Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Nc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 68.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added isopropylamine (1.3 ml, 14.4 mmol). The mixture was heated at 70° C. overnight. The mixture was then cooled to rt, diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 125 mg (yield 68%) of the title compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[C:18]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:20]([OH:27])=[C:21]([CH2:23][C:24](O)=[O:25])[CH:22]=1>C(Cl)Cl>[Cl:16][C:17]1[C:18]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:20]2[O:27][C:24](=[O:25])[CH2:23][C:21]=2[CH:22]=1
Reactant: O=C(O)Cc1cc(Cl)c(N2CCCCC2)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g (31.5 mmole) of dicyclohexyl carbodiimide in 40 ml of absolute methylene chloride is added at room temperature over a period of approximately 3 minutes to a solution of 8.1 g (30 mmole) of crude 5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenylacetic acid in 50 ml of absolute methylene chloride. The reaction mixture is stirred for 30 minutes at room temperature. The precipitated dicyclohexylurea is filtered with suction and washed with methylene chloride. The filtrate is concentrated by evaporation in a vacuum rotary evaporator and the residue is chromatographed over silica gel using methylene chloride/hexane (1:1) as eluant. recrystallisation from hexane yields 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one having a melting point of 129°-131°.
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]#[C:9][C:10]2[CH:29]=[CH:28][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:12][CH:11]=2)[CH:6]=[N:5][C:4]2=[N:30][C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:32][C:3]=12>CO.C(Cl)Cl.[Pd]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:16][C@H:17]([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:15])=[CH:28][CH:29]=2)[CH:6]=[N:5][C:4]2=[N:30][C:31]([NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:32][C:3]=12
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC[C@H](NC(=O)c1ccc(CCn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OC
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A mixture of 1.0 g of dimethyl N-[4-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate in 250 mL of 50% methanol in methylene chloride and 0.8 g of 3% palladium-on-carbon is hydrogenated at 50 p.s.i. for three hours, filtered, and concentrated under reduced pressure. The solid is collected by filtration and dried to yield 0.72 g of dimethyl N-{4-[2-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)ethyl]benzoyl}-L-glutamate- mp 247° C. 1NMR (d6 -DMSO)δ1.21 (s, 9H), 1.90-2.12 (m, 2H), 2.42 (t, J=7.4 Hz, 2H), 2.92 (t, J=4 Hz, 2H), 2.97 (t, J=4 Hz, 2H), 3.55 (s, 3H), 3.61 (s, 3H), 4.38-4.45 (m, 1H), 6.61 (s, 1H), 7.27 (d, J=8.2 Hz, 2 H), 7.75 (d, J=8.2 Hz, 2 H), 8.64 (d, J=7.4 Hz, 1 H), 10.75 (s, 1H), 11.22 (s, 1H) . Anal. Calc. for C27H33N5O7 : C, 60.10; H 6.17; N, 12 . 98. Found: C, 59.94; H, 6.15; N, 12.72 .
