Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CO.C(Cl)Cl>[C:20]1(=[CH:19][CH2:18][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCC=C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(CC=C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 38.5 gm of sodium phenyl sulfinate and then 3.85 gm of sodium carbonate were introduced into 116 cc of methanol and 44 gm of freshly prepared 1-bromo-2-cyclohexylidene-ethane were added dropwise over 30 minutes and at room temperature. The reaction mixture was then agitated for 1 hour and 30 minutes at room temperature after which the reaction mixture was poured into 400 cc of ice water. The precipitate formed was vacuum filtered, washed with water and dried. The raw product thus obtained was dissolved at high temperature in a mixture consisting of methylene chloride and methanol. The solution obtained was dried over magnesium sulfate, concentrated to a small volume and admixed with isopropyl ether. The precipitate formed was vacuum filtered and dried to obtain 36.4 gm of (2-cyclohexylidene-ethyl)-phenyl sulfone, having a melting point of 70° C. A sample of this product, crystallized from isopropyl ether, had a melting point of 70° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:26][CH2:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2cc(OC)ccc2C=O)c1
Reactant: CCN
Product: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: (2′-formyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][NH:19][CH2:18][C:17]3[S:21][CH:22]=[CH:23][C:16]2=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(O)(C)C>[CH2:1]([N:19]1[CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[CH:23]=[CH:22][S:21][C:17]=2[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: c1ccc(C2CNCc3sccc32)cc1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc(CN2Cc3sccc3C(c3ccccc3)C2)cc1
Yield: 52 %

Procedure:
Benzyl chloride is condensed with 4-phenyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (Example 3), according to the procedure of Example 8. Hydrochloride; M.p. = 185° C (isopropanol); Yield: 52%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([O:25]C(OC)=O)=[CH:16][C:15]=2[NH:30][C:31]([CH:33]2[O:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:36]=3[N:35](C(OCC)=O)[CH2:34]2)=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].Cl>CO.O>[C:43]([C:41]1[CH:40]=[CH:39][C:37]2[O:38][CH:33]([C:31]([NH:30][C:15]3[CH:16]=[C:17]([OH:25])[C:18]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:19][C:14]=3[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[O:32])[CH2:34][NH:35][C:36]=2[CH:42]=1)#[N:44]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)NCC(C(=O)Nc1cc(O)c(C3CCCC3)cc1C1=CCNCC1)O2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Ethyl 2-(2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (50 mg, 0.08 mmol) and NaOH (162 mg, 4.05 mmol) were dissolved in 5:1 methanol/water (3.6 mL) and heated at 60° C. for 2 h. The mixture was added to 1N HCl (25 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Removal of the Boc protecting group was achieved by dissolving the compound in dichloromethane (3.0 mL) and TFA (3.0 mL) and stirring for 10 min before being concentrated in vacuo. HPLC purification (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-(4-cyclopentyl-5-hydroxy-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (7 mg, 19% yield). LC/MS m/z 562.2 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 9.56 (s, 1H), 9.15 (s, 1H), 7.16 (s, 1H), 7.01 (m, 3H), 6.90 (s, 1H), 6.45 (s, 1H), 5.56 (s, 1H), 4.89 (q, J=3.0 Hz, 1H), 3.61 (s, 2H), 3.56-3.53 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (m, obscured by H2O peak, 1H), 3.23-3.16 (m, 3H), 2.44 (s, 2H), 1.93 (m, 1.97-1.90, 2H), 1.78-1.71 (m, 2H), 1.65-1.62 (m, 2H), 1.56-1.45 (m, 2H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)[C:41](N[C@@H]2[C@H]3[C@H](CNC3)CC2)=[O:42])CCCCC1>>[CH3:41][O:42][C:10]1[CH:3]=[CH:4][C:5]([CH2:6][N:24]2[CH2:25][C@@H:26]3[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]3[CH2:23]2)=[CH:8][CH:9]=1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: COc1ccc(CN2C[C@H]3CC[C@H](NC(=O)C(c4ccccc4)C(C)C)[C@H]3C2)cc1

