Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:14]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc(N2CCNC2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1NCCN1c1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3-amino-phenyl)-imidazolidin-2-one (0.27 g, 1.5 mmol), benzaldehyde (0.17 ml, 1.7 mmol) and acetic acid (0.13 ml, 2.2 mmol) in dry tetrahydrofuran (10 ml) was stirred at room temperature for 6 hrs. Sodium borohydride (0.14 g, 3.8 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (25 ml) then extracted with dichloromethane (3×50 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7 min. Mass spectrum (ES+) m/z 268 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:6]([C:11]([F:14])([F:13])[F:12])=[N:7][NH:8][C:9]=1[NH2:10].O=[C:21]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:22][C:23](OCC)=[O:24].C(=O)(O)[O-].[Na+]>OS(O)(=O)=O.O1CCOCC1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:6]([C:11]([F:13])([F:14])[F:12])=[N:7][N:8]2[C:23]([OH:24])=[CH:22][C:21]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:10][C:9]=12
Reactant: Nc1[nH]nc(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cc(-c2ccncc2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Temperature: 120 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
A mixture of 4-(2,3-dichlorobenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (100 mg, 0.332 mmol), ethyl 3-oxo-3-(pyridin-4-yl)propanoate (75 mg, 0.387 mmol) in conc. H2SO4 (1.5 mL) and dioxane (15 mL) was placed in a sealed tube and stirred at 120° C. for 16 h. After cooled to room temperature, the pH of the mixture was carefully adjusted to 8 with saturated aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM (50 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, filtered and concentrated. The residue was purified by silica gel column and reverse-phase Prep-HPLC to give the title product (14 mg, 10%) as a yellow solid; LC/MS: MS (ES+) m/e 439 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 4.29 (s, 2H), 6.35 (s, 1H), 6.89 (dd, J=1.2, 7.8 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.52 (dd, J=1.2, 7.8 Hz, 1H), 7.83 (d, J=6.0 Hz, 2H), 8.80 (d, J=6.0 Hz, 2H), 12.81 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([N:20]1[C:8]2[N:9]([C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:19]1)(=[O:23])[CH3:22]
Reactant: O=c1c2cccnc2c(-c2ccccc2)c2n1CCN2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCn2c1c(-c1ccccc1)c1ncccc1c2=O

Procedure:
Reflux a mixture of 2,3-dihydro-10-phenylimidazo-[1,2-g][1,6]naphthyridin-5(1H)-one (5.5 g), acetic anhydride (10 ml), and pyridine (60 ml) for 30 hours. Cool the reaction mixture and evaporate the volatile reagents--i.e., excess pyridine and acetic anhydride. Partition the residue between chloroform and water, and dry, filter, and concentrate the organic solution Chromatograph the residue over silica gel, elute the column with chloroform, and crystallize the eluate from chloroform-petroleum ether to obtain 1-acetyl-2,3-dihydro-10-phenyl-imidazo[1,2-g][1,6]naphthyridin-5(1H)-one, mp 229°-231° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[CH:16]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[NH:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:24]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[NH:25][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: N=C(N)c1ccccc1OCC1CC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC3CC3)nc2n1
Yield: 54.2 %

Procedure:
In a similar manner to Example 29 reaction of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) with 2-cyclopropylmethoxybenzamidine hydrochloride (1.45 g) and triethylamine (1.30 g) in acetonitrile (50 ml) yielded a white solid (1.18 g) which was collected, dissolved in chloroform and the chloroform solution was extracted twice with 2 Normal hydrochloric acid. The chloroform solution was evaporated under reduced pressure and the residue was recrystallized from ethanol to yield the title compound, 0.52 g, m.p. 186-187° C.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:21][C:22]2[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=3)=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2nc(NCC(F)(F)F)c(Cc3c(O)nc(C(C)C)c4cc(OC)c(OC)cc34)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (362 mg, 1.46 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. solution of LiOH (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 51 as a yellow solid (130 mg, 15% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:18]2[CH2:19][CH2:14][CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Sc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.2 %