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16](=[N:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.B.N1C=CC=CC=1.Cl>C(O)C.C1COCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1
Reactant: CC(=NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a suspension of 2-chloro-8-(1-hydroximinoethyl)phenoxathiin (C.A. 66, 2519a, 1967) (425 mg, 1.456 mmol) in ethanol (12 mL) and THF (5 mL) at room temperature there was added pyridine-borane (271 mg, 0.3 mL, 2.92 mmol) and 4M ethanolic HCl (1.1 mL, 4.4 mmole); the mixture was stirred at room temperature overnight, there was added more pyridine-borane (0.35 mL) and 4M ethanolic HCl (2 mL) and stirring was continued for 2 hours. The solvents were evaporated, the residue diluted with water and ethyl acetate and basified with 1N aqueous NaOH. From the organic phase a crude product was obtained which was chromatographed on silica gel, eluting with a 1:1 mixture of ethyl acetate-hexane, to afford the title product (344 mg) as a white solid, m.p.: 103°-105° C.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[Na+].CC(O)C.F[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1>C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[C:14]([NH2:27])[N:13]=1)[CH3:3]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
Sodium t-butoxide (1.30 g, 13.53 mmol) was added to 2-propanol (16.95 ml, 220 mmol) portionwise with stirring over 5 mins. 2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2 g, 8.43 mmol) was added and the reaction mixture heated and stirred at 50° C. for 4 hours and then allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate (75 ml), washed with water (3×25 ml) and the combined aqueous layers extracted again with ethyl acetate (2×25 ml). The combined organic layers were dried by passage through a hydrophobic frit, filtered and evaporated to give an off-white solid (2.30 g). This material was dissolved in dichloromethane and purified using an aminopropyl SPE cartridge (70 g) eluted with a 0-100% ethyl acetate in cyclohexane gradient. The appropriate fractions were combined and evaporated to give a white solid (1.6 g) which was further purified by column chromatography using a reverse phase (C18) Flashmaster II system loading in 1:1 MeOH/DMSO and eluting with 0-50% acetonitrile (+0.1% TFA) in water (+0.1% TFA) gradient over 40 mins. collecting fractions in vials containing ca. 2 mL of saturated aqueous sodium bicarbonate solution. The appropriate fractions were combined, and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried by passage through a hydrophobic frit and evaporated to give the title compound as a white solid (888 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([N:17]([CH2:25][C:26]([N:28]([O:30]C)C)=O)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16].NO>O1CCCC1>[CH2:14]([N:17]([CH2:25][C:26]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[N:28][OH:30])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=[CH2:16]
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: NO
Solvent: C1CCOC1
Product: C=CCN(CC(=NO)c1ccc(F)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
2-Bromo-5-fluoro-pyridine (6.475 g, 36.79 mmol) in tetrahydrofuran (20 mL) is added drop wise to isopropylmagnesium chloride (20 mL, 40.00 mmol of a 2 M solution in tetrahydrofuran) with stirring under nitrogen at room temperature. The resulting reaction mixture is stirred at room temperature for 2 hours. tert-Butyl N-allyl-N-[2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (4.43 g, 17.15 mmol) in tetrahydrofuran (15 mL) is then added drop wise at room temperature and the resulting mixture is stirred at room temperature for 4 hours 30 minutes. The reaction is quenched by the addition of aqueous ammonium chloride solution followed by ethyl acetate. The layers are separated and the aqueous phase is re-extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting dark oil is taken up in ethanol (60 mL) with stirring. A 50 wt % aqueous solution of hydroxylamine (3 mL, 55.09 mmol) is added and the resulting solution is heated at 60° C. over the weekend. The reaction is then cooled to room temperature and is concentrated under reduced pressure. The crude product is purified by silica gel chromatography using a 0-35% gradient of isohexanes in ethyl acetate to give the title compound as a mixture of E/Z isomers (4.9 g, 92%). ES/MS (m/e): 310 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32]O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:13]([O:29][CH2:30][CH:31]([O:34][CH3:35])[CH2:32][O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Reactant: OCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CO)c1)OC
Reaction time: 18 h

Procedure:
To a suspension of 2.8 g of sodium hydride in 25 ml of dimethylformamide was added at 0° C. over 30 minutes a solution of 1,3-benzenedimethanol in 75 ml of dimethylformamide. After 30 minutes a solution of 3-(hexadecyloxy)-2-methoxy-1-propanol, 4-methyl benzene sulfonate in 25 ml of dinethylformamide was added over 30 minutes. After stirring 18 hours the mixture was poured into water and extracted with ethylacetate. The solution was dried and the product was purified by chromatography giving 4.7 g.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O>[C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCn1ccnc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NCCCn1ccnc1-c1ccccc1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of N-[3-(2-phenylimidazol-1-yl)propyl]phthalimide (17.0 g), sodium hydroxide (1.1 g) and water (5.4 ml) was heated at 95° C. for 48 hours. On cooling, a mixture of concentrated hydrochloric acid (66 ml) and water (13 ml) was added and the mixture boiled under reflux for 6 hours. After standing at ambient temperature for 16 hours, the mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The residue was treated with water (16 ml) then cooled and sodium hydroxide (24 g) added in portions. The solution was extracted with diethyl ether and then with dichloromethane. The combined organic extracts were dried and evaporated to give an oil which was distilled under reduced pressure to give 3-(2-phenylimidazol-1-yl)propylamine, b.p. 128° C. (0.05 mmHg).
