OH:7])=[O:6])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)O)cc1
Temperature: 0 °C
Yield: 68 %

Procedure:
5M Aqueous sodium hydroxide solution (26 ml) was added to a solution of (S)-proline (582 g) in water (3.5 L) and acetone (3.5 L). The mixture was treated with ice (3.5 kg), cooled in an ice/acetone bath, treated over a one hour period with a solution of 4-methoxyphenylacetyl chloride (944 g) in acetone (1.75 L) with vigorous stirring and the simultaneous addition of sufficient 5M aqueous sodium hydroxide solution in order to keep the pH within the range 9.5-9.7. The reaction was stirred for 30 minutes, treated with concentrated hydrochloric acid (6 ml) and partially evaporated under reduced pressure to remove the majority of the acetone. The residue was treated with ice (2 kg), concentrated hydrochloric acid (750 ml) and the mixture stirred at room temperature for one hour. The resulting precipitate was collected, washed with water and recrystallised from toluene/ethanol to give the desired product as a colourless solid (905 g, 75%), m.p. 138°-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4,-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH:59]1[CH2:64][CH2:63][CH:62]([N:65]2[CH2:70][C:69]3[CH:71]=[N:72][CH:73]=[CH:74][C:68]=3[NH:67][C:66]2=[O:75])[CH2:61][CH2:60]1>O1CCCC1>[O:75]=[C:66]1[NH:67][C:68]2[CH:74]=[CH:73][N:72]=[CH:71][C:69]=2[CH2:70][N:65]1[CH:62]1[CH2:61][CH2:60][N:59]([C:35]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:36])[CH2:64][CH2:63]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1Nc2ccncc2CN1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3cnccc3NC2=O)CC1
Reaction time: 1 h
Yield: 24.4 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. Solid 3-piperidin-4-yl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one bisTFA salt (0.90 mmol) followed by triethylamine (0.065 mL) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with 1N NaOH and concentrated. The crude product was purified by chromatography (silica gel, 0 to 15% methanol in methylene chloride gradient elution) to give the title compound (0.013 g, 24% yield). MS 592.2286 (M+1).