Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)/[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]\[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Reactant: O/N=C\c1ccco1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
In 45 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 11.6 g (40 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 6.1 g (54.9 mmol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed three times with 50-ml portions of water, and the ethyl acetate layer was dried and the solvent was evaporated under reduced pressure. The residue was recrystallized three times from ethyl acetate-hexane to give 5.5 g of isobutyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 159°-160° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, m.p. 77-78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42-7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H). Elemental Analysis for C26H22F3NO3: Calculated: C, 68.87; H, 4.89; N, 3.09. Found: C, 69.00; H, 4.66; N, 3.06.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(Cl)nc(N(C)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 192 h
Yield: 62.4 %

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinazoline, (38.3 g, 0.19M assuming 100% yield from previous step), N-methylaniline (19.26 g, 0.18M), sodium acetate (16.4 g, 0.2M) in tetrahydrofuran (2 liters) and water (1 liter) was stirred at room temperature for 8 days. Reaction was then concentrated to low volume (about 500 ml) and an oil separated out which solidified. The solid was filtered off and extracted with dichloromethane. Silica gel column chromatography followed by evaporation to dryness gave a residue which was washed with 40-60° petroleum ether (to remove trace impurity) to yield title compound (31.25 g) m.p. 133°-134°.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])[CH:21]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1)[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:16]
Reactant: Cc1cc(CC(=O)c2ccoc2C)ccn1
Reactant: COC(OC)N(C)C
Product: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Temperature: 100 °C
Yield: 99.9 %

Procedure:
A mixture of 1-(2-methyl-3-furanyl)-2-(2-methyl-4-pyridinyl)ethanone (0.430 g, 2.000 mmol) in N,N-dimethylformamide dimethyl acetal (0.266 ml, 2 mmol) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and the solvent was evaporated to give the title compound (540 mg) which was used crude in the next step. LC/MS [M+H]+=271.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16](=[O:22])[NH:17][N:18]=[CH:19][C:20]=1Cl.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:19]=[N:18][NH:17][C:16](=[O:22])[C:15]=2[Cl:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1[nH]ncc(N2CCN(Cc3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of 7 g of 1-benzylpiperazine, 6.55 g of 4,5-dichloro-3(2H)-pyridazinone and 11 g of K2CO3 in 150 ml of DMF is heated at 110° C. for 4 hours and then concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. The product obtained is taken up in iso ether and triturated and the precipitate formed is isolated with suction. This gives 7 g of the expected product, which is recrystallized from iso ether; m.p.=173-175° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[CH2:13])C([O-])=O)=[CH:5][CH:4]=1.NC1N=CC(/C=C/[C:24]([O:26]CC2C=CC=CC=2)=[O:25])=CC=1>>[CH3:14][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:13]/[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Reactant: C=C(C(=O)[O-])c1ccc(N(C)C)nc1
Product: CN(C)c1ccc(/C=C/C(=O)O)cn1
Yield: 36 %

Procedure:
According to the procedure of Preparation 2 (b), except substituting benzyl (E)-3-[6-(dimethylamino)pyridin-3-yl-acrylate for benzyl (E)-3-(6-aminopyridin-3-yl)acrylate, the title compound (0.20 g, 36%) was prepared as a white solid: MS (ES) m/e 193 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2ccccc2)c1
Product: ClCc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 5-phenyl-3-pyridylmethanol (4.50 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5-phenylpyridine (4.28 g, yield 86%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: [CH2:1]([PH:7](=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>>[CH2:1]([P:7]([CH2:14][OH:15])(=[O:13])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=O
Reactant: CCCCCC[PH](=O)OCCCC
Product: CCCCCCP(=O)(CO)OCCCC

Procedure:
The title compound was prepared from n-hexylphosphinic acid, n-butyl ester and paraformaldehyde according to the method described in Procedure 31. Purification by chromatography, eluting with dichloromethane containing 5% methanol, gave an oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].[C-]#N>CCCCCC.C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:16][C:17](=[O:18])[N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])([CH3:15])[CH3:14]
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Reactant: CNC1CCCCC1
Agent: [C-]#N
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CN(C(=O)NC(C)(C)c1cccc(Cl)c1)C1CCCCC1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
A solution of 1.2 g of N-methyl-N-cyclohexylamine in 5 ml of n-hexane was added to a solution of 0.01 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as shown in Synthesis Example 1) in 10 ml of benzene. The mixture was kept at room temperature for 6 hours and concentrated under reduced pressure to obtain crystals, which were recrystallized from n-hexane to give 2.8 g of the title compound as white crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:7][N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=1.CO>O1CCCC1>[CH3:3][C:4]1[C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=2)=[CH:7][N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=1
Reactant: Cc1nn(-c2ccccn2)cc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)cc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Sodium borohydride (0.25 g) was added to a mixture of 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzaldehyde (3.50 g), methanol (5 ml), and tetrahydrofuran (25 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, diluted hydrochloric acid was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and 4-[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-ylmethoxy]benzyl alcohol (3.41 g, yield: 97%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 83–84° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: NCCCCc1ccccn1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)NCCCCc1ccccn1
Yield: 67.3 %

