Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][CH:36]([OH:49])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=1>>[C:46]([NH:45][C:42]1[CH:43]=[CH:44][C:39]([O:38][CH2:37][CH:36]([OH:49])[CH2:35][NH:34][C:16]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]2[C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:33][CH:32]=2)=[O:18])=[CH:40][CH:41]=1)(=[O:48])[CH3:47]
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Nc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(NC(C)=O)cc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and N-(4-{[(2RS)-3-amino-2-hydroxypropyl]oxy}phenyl)acetamide, the title compound was obtained in 66% purity by HPLC. MS(ESI+): m/z=546.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH:11][C:14](=[O:16])[CH3:15])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cccc(C)c1C(=O)O
Reaction time: 1 h

Procedure:
90.6 g (0.6 mol) of 6-methylanthranilic acid is added to a solution of 24.8g (0.62 mol) of NaOH in 500 ml of water and 63.4 g (0.62 mol) of acetic anhydride are then added dropwise. After stirring for one hour, the mixture is acidified to pH 3 with conc. HCl with cooling, and the precipitate which deposits is filtered off with suction, washed with waterand dried under reduced pressure at 50° C. Yield: 107 g (0.55 mol)=92% of theory, m.p.: 189°-190° C.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:11])[CH:3]=1.Br[CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.CC(CC)=O>[F:10][C:9]1[C:2]([F:1])=[CH:3][C:4]2[O:11][C:13]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=2[CH:8]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: O=Cc1cc(F)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCO
Product: O=C(O)c1cc2cc(F)c(F)cc2o1
Yield: 60.8 %

Procedure:
A mixture of 6.5 g (41.1 mmol) of 4,5-difluoro-2-hydroxybenzaldehyde, 10.4 ml (61.7 mmol) of diethyl bromo-malonate, 11.3 g (82.2 mmol) of potassium carbonate and 50 ml of ethyl methyl ketone was boiled at reflux for 3 hours while stirring, filtered and concentrated in a vacuum. The brown oil obtained was dissolved in 65 ml of ethanol, treated with 6.5 g of potassium hydroxide pellets and heated at reflux for one hour while stirring. The mixture was concentrated in a vacuum and the residue was treated with 65 ml of water and 65 ml of 3N sulfuric acid and heated at reflux over 30 minutes. Subsequently, the mixture was filtered and the residue was washed with water and triturated in 50 ml of hexane over 30 minutes. The solid was filtered off and dried. There were obtained 4.95 g (60%) of 5,6-difluorobenzofuran-2-carboxylic acid as a light yellow solid with m.p. 270°.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].CSC.B.Cl>C1COCC1>[CH:1]([S:4]([CH2:7][CH2:8][NH2:9])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)CC#N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)S(=O)(=O)CCN
Reaction time: 0.67 h

Procedure:
Prepared according to Procedure K. 2-iso-Propylsulfonylacetonitrile (0.50 g, 3.39 mmol) was dissolved in THF and warmed to reflux under N2. Borane dimethylsulfide (2M, 1.7 mL, 3.39 mmol) was added dropwise and the reaction was stirred for an additional 40 minutes at reflux. After cooling the reaction to rt, HCl (2 M in MeOH) was added to the reaction slowly due to gas evolution. The volatiles were removed and fresh methanol was added to the resulting residue. Again, the volatiles were removed and the resulting residue was taken up in CH2Cl2 (25 mL) and washed with saturated potassium carbonate (aqueous). The organic layer was dried over sodium sulfate and the volatiles were removed to afford the title compound. GC-MS m/z 152 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:61]=[CH:60][CH:59]=[CH:58][C:53]=1[O:54][CH2:55]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:55][O:54][C:53]2[CH:58]=[CH:59][CH:60]=[CH:61][C:52]=2[F:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCOc1ccccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCOc4ccccc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 50.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (62 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (86 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(2-fluorophenoxy)-1-ethanol (45 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 47%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]N(C=O)C.[H-].[Na+].Br[CH2:25][CH:26]=[CH2:27]>O>[C:1]1([N:7]2[C:12](=[O:13])[N:11]([CH2:27][CH2:26][CH2:25][CH3:17])[C:10](=[O:14])[C:9]([C:15]#[N:16])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCn1c(=O)c(C#N)nn(-c2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Intermediate c (9 g, 0.042 mol) was added to DMF (80 mL) under an ice bath. To the mixture was added NaH (1.3 g, 0.054 mol) in batch under an ice bath. After stirring for 30 min, 3-bromopropylene (2.9 mL, 0.042 mol) was added dropwise. After the dropwise addition, the reaction was conducted at 50° C. for 4 h. After completion of the reaction, the reaction solution was poured into water (300 mL). A great deal of solid separated out and was filtered by suction. The filtered cake was washed with water and dried to produce Intermediate f (7.9 g) in a yield of 82%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[N:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[Cl:37][C:38]1[C:39]([C:48]([F:51])([F:50])[F:49])=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([C:48]([F:50])([F:49])[F:51])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[N:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[CH2:32][CH2:33]2)=[O:46])[C:42]=1[CH3:43]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ncccn2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Pyrimidinyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: MS (ES) M+H expected=389.1, found=389.0; HPLC retention time=3.99 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minute gradient of 20% to 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/99.9% acetonitrile).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:32])[CH3:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([N:19](CC2C=CC(OC)=CC=2)[CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:33])[N:11]([CH:30]([CH3:31])[CH3:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2ccc(F)c(N)c2)c(=O)n3C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1ccc(F)c(N)c1)c(=O)n2C(C)C
Yield: 32.5 %

