Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.[CH:5]1([C:15]([CH3:33])([CH3:32])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.C1COCC1.[ClH:39]>CO>[ClH:39].[ClH:39].[CH:5]1([C:15]([CH3:33])([CH3:32])[CH2:16][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: COc1ccc(N2CCN(C(=O)C(C)(C)C3OCCc4ccccc43)CC2)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(N2CCN(CC(C)(C)C3OCCc4ccccc43)CC2)cc1

Procedure:
Triethylamine (1 ml) is added dropwise to a mixture of 2-(isochroman-1-yl)-2-methylpropionic acid (LXXII, 0.502 g, 2.3 mmol), 1-(4-methoxyphenyl)piperazine dihydrochloride (XI, 0.668 g, 2.5 mmol), diethylcyanophosphonate (0.44 ml, 2.9 mmol), DMF (2.4 ml) and dichloromethane (2.4 ml). After the mixture had stirred for 2.5 hr, aqueous saturated sodium bicarbonate is added and the mixture is stirred for 70 min. The mixture is then partitioned between dichloromethane and saline, the phases separated and the organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (1/99). The appropriate fractions are pooled and concentrated to give a residue. Ethyl acetate and hexane are added and the solids are collected and dried to give 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII), mp 119.5-121°. Borane-methyl sulfide (1.1 ml) is added to a mixture of 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII, 0.397 g, 1.0 mmol) and THF (98 ml). The mixture is heated for 3.5 hr at 76° and then cooled in an ice/water bath. Hydrochloric acid (10%, 1.3 ml) is added, followed by methanol. The mixture is concentrated and methanol is again added and removed under reduced pressure. The methanol addition/removal is repeated twice more and the resulting material is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95) followed by ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give the free base of the title compound.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 160d from 2,6-dinitrobenzonitrile and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 89% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.81 (m, 1H), 2.03 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.33 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.93 (m, 2H).
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:9](=[O:16])([O-])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1)#[N:25]>O1CCCC1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C@H:32]2[CH2:37][N:36]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16])[CH2:35][CH2:34][N:33]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:31]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: N#Cc1ccc([C@H]2CNCCN2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(C#N)cc2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-Chloroethyl chloroformate (2.7 g, 18.9 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 3.81 mmol) in dichloroethane (30 ml). The reaction mixture was vigorously stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure and methanol (40 ml) was added to the residue. The mixture was heated at 80° C. for one hour and the solvent was evaporated under reduced pressure to afford (2S)-2-(4-cyanophenyl)piperazine as white crystals. Di-tert-butyl di-carbonate (1.9 g, 8.71 mmol) was added to a solution of triethylamine (1.2 g, 11.9 mmol) and (2S)-2-(4-cyanophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred at 50° C. for one hour. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].[Na].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(O)(=O)C>C(O)C>[O:17]=[C:18]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][CH2:2][CH3:3])=[N:8][CH:25]=[C:19]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCSc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2SCC)[nH]c1=O
Temperature: 0 °C
Yield: 67 %

Procedure:
2-Ethylthiobenzamidine hydrochloride (2.12 g., 10.0 mmoles) was added to a cooled (ice-water) solution of sodium (0.46 g., 20 mg.-atoms) in ethanol (12 ml.). To this mixture was added a solution of diethyl ethoxymethylenemalonate (2.16 g., 10.0 mmoles) in ethanol (4 ml.). The mixture was heated under reflux for 3.5 hours. The cooled mixture was poured into ice-water (400 ml.) and acidified to pH 6 with glacial acetic acid. The precipitate was collected and recrystallized from acetonitrile to give the title compound (2.04 g., 64.6%), m.p. 117°-120°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH3:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (2.0 g, 7.38 mmol) from above was dissolved in tetrahydrofuran (50 mL). The solution was cooled to −78° C. and sodium bis(trimethylsilyl)amide (1.0 M, 9.0 mL) was added. The mixture was stirred at −78° C. for 1 hr and methyl iodide (1.2 mL, 19.5 mmol) was added. The mixture was warmed to room temperature and stirred for 2 hrs. The mixture was extracted with ether and washed with dilute hydrochloric acid. The organic layer was dried, filtered and concentrated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-methyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester as an oil (789 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:27](=[O:28])[CH2:26][N:25]([CH3:29])[C:24]2=[O:30])[CH:19]=[C:20]([Cl:22])[CH:21]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@:26]32[N:25]([CH3:29])[C:24](=[O:30])[N:23]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[C:20]([Cl:22])[CH:19]=2)[C:27]3=[O:28])=[CH:4][CH:3]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: BrCCCCC(Br)c1ccc(Br)cc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,5-dibromopentyl)benzene (4.2 g, 10.9 mmol) (Preparation 14) and 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (2.59 g, 10 mmol), the above titled compound was obtained as a white solid (3.1 g, mp=118° C.). 1H NMR (CDCl3): 7.41 (2H, d, J=8.4 Hz), 7.30 (1H, m), 7.00 (2H, d, J=8.4 Hz), 6.90 (2H, m), 3.03 (3H, s), 2.91 (1H, dd, J1=12.9 Hz, J2=3.6 Hz), 2.55 (1H, dq), 2.1-2.3 (1H, m), 1.8-2.05 (5H, m), 1.3-1.6 (1 H, m).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[ClH:1].[N:6]1[CH:7]=[CH:8][C:3]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 120 °C
Yield: 59 %