Procedure:
The reaction of 2-(4-aminobutyl)pyridine (3.0 g) and methyl isothiocyanate (1.6 g) in ethanol (25 ml) for 0.5 hours followed by chromatography of the product on silica and elution with ethyl acetate affords N-methyl-N'-(4-(2-pyridyl)butyl)thiourea (3.0 g) as a colourless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([S:12][CH2:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])(=[O:11])[CH3:10]>>[C:9]([S:12][CH2:13][CH:14]([CH3:18])[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:16])(=[O:11])[CH3:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Product: CC(=O)SCC(C)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
Following the procedure of Example 16, L-valine is reacted with 3-acetylthio-2-methyl-propanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-valine.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][C:24](=[O:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][C:24](=[O:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC(=O)[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
10% Pd/C (900 mg) was added to a solution of compound 1.9a (2.0 g, 4.5 mmol) in EtOAc (150 mL) and the resulting slurry was hydrogenated in a Parr apparatus (50 psi) at 50° C. for 16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of diatomaceous earth (CELITE®) and the solvent was removed under vacuum, providing compound 2.0a (1.6 g, 80% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:45]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:45])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2)cc1)Oc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A slurry of 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.544 g, 0.953 mmol) and sodium hydride (0.042 g, 1.05 mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 h, then cooled to 0° C. Iodomethane (0.60 mL, 9.53 mmol, d=2.28) is added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, dried, concentrated, and purified by flash chromatography to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.0 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.26-7.19 (m, 2H), 7.15 (d, 2H, J=8.9 Hz), 6.97 (t, 1H, J=8.0 Hz), 6.82 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.9 Hz), 4.46, 4.38 (ABq, 2H, J=15.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.97 (t, 2H, J=7.1 Hz), 3.67-3.59 (m, 1H), 3.78 (t, 1H, J=8.9 Hz), 3.26, 3.10 (ABq, 2H, J=14.2 Hz), 2.99 (t, 1H, J=8.9 Hz), 2.85 (s, 3H), 2.28-2.21 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+]. 585 (M+H)+. Rf=0.35 in 50% acetone in hexanes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(N2CCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Methyl 4-aminophenylacetate (0.4 g, 2.4 mmol), 1,4-dibromobutane (0.29 mL, 2.4 mmol) and potassium carbonate (0.34 g, 2.6 mmol) were dissolved in dimethylformamide (30 mL), and the mixture was stirred overnight at 80° C. The solvent was evaporated, and the residue was worked up according to a conventional method and purified by silica gel column chromatography to give the title compound (0.13 g, 0.59 mmol).
Reaction SMILES: [P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH2:31])([O:4][P:5]([O:8][P:9]([OH:12])([OH:11])=[O:10])([OH:7])=[O:6])(=[O:3])[OH:2].C(=O)([O-])[O-].[K+].[K+].[C:38](ON1C(=O)CC(S(O)(=O)=O)C1=O)(=[O:40])[CH3:39].[Na]>O.CS(C)=O>[P:1]([O:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:29]3[N:28]=[CH:27][N:26]=[C:24]([NH2:25])[C:23]=3[N:22]=[CH:21]2)[C@H:17]([OH:30])[C@@H:16]1[NH:31][C:38](=[O:40])[CH3:39])([O:4][P:5]([O:8][P:9]([OH:11])([OH:12])=[O:10])([OH:7])=[O:6])(=[O:2])[OH:3]
Reactant: CC(=O)ON1C(=O)CC(S(=O)(=O)O)C1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](N)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)OP(=O)(O)OP(=O)(O)O
Yield: 11.9 %