Procedure:
The above prepared 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-[(4-methoxy-benzyl)-methyl-amino]-1H-[1,6]naphthyridin-2-one (5.3 g) was combined with TFA (50 mL) in DCM (150 mL) and heated at reflux overnight. The volatiles were removed under reduced pressure, the residue dissolved in 10% HCl and washed with EtOAc (3×). The aqueous layer was made basic (pH=11), extracted with EtOAc and the combined organics were dried (Na2SO4) and concentrated to give 3-(3-amino-4-fluoro-phenyl)-1-isopropyl-7-methylamino-1H-[1,6]naphthyridin-2-one (1.26 g, 32% yield over two steps). 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.70 (s, 1H), 7.06 (dd, J=8.4, 2.0 Hz, 1H), 6.94 (dd, J=11.6, 8.4 Hz, 1H), 6.88 (m, 1H), 6.72 (m, 1H), 6.39 (s, 1H), 5.07 (m, 1H), 5.06 (s, 2H), 2.83 (d, J=4.8 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 327.1 [M+H]+.
Reaction SMILES: C[N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[NH2:7]C1(C)CC(C)(C)C[C:10]([NH2:17])(C)C1.NCCNCCN.[OH2:26]>>[NH2:7][C:6]([NH2:2])=[O:26].[NH2:17][C:10]([O:5][CH2:4][CH3:3])=[O:26]
Reactant: CC1(C)CC(C)(N)CC(C)(N)C1
Reactant: CN(C)CCO
Reactant: O
Agent: NCCNCCN
Product: CCOC(N)=O
Product: NC(N)=O

