Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:45])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:35]=[CH:36][CH:37]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>O1CCOCC1.O>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:45])=[N:13][C:14]2[N:15]([N:29]=[C:30]([C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[CH3:44])[CH:35]=[CH:36][CH:37]=3)[CH:31]=2)[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(-c4ccccc4C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c4cc(F)c5c(c4C)CCCO5)n3n2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a solution of (2S)-methyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-(2′-methyl-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (1.28 g, 2.1 mmol) in dioxane (12 mL) was added 1 N NaOH aqueous solution (9 mL, 9 mmol). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was diluted with water (50 ml) and neutralized with acetic acid. The resulted mixture was extracted with ethyl acetate (3×100 ml). The organic phase was combined and dried by sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC to afford (840 mg, 66%) of the title compound. Preparative HPLC condition: Waters Sunfire OBD C18 30×100 mm 5 u, 15 to 60% B over 18 minute gradient, 2 minute hold time, A=5% acetonitrile 95% water 10 mM Ammonium Acetate, B=95% acetonitrile 5% water 10 mM Ammonium Acetate. Flow rate: 40 ml/min. 1H NMR (400 MHz, DMSO-d6) δ 7.86-7.75 (m, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.40-7.22 (m, 5H), 7.18 (s, 1H), 7.09 (d, J=11.0 Hz, 1H), 4.83 (s, 1H), 4.34-4.22 (m, 2H), 2.82-2.66 (m, 5H), 2.24 (s, 3H), 2.13-2.02 (m, 2H), 1.83 (s, 3H), 1.09 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH2:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:20].[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([CH3:29])[C:27]=1[F:28].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:28][C:27]1[C:26]([CH3:29])=[CH:25][C:24]([NH:17][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([CH3:20])[CH:4]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(B(O)O)cc(C)c1F
Reactant: COC(=O)[C@H](N)CCCCOCc1ccc(F)c(C)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.6 %

Procedure:
To a suspension of crude (R)-methyl 6-(4-fluoro-3-methylbenzyloxy)-2-aminohexanoate (0.128 g, 0.453 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.152 g, 0.906 mmol), Cu(OAc)2 (0.090 g, 0.498 mmol), and molecular sieves 4 Å (0.400 g) in 5 mL of dichloromethane, was added triethylamine (0.13 mL, 0.906 mmol). After stirring at room temperature under O2 (1 atm) for 44 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as light yellow oil (0.126 g, 68% yield). GC-MS: tR=7.0 min; m/z 405 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(N(CC)CC)C.[CH2:24]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])O.[Na+]>CCOCC.O>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=1)#[N:12]
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccccc1Sc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1

Procedure:
In 2 ml of thionyl chloride was dissolved 1.03 g of 4-hexyloxybenzoic acid and the solution was refluxed for 1 hour. The excess thionyl chloride was distilled off and the residue was dried in vacuo to give 4-hexyloxybenzoyl chloride. Separately, 1.00 g of 2-(2-aminophenylthio)benzonitrile and 0.89 g of triethylamine were dissolved in 10 ml of ether and while the solution was stirred with ice-cooling, a solution of the above 4-hexyloxybenzoyl chloride in 5 ml of ether was added. The mixture was stirred overnight. Next morning, water and an aqueous solution of sodium hydrogen carbonate were added in the order mentioned and the resulting precipitate was extracted with ethyl acetate. The extract was dried over magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane to give 1.27 g of the title compound as white prisms.
Reaction SMILES: [Br:1][C:2]1[C:21](Br)=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].C(O)(=O)C.C([O-])(=O)C.[Na+].[H][H]>[Pd]>[Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: NC(=O)C1(N2C(=O)c3ccc(Br)c(Br)c3C2=O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)C1(N2C(=O)c3cccc(Br)c3C2=O)CCCCC1