Procedure:
4-Bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboronic acid (10.0 g) were dissolved in a solvent mixture of toluene (250 mL) and water (250 mL), and to the solution were sequentially added tetrakis(triphenylphosphine)palladium(0) (5.0 g) and anhydrous sodium carbonate (25.4 g), followed by heating under reflux at 120° C. for 19 hours. After the resultant mixture was cooled to room temperature, ethyl acetate was added thereto, and the thus-obtained mixture was extracted with water. Concentrated HCl was added to the aqueous layer, to thereby make the mixture acidic. The aqueous layer was washed with ethyl acetate, and was concentrated. The resultant solid was collected by filtration, to thereby give the title compound (8.37 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Fc1ccc(CBr)cc1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc(F)cc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 4-fluorobenzyl bromide.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[H][H]>[Pd].CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([OH:9])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: [H][H]
Reactant: CO[C@@H]1CN(Cc2ccccc2)CC[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CNCC[C@@H]1O
Yield: 52.8 %

Procedure:
A mixture of 11.5 g of intermediate (2) and 150 ml of methanol was hydrogenated at normal pressure and at room temperature with 2 g of palladium-on-charcoal catalyst (10%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3) 85/15). The pure fractions were collected and the eluent was evaporated, yielding 3.6 g (53%) of cis-3-methoxy-4-piperidinol as an oily residue (intermediate 3).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([N+:10]([O-:12])=[O:11])=[N:3]1.[NH4+:13].[OH-]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH2:13])=[O:8])[C:4]([N+:10]([O-:12])=[O:11])=[N:3]1
Reactant: Cn1cc(C(=O)Cl)c([N+](=O)[O-])n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cn1cc(C(N)=O)c([N+](=O)[O-])n1

Procedure:
Seven gm. of 1-methyl-3-nitro-4-pyrazolecarbonyl chloride was added in portions to 50 ml. of concentrated NH4OH. The mixture was heated at reflux for 15 to 20 minutes, evaporated to dryness, and cooled. The resultant crystallized product was identified as 1-methyl-3-nitro-4-pyrazolecarboxamide, m.p. 190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[CH2:35](O)[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][O:13][CH:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([O:17][CH2:35][CH3:36])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetic acid (8.0 g.) in ethanol (200 ml.) containing concentrated sulphuric acid (1 ml.) was heated under reflux for 90 minutes, then cooled to room temperature, and carefully neutralised by addition of an excess of saturated aqueous bicarbonate solution. The mixture obtained was evaporated and the residue extracted thoroughly with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylacetate (6.65 g.), m.p. 50°-51° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[NH:9][CH:8]=[C:7]([C:15]([NH:17][N:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23])=[O:16])[C:6]2=[O:24].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][CH:8]=[C:7]([C:15]([NH:17][N:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23])=[O:16])[C:6]2=[O:24]
Reactant: COc1cc2[nH]cc(C(=O)NN3CCNC3=O)c(=O)c2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NN1CCNC1=O)c1c[nH]c2cc(O)c(O)cc2c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
To a suspension of 1,4-dihydro-6,7-dimethoxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-3-quinolinecarboxamide (23.1 g, 69.5 mmol) in 1.2 l of dichloromethane, a solution of boron tribromide (104.5 g, 417 mmol) was added dropwise at 0° C. After stirring for 3 days at room temperature, the precipitate was filtered off, washed with dichloromethane and was then added to 300 ml of methanol under ice cooling. After stirring for 2 hours, the solid was filtered off, washed with methanol and dried in vacuo. Yield: 24.8 g (still contained some starting material). The reaction was repeated to give 18.4 g of the title compound after methanol treatment, melting point>300° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][OH:34])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]3[N:17]([CH2:32][CH2:33][O:34][S:43]([CH3:42])(=[O:45])=[O:44])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)[N:20]=3)[CH2:14][CH2:15]2)[C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile (22.8 mg; 0.47 mmol; 1.00 eq) was dissolved in dichloromethane (10.00 mL) and chilled to −78° C. The solution was charged with triethylamine (0.20 mL; 1.41 mmol; 3.00 eq) and methanesulfonyl chloride (0.05 mL; 0.70 mmol; 1.50 eq). The reaction was stirred, cold, for 1 hour, then allowed to warm to ambient temperature. The reaction mixture was quenched by dropwise addition of sodium bicarbonate (saturated aq; 10 mL). The organic layer was separated, dried over sodium sulphate, filtered and concentrated to yield methanesulfonic acid 2-[2-[1-(6-amino-5-cyano-pyrimidin-4-yl)-piperidin-4-yl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-imidazol-1-yl]-ethyl ester (259 mg; 0.47 mmol; 99.8%). LC-MS: (M+1=554, obsd.=554).
Reaction SMILES: C(OC(=O)CC1C=CC(C#C[C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4CC4)C)CC[C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=CC=1F)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:39]1CCC[CH2:40]1>>[CH3:40][O:39][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:24][CH2:26][C:17]2([CH3:29])[CH3:30]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc2c(c1)C(C)(C)CNC2
Yield: 100 %