Procedure:
The title compound was prepared by substituting 4-methoxybenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.57 (dd, J=8.3, 10.9, 1H), 7.63 (dd, J=2.8, 7.4, 2H), 7.39-7.28 (m, 4H), 7.28-7.23 (m, 1H), 6.98 (dd, J=8.7, 10.2, 2H), 4.41-4.30 (m, 1H), 3.68 (s, 3H), 3.57 (d, J=12.9, 0.5H), 3.48 (d, J=12.9, 0.5H), 3.42 (d, J=12.9, 0.5H), 3.31 (d, J=12.8, 0.5H), 3.21 (d, J=10.4, 1H), 2.90 (dd, J=2.8, 8.9, 0.5H), 2.69-2.59 (m, 1H), 2.56 (dd, J=2.9, 9.0, 1H), 2.53-2.46 (m, 1H), 2.45-2.33 (m, 1H), 2.32-2.26 (m, J=10.0, 1H), 2.24 (t, J=5.2, 1H), 2.15 (dt, J=6.3, 12.3, 0.5H), 1.96-1.88 (m, 0.5H), 1.88-1.79 (m, 0.5H), 1.79-1.65 (m, 1H), 1.48-1.24 (m, J=19.9, 48.8, 3H), 1.20 (dd, J=4.3, 6.4, 3H), 0.70 (dd, J=2.0, 6.7, 2H); MS (ESI+) m/z 407 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([C:15](O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]1[C:21]([NH2:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:18][N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]=[C:15]1[CH:13]1[CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CNc1ccccc1N
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C2CN(C(=O)OCc3ccccc3)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-2 (3.0 g, 12.75 mmol) was dissolved in THF (64 mL) and N-methylbenzene-1,2-diamine (2.02 g, 16.58 mmol), EDC (2.93 g, 15.30 mmol), HOAt (2.08 g, 15.30 mmol), and Hunig's base (6.7 mL, 38.3 mmol) were added. After stirring for 18 h at room temperature, the reaction solution was concentrated. The residue was then dissolved in acetic acid (30 mL), stirred at room temperature for 2 h, the solvent was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 5% aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes) to provide 1-3 as an off-white solid. MS: m/z=322.4 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.CC(OC([N:39]1[CH2:44][CH2:43][O:42][CH2:41][C@H:40]1[C:45](O)=[O:46])=O)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45]([C@@H:40]4[CH2:41][O:42][CH2:43][CH2:44][NH:39]4)=[O:46])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@@H]2COCCN2)c1
Reaction time: 0.08 h

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) was suspended in DCM (1 mL), (3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (52.9 mg, 0.229 mmol) and HATU (87 mg, 0.229 mmol) were added to the reaction mixture and stirred for 5 min. DIPEA (0.109 mL, 0.624 mmol) was added to the reaction mixture and stirred over the weekend. LCMS showed the coupling had gone to completion. Trifluoroacetic acid (0.25 mL, 3.24 mmol) was added to the reaction and left to stir for 1 h and 50 min. LCMS showed the reaction had gone to completion so the mixture was concentrated under a stream of nitrogen. The sample was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the required product (as TFA salts). The residue was dissolved in methanol and loaded onto a methanol pre-conditioned SCX-2 ion-exchange cartridge cartridge (10 g). The cartridge was washed well with methanol, followed by 2M ammonia in methanol. Evaporation of the solvent from the ammoniacal fractions gave the title compound as a colourless glassy solid (71 mg, 57%). LCMS (System A) RT=0.82 min, ES+ve m/z 594/596 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([CH:18]=O)=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.[NH2:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23]>CCO.CCOCC>[CH:1]1[C:9]2[C:8]3[C:10]([CH2:18][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:11]4[C:16](=[CH:17][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2cc2oc3ccccc3c12
Solvent: CCOCC
Solvent: CCO
Product: CC(CO)(CO)NCc1c2ccccc2cc2oc3ccccc3c12
Yield: 68.8 %