Procedure:
One-thousand-four-hundred-thirteen parts of the prepolymer is charged to a reaction vessel and agitated. A mixture of 34 parts N,N-dimethylethanolamine and 1,390 parts water is then gradually added to the agitating prepolymer over a ten minute period, and the temperature is maintained between 29° to 32° C. Within one to two minutes after the completion of the addition of the N,N-dimethylethanolamine and water, a mixture of 15 parts 1-amino-3-amino-methyl-3,5,5-trimethylcyclohexane and 6 parts diethylenetriamine and 141 parts water is gradually added to the prepolymer dispersion over a four to five minute period, and the temperature is maintained between 32° to 35° C. to form a colloidally dispersed urea-urethane polymer. The acetone and methyl ethyl ketone are then distilled from the dispersion to yield a very stable, essentially organic solvent-free, aqueous colloidal polyurea-urethane ionomer dispersion with the following analysis: nonvolatile content of 39 percent by weight, pH of 9.2, and a viscosity of about 113 Stokes. The colloidal dispersion is only slightly opaque and is infinitely dilutable with water. Films from this product can be cured under ambient conditions and are of very high gloss and have a Shore hardness of A55. The polymer is an elastomer exhibiting an ultimate tensile strength of about 1,200 psi and elongation at break of about 900 percent. The films have very good resistance to water spotting.
Reaction SMILES: [C:1]1([C:7]2[NH:18][C:10]3=[N:11][CH:12]=[C:13]([C:15]([OH:17])=O)[CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:1]1([C:7]2[NH:18][C:10]3=[N:11][CH:12]=[C:13]([C:15]([NH:28][C:24]4[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=4)[C:21]([O:20][CH3:19])=[O:29])=[O:17])[CH:14]=[C:9]3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnc2[nH]c(-c3ccccc3)cc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(NC(=O)c2cnc3[nH]c(-c4ccccc4)cc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a solution of 2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (238 mg, 1 mmol, compound B of Example 1) in dimethyl formamide (5 mL) were added sequentially, methyl-3-aminobenzoate (151 mg, 1 mmol), triethylamine (0.1 mL) and BOP (500 mg, 1.2 mmol). After stirring the mixture at RT for 16 h, water was added and the solid formed was filtered, washed sequentially with water, 1N HCl, NaHCO3 and water to afford methyl 3-(2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamido)benzoate (100 mg) as a beige solid. LC/MS; (M+H)+=372.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:7]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 3-bromobenzoic acid (500 mg, 2.49 mmol), 3-(trifluoromethyl)aniline (0.31 ml, 2.49 mmol) and DIEA (2.06 ml, 12.45 mmol) in DMF (6 ml) was treated with HATU (1.04 g, 2.74 mmol) and the reaction mixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with sat'd NaCl(aq.), dried (MgSO4), filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc) gave a yellow oil which solidified on standing (622 mg, 73%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(O)=O.O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:7][CH2:6][CH:2]=[O:1]
Reactant: OCCCCSCCC1OCCO1
Solvent: O
Solvent: O=CO
Product: O=CCCSCCCCO
Temperature: 25 °C

Procedure:
4-(2-(1,3-Dioxolan-2-yl)ethylthio)butan-1-ol (example 281, step a) (500 mg) was dissolved in an 80% solution of aqueous formic acid (6 mL) and the reaction mixture was stirred at room temperature over the weekend. The mixture was diluted with water (10 mL) and extracted with ether (3×10 mL) then the organics were washed with brine (10 mL), dried over sodium sulphate, filtered and evaporated to afford 3-(4-hydroxy-butylsulfanyl)-propionaldehyde as an oil. This was dissolved in dry methanol and (2-isopropyl-thiazol-4-yl)-(1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-methanone trifluoroacetate (Example 22, step b) (606 mg) and 3 Å molecular sieves were added. Acetic acid (0.2 mL) was added and the mixture stirred for 5 minutes under argon before cooling to 0° C. and addition of sodium triacetoxyborohydride (633 mg). The cooling bath was removed and the reaction mixture stirred at room temperature overnight. The mixture was filtered then applied directly to an SCX-2 cartridge and washed with methanol before eluting the product with 2N ammonia in methanol. Further purification was by silica gel chromatography eluting with 10% methanol in DCM to afford the subtitled compound as a pale green oil. Yield 0.37 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C.CCCC(C)C>[C:14]1([CH2:13][O:12][C:10]2[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH:23]3[CH2:24][CH2:25][O:20][CH2:21][CH2:22]3)[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: OC1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.75 g, 30.0 mmol), tetrahydro-4H-pyran-4-ol (4.28 mL, 45.0 mmol) and triphenylphosphine (11.8 g, 45.0 mmol) were stirred under argon in THF (166 mL) and cooled to 5° C. in an ice bath. DEAD (19.6 mL, 45.0 mmol) was added dropwise to the mixture, maintaining the internal temperature below 10° C. Stirring was continued for 16 hours then the reaction mixture reduced in vacuo and the residue redissolved in ethyl acetate (60 mL) and isohexane (60 mL). The precipitate was removed, the filtrate concentrated in vacuo and purified by chromatography on silica, eluting with 0-25% ethyl acetate in isohexane (a small quantity of DCM used to assist column loading), to give the desired compound as a colourless oil (9.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][C:9](=O)[CH:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(N1CCNC(=O)C1C1C=CC=CC=1)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CN2CCNC(=O)C2c2ccccc2)cc(OC)c1OC
Agent: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Product: COc1cc(CN2CCNCC2c2ccccc2)cc(OC)c1OC