Procedure:
A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-1-one (Intermediate 17, 3.5 g, 17 mmol) in 100 mL of anhydrous tetrahydrofuran was treated with lithium aluminum hydride (1.3 g, 34.25 mmol) in small portions and the resulting suspension was refluxed for 3 hours under argon. The reaction mixture was then cooled in an ice bath and cautiously quenched with saturated aqueous sodium sulfate solution and the resulting slurry was filtered and the filter-cake washed well with ethyl acetate. The filtrate and washings were evaporated in vacuo to a brown oil which was dissolved in chloroform, the solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (3.2 g, ˜100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[NH:17]1[CH:21]=[CH:20]N=C1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:20]=[CH:21][N:17]=1
Reactant: c1c[nH]cn1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Product: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that imidazole (3.1 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (5% MeOH/CH2Cl2) to yield a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@:14]45[C:15]=2[C:16]=1[O:17][CH:13]4[C:12](=[O:22])[CH:11]=[CH:10][C@@:9]35[O:23][CH3:24]>CO.[Pd].C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@:14]45[C:15]=2[C:16]=1[O:17][CH:13]4[C:12](=[O:22])[CH2:11][CH2:10][C@@:9]35[O:23][CH3:24]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c3c1OC1C(=O)CC[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314

Procedure:
7,8-Didehydro-3,14-dimethoxy-4,5-epoxy-17-methylmorphinan-6-one (14) (5.0 g, 15.27 mmol) was hydrogenated in methanol (75 ml) over 500 mg Pd/charcoal (10%) at 3 atm. After filration through Celite the solvent was removed under reduced pressure to afford 4.92 g (98% theory) of a white solid 15, mp 140°-142° C. Recrystallization from ethanol gave 4.52 g (90% theory) of 15 as a white solid, mp 146°-146.5° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:36](=[O:38])[CH3:37])[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25](O)[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:13][CH:14]=2)[CH:9]=1.[OH-:40].[Na+]>CO>[C:36]([C:11]1[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=2[CH2:33][CH2:34][CH2:35][OH:40])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])[CH:17]=[CH:16]2)(=[O:38])[CH3:37]
Reactant: CCCc1c(OCCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc(OCCCOc2ccc3ccc(OCCCC(=O)O)cc3c2C(C)=O)c(CCCO)c1
Yield: 64 %

Procedure:
A mixture of 1.44 g of 4-[[8-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester and 27 ml of 1N sodium hydroxide in 54 ml of methanol was stirred at reflux for an hour. The methanol was removed in vacuo and the clear solution was acidified to pH 3. The precipitate was extracted with chloroform and dried. The resulting semi-solid was purified by flash column chromatography (eluting with 2% methanol/ethylacetate) to yield 0.9 g (64%) of 4-[[8-Acetyl-7-[3-(4-acetyl-3-hydroxypropylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid of mp 121°-124°.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>CO.C(Cl)(Cl)Cl.CCOCC.C(Cl)Cl>[ClH:30].[ClH:30].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][N:34]3[CH2:33][CH2:32][O:31][CH2:36][CH2:35]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.0 g. (10.1 mm.) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 2.10 g. (10.1 mm.) of γ-morpholinobutyric acid hydrochloride and 2.18 g. (10.6 mm.) of dicyclohexylcarbodiimide were added to 200 ml. of methylene chloride. The reaction mixture was stirred at room temperature for 16 hours and after cooling the by-product of dicyclohexylurea was removed by suction filtration. The mother liquor was evaporated to give a residue which after the usual work-up was converted to a dihydrochloride by the addition of an ether solution of hydrogen chloride. Recrystallization from methylene chloride/diethyl ether gave a total of 3.23 g. (52%), m.p. 154°-160° C. The nuclear magnetic resonance and infrared spectra were in agreement with the proposed structure; the material was pure by thin layer chromatography (10% MeOH/CHCl3).