Reaction SMILES: Br[C:2]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:5]2=[CH:6][N:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:9]([OH:10])=[C:4]2[C:3]=1Br.C([O-])=O.[NH4+]>[Pd]>[OH:10][C:9]1[C:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[N:7][CH:6]=[C:5]2[N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:2]=[CH:3][C:4]=12
Reactant: COc1ccc(Cn2c(Br)c(Br)c3c(O)c(C(=O)NCC(=O)O)ncc32)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)ncc32)cc1

Procedure:
Prepared in analogy to that of Example 6(a) from {[2,3-dibromo-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carbonyl]-amino}-acetic acid, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 356 (M+H)+.
Reaction SMILES: C([C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H](C2C=CC(C3C=NC(N)=CC=3)=CC=2)C)[CH2:6][CH2:5]1)C=C>O1CCCC1>[C:26]1([CH:4]2[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Solvent: C1CCOC1
Product: O=C1NCCC(c2ccccc2)O1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg, 0.23 mmol) in tetrahydrofuran (10 mL) was added BH3 THF (3.0 mL, 1 mol/L, 4 mmol) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched by water. Then NaOH (2 mL, 3 mol/L) and H2O2 (1 mL) was added to the above mixture. When the reaction was over, the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-3-hydroxypropyl)-6-phenyl-1,3-oxa zinan-2-one (40 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:19]=[CH:18][C:12]3[N:13]=[C:14]([NH:16][CH3:17])[S:15][C:11]=3[C:10]=2[N+:20]([O-])=O)[C:5]([O:23][CH3:24])=[CH:4][C:3]=1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(OCC)(=O)C.CO.[Pd]>[NH2:20][C:10]1[C:11]2[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=2[CH:18]=[CH:19][C:9]=1[O:8][C:6]1[C:5]([O:23][CH3:24])=[CH:4][C:3]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:2]([Cl:1])[CH:7]=1
Reactant: CNc1nc2ccc(Oc3cc(Cl)c(CC(=O)OC)cc3OC)c([N+](=O)[O-])c2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1nc2ccc(Oc3cc(Cl)c(CC(=O)OC)cc3OC)c(N)c2s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 19.3 (230 mg, 0.53 mmol) was dissolved in mixture of ethyl acetate (3 mL) and methanol (1 mL). 10% Pd/C (56 mg, 0.053 mmol) was added and the reaction mixture was stirred for 1.5 h under H2 at room temperature. The reaction mixture was filtered, the residue concentrated under reduced pressure to afford 19.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (100 mg, 0.22 mmol) and 2-furanylboronic acid (50 mg, 0.45 mmol) in DME (3 ml) was added potassium tert-butoxide (220 mg, 1.96 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then evaporated in vacuo and purified using an SCX cartridge eluting with methanol followed by ammonia (2M in methanol). The appropriate fractions were combined and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E109). MS (ES+) m/e 442 [M+H]+.