Procedure:
A solution of 1-(3,4-dibromophthalimido)cyclohexanecarboxamide in acetic acid containing one equivalent of sodium acetate is reduced with hydrogen in the presence of palladium on carbon to give the product 1-(3-bromophthalimido) cyclohexanecarboxamide, m.p. 199°-200°C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:52]=[CH:51][CH:50]=C[C:46]=1[C:47]#[N:48]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:51][CH:52]=[CH:45][C:46]=3[C:47]#[N:48])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccccc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C#N)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)benzonitrile and isolated as white solid (6.1 mg, 37%). MS (m/e): 398.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26](O)=[O:27])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:12](=[O:29])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([CH2:26][OH:27])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(=O)O)ccc2c1=O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CO)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinecarboxylic acid (6.31 g, 14 mmol) and N-methylmorpholine (1.8 mL, 16.8 mmol) in tetrahydrofuran (50 mL) was added ethyl chloroformate (1.6 mL, 16.8 mmol) at 0° C. and the mixture was stirred at 0° C. for 10 min. To the obtained mixture were added sodium tetrahydroborate (1.59 g, 42 mmol) and methanol (5 mL) and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(6-hydroxymethyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (4.73 g, 77.4%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:17](=[O:23])[CH2:18][CH2:19][C:20]=2[O:21][CH3:22])=[C:11]([CH3:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:17](=[O:23])[C:18](=[CH:39][CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[CH2:19][C:20]=2[O:21][CH3:22])=[C:11]([CH3:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CCOCC1
Reactant: COC1=C(c2c(C)cc(OCc3ccccc3)cc2C)C(=O)CC1
Agent: CC(C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(OCc3ccccc3)cc2C)C(=O)C(=CC2CCOCC2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-benzyloxy-2,6-dimethylphenyl)-3-methoxycyclopent-2-enone (1.93 g, 6.0 mmol) in THF (25 ml) under a nitrogen atmosphere at −78° C. is added a solution of lithium diisopropylamide (3.33 ml, 6.0 mmol, 1.8M in tetrahydrofuran) dropwise over 1 minute. The reaction is then stirred at −78° C. for 30 minutes followed by the addition of 4-tetrahydropyran carbaldehyde (0.684 g, 6.0 mmol) in one portion. After a further 5 minutes at −78° C. the reaction is allowed to warm to ambient temperature and stir for an additional 1 hour. Potassium tert-butoxide (1.10 g, 9.82 mmol) is then added in one portion and the reaction mixture is allowed to stir for a further 1 hour at room temperature. After quenching with saturated ammonium chloride solution (50 ml) the crude product is extracted into ethyl acetate (50 ml), and the organic phase is dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography affords 2-(4-benzyloxy-2,6-dimethylphenyl)-3-methoxy-5-[1-(tetrahydropyran-4-yl)-methylidene]cyclopent-2-enone as a white solid.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:11]2[C@@:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])([N:7]=[C:8]([NH2:12])[S:9][CH2:10]2)[CH2:5][O:4]1.S(=O)(=O)(O)O.[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[CH:16][C:17]([N+:25]([O-:27])=[O:26])=[CH:18][C:13]=1[C@:6]12[CH2:5][O:4][C@H:3]([CH2:2][F:1])[C@H:11]1[CH2:10][S:9][C:8]([NH2:12])=[N:7]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@H](CF)[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
(4aS,5S,7aS)-5-(fluoromethyl)-7a-(2-fluorophenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (45.85 g, 161.26 mmol) was dissolved in TFA (192 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 33.65 mL, 161.26 mmol) was added, followed by fuming nitric acid (7.78 mL, 185.44 mmol) dropwise over 25 mins. After stirring at 0° C. for 30 mins, the reaction mixture was poured onto ice (500 g)/CHCl3 (500 mL) and basified to pH 12 with 6N NaOH (aq.). The two layers were separated and the aqueous layer was extracted with CHCl3 (2×500 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the product as a light orange foam (52.11 g, 98%). 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13.26, 3.92 Hz, 1H) 3.03 (dt, J=7.77, 3.82 Hz, 1H) 3.08 (dd, J=13.39, 3.28 Hz, 1H) 3.85 (dd, J=8.84, 2.27 Hz, 1H) 4.49-4.67 (m, 4H) 7.22 (dd, J=10.99, 8.97 Hz, 1H) 8.16-8.23 (m, 1H) 8.43 (dd, J=6.82, 2.78 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]1[CH:28]=[C:27]([C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:26]=[C:25]([CH3:39])[C:23]=1[NH2:24].N1C=CC=CC=1.FC1C=CC([N+]([O-])=O)=CC=1C(Cl)=O.C(=O)([O-])O.[Na+]>ClCCl.O1CCCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([NH:24][C:23]1[C:25]([CH3:39])=[CH:26][C:27]([C:29]([F:38])([C:30]([F:31])([F:32])[F:33])[C:34]([F:35])([F:36])[F:37])=[CH:28][C:22]=1[CH3:21])=[O:8])#[N:2]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: N#Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a suspension of 3-cyano-5-nitro-benzoic acid (7.2 g, 37.5 mmol) (Example I5) in dichloromethane (40 ml) was added oxalyl chloride (3.808 ml, 45 mmol) at ambient temperature, followed by N,N-dimethylformamide (0.2 ml). The reaction mixture was stirred for 1 hour at ambient temperature and then heated to reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated. The residue was suspended in tetrahydrofuran (50 ml). 2,6-Dimethyl-4-(heptafluoroprop-2-yl)aniline (9.761 g, 33.7 mmol) (prepared according to EP 1,006,102) was dissolved in tetrahydrofuran (50 ml) and pyridine (6.035 ml, 75 mmol) was added. The mixture was cooled to 0° C. and the solution of 2-fluoro-5-nitro-benzoyl chloride was added. The reaction mixture was stirred at ambient temperature for 12 hours. Then aqueous sodium hydrogen carbonate (saturated) (100 ml) was added and the organic phase extracted twice with ethyl acetate (2×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 6:1) to give 3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-5-nitro-benzamide (12 g, 77% yield). 1H-NMR (400 MHz, CDCl3): 8.99 (m, 1H), 8.72 (m, 1H), 8.6 (m, 1H), 7.80 (s, 1H), 7.4 (s, 2H), 2.33 (s, 6H) ppm.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:17])=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+].O>CN(C=O)C>[C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([I:18])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: O=C(Oc1ccc(O)c(Cl)c1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1cc(Cl)c(O)c(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of 5-benzoyloxy-1-chloro-2-hydroxybenzene were dissolved in 35 ml of DMF. 2.17 g of sodium iodide and 3.29 g of chloramin T were added. After one hour of stirring at room temperature, about 500 ml of water were added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with 5% strength sodium thiosulfate solution, dried and concentrated using a rotary evaporator. The resulting product was clean enough for the next reaction. Yield: 3.81 g (84%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].[CH3:17][NH:18]CCC.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([NH:18][CH3:17])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Reactant: CCCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(CO)cc(C(=O)NC)c1
Yield: 47.7 %