Procedure:
Using the procedure outlined in Example 1, benzo[b]naphtho[2,3-d]furan-11-carbaldehyde (2B) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 68.8% yield of 2-[[(benzo[b]naphtho[2,3-d]furan-11-yl)methyl]amino]-2-methyl-1,3-propanediol methanesuylfonate, mp 219°-220° (dec), (C,H,N,S), (EtOH/Et2O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([OH:12])=O)=[N:6][C:7]=1[C:8]#[N:9].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]([N:33]2[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1nc(C(=O)O)ccc1Br
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc(Br)c(C#N)n2)CC1
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
A mixture of 5-bromo-6-cyano-pyridine-2-carboxylic acid (875 mg, 3.85 mmol), HOBt (882 mg, 6.53 mmol), and EDC (1.11 g, 5.80 mmol) in DMF (32 mL) was stirred for 5 min and then treated with 1-isopropyl-piperazine (943 mg, 7.35 mmol). After 5 h, the mixture was diluted with DCM, washed with 1 N NaOH and water, dried, and concentrated. Purification of the residue by FCC gave a viscous foam that crystallized upon standing. Further purification by reverse-phase HPLC gave the title compound (476 mg, 37%). MS (ESI): mass calcd. for C14H17BrN4O, 336.06; m/z found, 337.2 [M+H]+. 1H NMR (d6-acetone): 8.43 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 3.70-3.68 (m, 2H), 3.51-3.49 (m, 2H), 2.73 (septet, J=6.6 Hz, 1H), 2.58-2.56 (m, 2H), 2.50-2.48 (m, 2H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][N:6]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[CH3:1][C:2]1([CH3:31])[NH:3][CH2:4][CH2:5][N:6]([CH2:8][C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)[N:12]=[N:11][N:10]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)CN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 2,2-dimethyl-4-({1-[3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (567 mg, 1.287 mmol, Intermediate 11) in methanol was added 4M hydrogen chloride in 1,4-Dioxane (7 ml, 28.0 mmol). The reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:30][CH3:31])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h
Yield: 57 %

Procedure:
The compound from step C (1 g, 2.4 mml) and EtI (42 mg, 2.6 mmol) were dissolved in anhydrous DMF (10 mL) Then NaH (144 mg, 3.6 mmol, 60%) was added to the mixture slowly at 0° C. After 30 minutes, the reaction mixture was quenched by saturate NH4Cl (10 mL), extracted with EA, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE: EA=20:1 to 5:1 to give the title compound (0.608 g, 57%). LC/MS m/z=444.1 [M+H]+. The two enantiomers were separated by SFC chiral separation.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3C(=CC=CC=3)C2=O)[CH:15]=1.CI.[CH2:39]([O:41]CC)C>CN(C)C=O>[C:34]([O-:35])(=[O:41])[CH3:33].[CH3:39][N:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][NH3+:26])[CH:15]=2)[C:4]1=[O:3]
Reactant: CCOCC
Reactant: O=C1c2ccccc2C(=O)N1CCCn1cc(-c2nc3ccccc3[nH]c2=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)[O-]
Product: Cn1c(=O)c(-c2cn(CCC[NH3+])c3ccccc23)nc2ccccc21
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A dispersion of sodium hydride, 55-60% in oil, (0.0075 g, 0.17 mmol) in dry dimethyl formamide (2 ml) was cooled to −20° C. A solution 2-{3-[3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl}-isoindol-1,3-dione (0.050 g, 0.11 mmol) in dry dimethyl formamide (2 ml), was added dropwise and the resulting mixture kept at −20° C. for 5 min and then at room temperature for another 15 min. The reaction mixture was cooled to −20° C and methyl iodide (0.017 g, 0.12 mmol, 7.7 μl) was added via a syringe. The resulting solution was allowed to reach room temperature whereupon 12 ml of diethyl ether was added. After 2 h at room temperature, 2-{3-[3-(4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl}-isoindole-1,3-dione was precipitated.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[Cl:13][CH2:14]Cl.[C:16]([Cl:19])(Cl)=[O:17]>N1C=CC=CC=1>[C:6]([O:17][CH3:16])(=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:14])=[O:11])=[CH:10][CH:9]=1.[C:16]([Cl:19])(=[O:17])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([Cl:13])=[O:12])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: ClCCl
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)OC)cc1
Product: O=C(Cl)c1ccc(C(=O)Cl)cc1
Yield: 94.2 %