Reaction SMILES: C([Li])CCC.[Li].C(Br)CCC.[CH3:12][O:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.CN(C)CCN(C)C.[F:28][C:29]([F:45])([F:44])[C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>O.O1CCCC1.C(OCC)C>[CH3:12][O:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:32]1[CH:41]=[CH:42][CH:43]=[C:30]([C:29]([F:44])([F:45])[F:28])[CH:31]=1)[OH:34]
Reactant: COCn1ccnc1
Reactant: O=C(c1ccccc1)c1cccc(C(F)(F)F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCBr
Solvent: CCOCC
Solvent: O
Product: COCn1ccnc1C(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere and at a temperature between -60° and -65° C. a butyllithium solution, prepared from 2.04 g. (0.29 g. at) of lithium and 15.8 g. (0.116 mol) of butyl bromide in 130 ml. of anhydrous diethyl ether, was added drop-wise to a solution of 9.8 g. (0.088 mol) of 1-(methoxymethyl)imidazole and 10.2 g. (0.088 mol) of N,N,N',N'-tetramethylethylenediamine in 250 ml. of anhydrous tetrahydrofuran. After 2 hours stirring, a solution of 22 g. (0.088 mol) of 3-(trifluoromethyl)benzophenone in 150 ml. of anhydrous tetrahydrofuran were added dropwise to the reaction mixture at a temperature between -60° and -65° C. The reaction mixture was stirred for one hour at -65° C. and it was then kept standing overnight at room temperature. Then 20 ml. of water were added to the reaction mixture and the solvents were distilled off. The residue was dissolved in dilute hydrochloric acid and the solution was washed with diethyl ether and made alkaline with potassium carbonate. The solid substance formed was filtered off and dissolved in chloroform. The solution was dried over sodium sulphate, the solvent was distilled off and the residue was crystallised from isopropyl alcohol. 1-(Methoxymethyl)-α-phenyl-α-(m-trifluoromethyl-phenyl)imidazole-2-methanol was obtained. Melting point 152.5°-153.5° C.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:64]=[CH:63][C:42]([C:43]([NH:45]/[C:46](/[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[CH:47]\[C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:64]=[CH:63][C:42]([C:43]([NH:45][CH:46]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH3:56])=[CH:50][CH:49]=3)[C:57]([NH:59][CH2:60][CH2:61][OH:62])=[O:58])=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1
Reactant: CCOc1ccc(/C=C(\NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: CCOc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Yield: 29.3 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(2-cyclopropylethoxy)-N-((Z)-2-(4-ethoxyphenyl)-1-{[(2-hydroxyethyl)amino]carbonyl}vinyl)benzamide (197 mg) to give 58 mg of the title compound (white powder).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:24])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:25]>C1COCC1>[ClH:25].[ClH:25].[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:24])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CN1CCC(O)(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccc3c(c2)CNC3)CC1

Procedure:
A solution of 5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (107 mg; 0.32 mmol) in THF (4 ml) was treated with concentrated hydrochloric acid (1.5 ml) then heated at reflux for 4 hours, then evaporated and re-evaporated with toluene to give 4-(2,3-dihydro-1H-isoindol-5-yl)-1-methyl-piperidin-4-ol dihydrochloride as a brown gum.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=1)=[C:14]2[CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:35]1([CH2:42][CH2:43][O:44][C:45]2[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O>CN(C=O)C>[N:35]1([CH2:42][CH2:43][O:44][C:45]2[CH:52]=[CH:51][C:48]([CH2:49][N:16]3[C:17]4[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=5)=[CH:19][CH:18]=4)[C:14]([CH3:34])=[C:15]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)=[CH:47][CH:46]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Reactant: ClCc1ccc(OCCN2CCCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Reaction time: 0.5 h

Procedure:
In an inert atmosphere NaH (2.7 g; 112 mmol) was suspended in DMF (80 ml). At 0-5° C. 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (11 g; 26 mmol) was added and the suspension was stirred for 30 minutes. Then a solution of 4-(2-azepan-1-yl-ethoxy)benzyl chloride (8 g; 26 mmol) in DMF (30 ml) was added dropwise within 1 hour. The cooling was shut down and the reaction mixture was stirred for another 2.5 hours. Then, water (1.2 ml) was carefully added dropwise to the reaction mixture and the reaction mixture was filtered through a thin layer of celite. Another 35 ml of water were added dropwise to the brightly yellow filtrate under intensive stirring.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=[O:14].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)CCC.[OH-].[Na+]>[OH2:14].[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1.[CH3:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:13](=[O:15])[N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:25]=3)=[CH:4][NH:5][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: Cc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2n1

Procedure:
A mixture of 3.0 g of ethyl 4-chloro-7-methyl-1,8-naphthyridine-3-carboxylate (prepared according to U.S. Pat. No. 3,786,043) and 1.42 g of phenylhydrazine in 30 ml of n-butanol is refluxed for 18 hours. The mixture is chilled in an ice bath and filtered to give a solid which is taken up in 50 ml of 1N sodium hydroxide and sufficient water to dissolve. The resulting solution is filtered to remove insoluble, washed with ether and neutralized with 3.0 g of ammonium chloride. The resulting mixture is filtered collecting a solid which is washed with water and dried to yield 7-methyl-2-phenylpyrazolo[4,3-c][1,8]naphthyridin-3(5H)-one hemihydrate, m.p. 305°-308°.