Procedure:
Stir a solution of 5-hydroxymethyl-isophthalic acid monoethyl ester (1.9 g, 8.4 mmol), N-methylpropylamine (947 μl, 9.2 mmol), 1-hydroxybenzotriazole (1.24 g, 9.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g, 9.2 mmol) in a mixture of dichloromethane (12 mL) and DMF (12 mL) at room temperature for 1.5 h. Concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (950 mg, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:28][C:29]1([CH3:36])[CH2:34][C:33](=[O:35])[O:32][C:30]1=[O:31]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([NH:21][C:33](=[O:35])[CH2:34][C:29]([C:30]([OH:32])=[O:31])([CH3:36])[CH3:28])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)Nc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 7-chloro-2-(5-aminobenzofuran-2-yl)-quinoline (0.28 g) and pyridine (0.12 ml) in a mixture of dichloromethane (10 ml) and N,N-dimethylformamide (20 ml), 2,2-dimethylsuccinic anhydride was added dropwise at ambient temperature- After being stirred at ambient temperature for 1 day, the resulting mixture was poured into ice-water. The appeared precipitates were collected by filtration, washed with water and recrystallized from ethanol to give 7-chloro-2-[5-(3-carboxy-3-methylbutyrylamino)benzofuran-2-yl]quinoline (0.13 g).
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][O:24][C:25](=[O:42])[CH:26](OS(C(F)(F)F)(=O)=O)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:28]1([CH2:27][CH:26]([O:22][C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([C:10]4[NH:11][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[CH:13]=3)[CH:18]=2)[C:25]([O:24][CH3:23])=[O:42])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 1.05 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.492 g, 1.58 mmol) and cesium carbonate (0.685 g, 2.10 mmol) in acetone (50 mL) was stirred under nitrogen at ambient temperature overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted two times with EtOAc. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40L column (120 g Silica Gel, 60 Å) using 25% to 60% methylene chloride in hexane as the eluent gave methyl 3-phenyl-2-{[6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}propanoate as a grayish solid (0.447 g, 95%), mp 140–141° C. Elemental Analysis for C30H25NO3 Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 80.26; H, 5.70; N, 2.94.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C.ClC(OC)=O.C[NH-]>C(Cl)(Cl)Cl>[CH3:16][NH:18][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14]
Reactant: CCN(CC)CC
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Agent: C[NH-]
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1cnc2cccc(C)n2c1=O

Procedure:
A solution containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. while stirring and cooling by ice-salt. To this mixture, 6.5 ml (0.08 mol) of methyl chloroformate dissolved in 40 ml chloroform are dropped at -20° C. during 10 minutes. After stirring for 5 minutes, a solution containing 2.5 g (0.08 mol) of methylamide (prepared from methylamine hydrochloride in chloroform by adding triethylamine) in 80 ml of chloroform is added dropwise to the reaction mixture at -18° C. during 30 minutes. After stirring below -10° C. for 1 hour, the reaction mixture is allowed to stand in the refrigerator overnight. Next day the reaction mixture is washed 3 times with 140 ml of 5% sodium hydrogen carbonate solution each and then with 140 ml of water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is stirred with 150 ml of 10% hydrochloric acid at room temperature for 1 hour, then the precipitated starting material, 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid weighing 10 g is filtered off. The pH value of the aqueous filtrate is adjusted to 9 by adding 20% sodium hydroxide solution and then extracted 3 times with 100 ml of chloroform each. The combined organic phase is dried over anhydrous sodium sulfate and evaporated. After recrystallization of the residue from ethanol, 3.2 g (45.5%) of the named lemon-yellow product are obtained, m.p.: 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(O)(=O)[C@H](CC(O)=O)O.C(N(CC)CC)C.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C(O)C[C@H](O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)[C@H](CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol), which was derived from L-malic acid by means known in the art, in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0-2%) as eluent gave 4.90 g (99%) of the title material as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).