Procedure:
A mixture of 4-bromobenzenethiol (4.697 g, 24.84 mmol), tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (6.939 g, 24.84 mmol) and K2CO3 (6.866 g, 49.68 mmol) in DMF (40 mL) were stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0° C. and diluted with water. The reaction mixture was extracted with ethylacetate (×2) and the combined organic extracts washed with saturated aqueous sodium thiosulphate solution (×2), water (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 330 g eluting with 0 to 50% Et2O/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-bromophenyl)thio)piperidine-1-carboxylate as a colourless oil (1.68 g, 18% Yield). H NMR (400.0 MHz, CDCl3) δ 0.97-0.86 (m, 2H), 1.44 (s, 9H), 1.80-1.76 (m, 1H), 2.12-2.08 (m, 1H), 2.92-2.86 (m, 1H), 3.14-3.08 (m, 2H), 3.89 (br d, 1H), 4.05 (br s, 1H), 7.30 (d, 2H) and 7.45-7.43 (m, 2H) ppm;
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[I:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1>CCO>[CH:5]1([C:3]2[N:15]=[C:12]3[CH:11]=[CH:10][C:9]([I:8])=[CH:14][N:13]3[CH:2]=2)[CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CC1
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Product: Ic1ccc2nc(C3CC3)cn2c1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A mixture of 2-bromo-1-cyclopropylethanone (18.0 g), 5-iodopyridin-2-amine (5.2 g) and EtOH (100 ml) was heated at reflux for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The resulting residue was diluted with DCM (200 ml), and washed with water (100 ml) and brine (100 ml). The DCM layer was dried over Na2SO4 and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (1.53 g) as a yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.[NH2:19][OH:20]>O>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
To 2-phenoxybenzaldehyde (4.96 g, 0,025 mole) were added anhydrous methanol (50 ml) and hydroxylamine hydrochloride (2.08 g, 0.03 mole), and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, which was extracted with methylene chloride and dried over magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-phenoxybenzaldoxime (3.95 g, yield: 74.1%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:12][C:11](=[O:13])[C:10]2[N:5]([S:6](=[O:18])(=[O:17])[C:7]3[S:16][CH:15]=[CH:14][C:8]=3[CH:9]=2)[CH2:4]1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH2:19]([O:21][CH:22]([O:1][CH2:2][CH:3]1[O:12][C:11](=[O:13])[C:10]2[N:5]([S:6](=[O:17])(=[O:18])[C:7]3[S:16][CH:15]=[CH:14][C:8]=3[CH:9]=2)[CH2:4]1)[CH3:23])[CH3:20]
Reactant: O=C1OC(CO)CN2C1=Cc1ccsc1S2(=O)=O
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(C)OCC1CN2C(=Cc3ccsc3S2(=O)=O)C(=O)O1
Yield: 54.3 %

Procedure:
A suspension of the product from Step C (10 g, 34.84 mmol) in anhydrous THF (200 mL) at 0° C. was combined with ethyl vinyl ether (5.02 g, 69.68 mmol) and p-toluenesulfonic acid (1.32 g, 6.9 mmol); this mixture was stirred until it became homogeneous. The reaction mixture was filtered through silica and the solvent evaporated to give a residue which was purified by column chromatography (silica, ethyl acetate/hexane, 3:7) to give 6.8 g (54%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[NH2:21][CH2:17][C:13]1[C:12]([CH2:19][CH3:20])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCc1c(CN)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.2 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.16 g, 0.53 mmol) in methanol (10 mL) was added ammonia (7N in methanol, 15 mL, 105 mmol), and the reaction mixture stirred for 4 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (60 mg, 0.52 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 2-(3-aminomethyl-2-ethyl-phenoxy)-4-chloro-benzonitrile hemifumarate (174 mg, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH3:16])[NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Nc1ncccc1N
Yield: 85 %

Procedure:
A solution of (S)-N-(3-nitro-2-pyridinyl)alanine ethyl ester (5.0 g, 0.0209 mole) in tetrahydrofuran (60 ml) was hydrogenated over 5% palladium on carbon (0.5 g) keeping the temperature of the solution at approximately room temperature to give (S)-N-(3-amino-2-pyridinyl)alanine ethyl ester. The solution of the reduction product was cooled in an ice bath and dried over magnesium sulfate under nitrogen. The solution was filtered and 4-chlorobenzoyl chloride (3.84 g, 0.022 mole) and triethylamine (2.22 g, 0.022 mole) were added simultaneously, dropwise, to the cooled and stirred solution. The reaction mixture was stirred at room temperature overnight under nitrogen and the solvents were removed under reduced pressure. The residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed twice with water, dried over magnesium sulfate, treated with charcoal, filtered and evaporated to an oil weighing 6.2 g (85% yield). A 2.2-g portion of the oil was dissolved in isopropyl alcohol and the solution was acidified with ethereal hydrogen chloride. The resulting solid was filtered and dried under high vacuum to give 1.70 g of title compound, mp 172°-177° C. with decomposition.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[H-].[Na+]>C1COCC1>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.9 %