Procedure:
Following the general procedure of Example 9, a slurry of 7.13 parts terephthalic acid in 80 parts dry dichloromethane was added to a mixture of 6.93 parts pyridine and 9.35 parts phosgene in 210 parts dry dichloromethane at 25° to 30° C. The ratio of equivalents of pyridine base/COOH acid group was 1.02. After carrying out the reaction and esterifying the resulting diacid chloride by the procedure as described in Example 1, there was obtained a 94.2% yield of theory of dimethyl terephthalate corresponding to a 94.2% yield of terephthaloyl chloride formed initially in the reaction.
Reaction SMILES: N=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[CH:13]=3)[S:3]1.C([OH:33])C>Cl>[F:29][C:27]([F:28])([F:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:33])[NH:6][C:5]3=[O:7])[CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: CCO
Reactant: N=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4C(F)(F)F)ccc3c2)S1
Agent: Cl
Product: O=C1NC(=O)C(Cc2cnc3cc(OCc4ccccc4C(F)(F)F)ccc3c2)S1
Yield: 44 %

Procedure:
In a mixture of 2N hydrochloric acid (5 mL) and ethanol (3 mL) was dissolved 2-imino-5-[[7-(2-trifluoromethylbenzyloxy)-3-quinolyl]methyl]thiazolidin-4-one (200 mg, 0.47 mmol.). The resulting solution was heated under reflux for 12 hours. After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate so that the aqueous phase was made to pH 7. The organic portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/8), to give 89 mg of the desired compound as pale brown crystalline powder (yield 44%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][CH:25]([C:36]([OH:38])=O)[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[NH2:48][C@H:49]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][OH:51]>O1CCOCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:16]([O:23][NH:24][CH:25]([C:36]([NH:48][C@H:49]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][OH:51])=[O:38])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(Cc1c[nH]c2ccccc12)NOCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)C(Cc1c[nH]c2ccccc12)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
1.24 g of dicyclohexylcarbodiimide was added to 30 ml Of a solution of 1.77 g of N-benzyloxy-DL-tryptophane and 0.70 g of N-hydroxysuccinimide in anhydrous dioxane, with ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, whereby a light brown solution was obtained. Separately, 0.8 ml of triethylamine was added to 20 ml of a suspension of 0.89 g of methyl L-serinate hydrochloride in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. Thereto was added the above light brown solution. The resulting mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with 200 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent, to obtain 2.07 g of methyl (N-benzyloxy-DL-tryptophyl)-L-serinate as a brown oily substance.
Reaction SMILES: [Na].[CH2:2]([C:9]([CH3:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12](O)(=O)[CH3:13]>CO>[C:3]1([CH:2]([C:9](=[O:10])[CH2:11][CH2:9][CH2:2][CH2:3][CH2:4][CH2:12][CH3:13])[CH2:5][CH2:6][CH3:7])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CC(=O)O
Agent: [Na]
Solvent: CO
Product: CCCCCCCC(=O)C(CCC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution prepared from 3 g sodium metal in 100 ml absolute methanol there was added 45 g methyl benzyl ketone. The resulting solution was refluxed for 30 minutes, cooled to 0° C. and 39 g 2-methylene-3-quinuolidinone was added. The solution was stirred at ambient temperature during 48 hours, netralized by the addition of 3 ml acetic acid and the solvents were removed under reduced pressure. There was obtained a crude oil which was extracted with chloroform. After evaporation of the solvent there was obtained 52 g (a yield of 60%) of the desired product, M.P. from acetone, 125.7° C. Treatment with hydrochloric acid gave the corresponding hydrochloride salt, M.P. above 300° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=O.[F:23][C:24]([F:32])([F:31])[C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:23][C:24]([F:32])([F:31])[C:25]([C:26]1[C:27]([CH3:28])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:30]
Reactant: COc1ccc(C(=O)c2cc(OC(F)(F)F)ccc2N)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: COc1ccc(-c2c(C(=O)C(F)(F)F)c(C)nc3ccc(OC(F)(F)F)cc23)cc1
Reaction time: 17 h
Yield: 58 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-methoxy-phenyl)-methanone [example A8] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 17 h and a grandient of heptane/ethyl acetate was used. Yield: 58%; MS: m/z=429 (M).