Procedure:
1-(3',4',5'-Trimethoxy benzyl)-2-phenyl-3-keto piperazine prepared according to Example 13, is reduced by following the procedure described hereinabove in Example 8 (a) whereby, in place of 1-diethylamino ethyl-3-keto-2-phenyl piperazine, the equimolecular amount of said 1-(3',4',5'-trimethoxy benzyl-2-phenyl-3-keto piperazine is used. The resulting 2-phenyl piperazine compound is obtained in the form of a yellow oil boiling at 185-195° C./0.08 mm. Hg.
Reaction SMILES: CO.[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH:14](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC>C(#N)C>[CH3:14][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1ccnc2ccccc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC#N
Product: COc1ccnc2ccccc12
Reaction time: 13 h

Procedure:
To 15 mL of methanol containing 4.02 g of 4-hydroxyquinoline and 130 mL of an acetonitrile solution, 5.01 g of diisopropylethylamine and 19.4 mL of a 2.0 mol/L trimethylsilyldiazomethane/hexane solution were added at room temperature, and the mixture was stirred for 13 hours, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate 2:1] to obtain 1.79 g of a yellow oily substance, 4-methoxyquinoline.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4].C(=O)([O-])[O-].[K+:37].[K+]>CO.O>[K+:37].[C:23]([NH:22][C:20]([N:7]1[C@@H:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:5]([C:3]([O-:4])=[O:2])[O:9][CH:8]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1OC(c2ccc(OC)cc2OC)N(C(=O)NC(C)(C)C)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2O[C@@H](C(=O)[O-])[C@H](c3ccccc3)N2C(=O)NC(C)(C)C)c(OC)c1

Procedure:
(4S,5R)-N-(t-Butylaminocarbonyl)-2-(2,4dimethoxyphenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester (PREPARATION 2—less polar isomer, 6.27 g, 14.2 mM) is stirred at 20-25° under nitrogen in methanol (50 mL). To this mixture is added a solution of potassium carbonate (2.50 g, 18.1 mM) in water (6 mL). After 6 hr the reaction is concentrated under reduced pressure to remove the methanol and the residue freeze dried to give the title compound (admixed with potassium carbonate salts as a powder), NMR (DMSO-d6, TMS) 1.10, 3.77, 4.17, 4.70, 5.16, 6.50, 6.60 and 7.14-7.42 δ.
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[C:13](=[O:16])([O-])O.[Na+].[C:18]1(=O)[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C(O[CH2:33][CH3:34])(=O)C>CN(C)C=O>[C:2]1([CH2:1][CH2:33][CH2:34][N:5]2[CH2:4][C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH2:18][N:22]4[C:21](=[O:23])[C:20]5=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]5[C:13]4=[O:16])[CH:7]=3)[CH2:1]2)[CH:3]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)CN(CCCc1ccccc1)C2
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 1.835 g (6.863 mM) of 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethanol and 1.43 ml (10.3 mM) of triethylamine in 50 ml of tetrahydrofuran was added 0.64 ml (8.24 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of diethyl ether. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude 2-(3-phenylpropan-1-yl)-2,3-dihydro-1H-isoindol-5-ylmethyl methanesulfonate thus obtained was dissolved in 60 ml of N,N-dimethylformamide, followed by addition of 1.40 g (7.55 mM) of potassium phthalimide, and the mixture was stirred at 100° C. for 4 hours. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic solution was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=3/1 to 2/1) to provide a mixture of the objective compound and phthalimide. This product was dissolved in ethyl acetate and the solution was washed serially with aqueous solution of sodium hydroxide and saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate (Na2SO4) and the solvent was distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14](OCC)=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(Cl)[Cl:28]>>[ClH:28].[N:22]1([CH2:21][CH2:20][NH:19][C:14]([CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C1c2ccccc2-c2ccccc21
Reactant: NCCN1CCCC1
Reactant: ClCCl
Product: Cl
Product: O=C(NCCN1CCCC1)C1c2ccccc2-c2ccccc21
Temperature: 150 °C

Procedure:
One mol (238 g) of ethyl 9-fluorene carboxylate is treated with 1.6 mol of 2-amino-ethyl pyrrolidine. Heated for 2 hours at 150° C., the ethanol distills over as it is formed. The reaction mass obtained is dissolved in methylene chloride, washed three times with water, dried, filtered and distilled to dryness.