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 0 °C

Procedure:
A mixture of 21.1 g. of 2-chloro-5-(4-chlorophenyl)pyridine and 19.5 g. of 95% hydrazine in 200 ml. of pyridine is heated at reflux temperature for 48 hours. The reaction mixture is cooled, poured into an ice-water mixture and filtered. The solid is collected, washed with water and air dried to yield 17.0 g. of the product of the Example as a tan solid.
Reaction SMILES: [C:1]1([CH:7]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][O:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][NH:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]=O>C(O)=O>[C:1]1([CH:7]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:29])[C:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][O:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:9][N:10]([CH3:30])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: CNCCC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)c1ccccc1
Solvent: O=CO
Product: CN(C)CCC(Oc1ccc2c(=O)c(-c3ccccc3)coc2c1)c1ccccc1

Procedure:
30 g of formic acid, is added dropwise to 38.5 g of 7-(1phenyl-3-methylaminopropoxy)-isoflavone, while stirring and cooling, and 7 g of 25% formaldehyde solution is then added dropwise at 20°. The mixture is heated on a waterbath until evolution of gas ceases and is cooled, poured onto ice and worked up in the customary manner to give 7-(1-phenyl-3-dimethylaminopropoxy)-isoflavone. M.p. 128°-130°.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]=[CH:3][CH3:4].Cl.O.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]([CH3:4])[CH2:2][CH2:1][OH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccccc1
Reactant: CC=CCO
Agent: Cl
Solvent: O
Product: CC(CCO)c1ccccc1
Temperature: 5 °C

Procedure:
A reaction vessel was fitted with a mechanical stirrer, thermometer and a reflux condenser capped with an additional funnel. While under a positive flow of dry nitrogen, the system was flame dried. The vessel was charged 250 ml of benzene and then 25 gm of aluminum chloride was added as quickly as possible. This mixture was cooled with stirring to 5° C. in an ice/salt bath and a solution of 7.2 gm (0.1 mol) of crotyl alcohol in 45 ml of benzene was added dropwise while maintaining the temperature below 5° C. Next, 50 ml of concentrated hydrochloric acid was added cautiously. After warming to room temperature, 50 ml of water was added and the lower organic phase removed. The aqueous portion was then extracted with benzene. The combined organics were washed with aqueous 10% sodium bicarbonate and water. After drying over anhydrous magnesium sulfate, filtering and evaporating, a dark oil was recovered. This was vacuum distilled to give 8.2 gm of colorless 3-phenyl butanol (ND25 = 1.5210).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4)ncnc32)[C@]1(C)F
Yield: 95.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 8 ml) was added benzylamine (about 0.56 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 3% methanol in dichloromethane as eluent furnished title compound (0.22 g) as a colorless solid. Yield: 97%; 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.13-7.96 (m, 3H), 7.59-7.57 (m, 1H), 7.49-7.28 (m, 7H), 6.57 (d, 1H, J=23.1 Hz), 6.24 (bs, 1H), 4.89-4.79 (m, 3H), 4.50-4.43 (m, 1H), 2.18 (s, 3H), 1.90 (d, 3H, J=2.1 Hz), 1.47 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 534 (85%), [M+Na]+ 556 (100%). IR cm−: 3385, 1751, 1720, 1619, 1528, 1476, 1369, 1274, 1062, 712; HPLC: 95%.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]=[C:19]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][N:9]([C:37](=[O:38])[CH2:36][N:20]3[CH2:21][CH2:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:19]3=[O:18])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpyrrolidine (Example 17A, 0.22 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.40 (m, 20H), 4.14-4.25 (m, 2H), 4.09-4.12 (m, 2H), 3.38-3.61 (m, 4H), 2.75-2.87 (m, 2H), 2.49-2.63 (m, 2H); MS (DCI+) m/z 501 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[N:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=1>CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:19](/[CH:22]=[C:28]2/[CH:29]=[N:24][CH2:25][CH2:26][CH2:27]/2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2)=[O:5]
Reactant: C1=NCCCC1
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(/C=C2/C=NCCC2)ccc1Cl

Procedure:
2-Chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.152 g, Example 31a) and 2,3,4,5-tetrahydropyridine trimer (Org. Synth., 1977, Vol.56, 118-122, 0.038 g) were dissolved in methanol (3 ml) and heated at reflux for 4 h. The mixture was evaporated under reduced pressure then purified by HPLC eluting a gradient of 0-5% ethanol in dichloromethane to give the subtitle compound as a white foam (0.046 g).