Procedure:
3'-Amino-3'-deoxyadenosine 5'-triphosphate (15 mg, 26 mmol) and potassium carbonate (21 mg, 0.13 mmol) were dissolved in 2 ml of water. Sodium sulfosuccinimidyl acetate (36 mg, 0.13 mmol; Pierce Chemical, Rockford, Ill.) in 0.2 ml of dimethylsulfoxide (DMSO) was added at 0° C., and the reaction was allowed to proceed at room temperature for twenty-four hours. The product was purified by repeated injections on HPLC using a Synchropak RP-100 column (1×25 cm) applying a linear gradient of acetonitrile 5-22% TEAA (0.85 %/min, flow rate 3 ml/min, t=8.5 min). The appropriate fractions were collected and lyophilized to dryness. The product was obtained as a triethylammonium salt (8.5 mg, 39 %). UV: lmax =259 nm. High resolution MS for C12H18N6O13P3 : calcd. 547. 0145, found 547.0170 (MH3-).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[C:35]([O:36][CH3:37])=[CH:34][C:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:30][C:24]=2[CH:23]=1>>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[C:35]([O:36][CH3:37])=[CH:34][C:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][OH:33])[CH2:29][CH2:30][C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CCN(CCO)CC2
Yield: 36 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. Product was isolated as a white foam (34 mg, 36%). MS (ESI+): 539 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.97 (s, 1H), 7.35 (s, 1H), 6.68 (s, 1H), 5.36 (d, J=8 Hz, 1H), 5.25 (br s, 1H), 3.96 (m, 1H), 3.89 (s, 3H), 3.66 (t, J=5 Hz, 2H), 3.26 (m, 1H), 2.91 (m, 4H), 2.80 (s, 3H), 2.74-2.69 (m, 6H), 2.25 (m, 2H), 1.86 (m, 2H), 1.40 (m, 4H).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:21][CH2:20][C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:18]#[N:19])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO.O>[OH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:21][CH2:20][C:17]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:18]#[N:19])[CH2:16][CH2:15]1
Reactant: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Finely-ground 1-[(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)-methyl]-4-anilino isonipecotonitrile, hydrochloride (1:1) (5.0 g) is slurried in methanol (100 ml) and cooled in ice. To this mixture is added an aqueous solution of sodium borohydride (3.0 g) in water (25 ml). The resulting mixture is stirred for 15 hours at room temperature under nitrogen. Dilution of the reaction mixture mixture with water (200 ml), extraction with methylene chloride, and concentration of the dried organic solution give the title compound.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH:9]1[C:10]2[C@:15]([CH3:16])([CH:14]=[CH:13][C:12](=[O:20])[CH:11]=2)[C@@H:17]2[C@H:7]([C@H:6]3[C@@:2]([CH2:19][CH2:18]2)([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH2:8]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@]12C=CC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 76.7 %

Procedure:
A solution of 10 g of androsta-1,4-diene-3,17-dione in 95 ml of carbon tetrachloride is refluxed with 6.4 g of N-bromosuccinimide and 0.4 g of benzoyl peroxide for seventy five minutes. After filtration of succinimide, the filtrate was cooled in ice until crystallization is complete. The mixture is then filtered and dried so obtaining 9.8 g of crude 6-bromoandrosta-1,4-diene-3,17-dione satisfactory for the next step. The analytical sample is crystallized from diethyl ether/n-hexane, m.p. 188°-190° C., [α]D20° +116, U.V. (95% EtOH) λmax=250 nm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccccc1O
Product: N#Cc1ccccc1OCc1ccccc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using 2-cyanophenol instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)-carbamate and benzyl bromide instead of 1-bromopropane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH:32]=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:28][C:29]1[CH:30]=[C:31]([CH:32]([OH:33])[CH:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[OH:20])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C

Procedure:
To a stirring solution of diisopropylamine (14.9 g, 19.4 mL, 148 mmol) in tetrahydrofuran (500 mL) at -78° C. was added, dropwise, n-butyllithium (59 mL of a 2.5M solution in tetrahydrofuran). After ten minutes, a solution of 4-pyridylcarbinol t-butyldimethylsilyl ether (30 g, 134 mmol) in tetrahydrofuran (150 mL) was added dropwise and the temperature allowed to rise to -15° C. The solution was again cooled to -78° C. and a solution of 3,4-dichlorobenzaldehyde (25.9 g, 134 mmol) in tetrahydrofuran (150 mL) added dropwise. After the solution was allowed to warm to -20° C., it was poured into saturated aqueous sodium hydrogen carbonate (2 L). The aqueous layer was extracted with ethyl acetate (3×400 mL), the combined organic layers dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was dissolved in tetrahydrofuran (400 mL) and to this solution was added tetrabutylammonium fluoride (148 mL of a 1.0M solution in tetrahydrofuran) dropwise. After ten minutes, the reaction mixture was concentrated at reduced pressure and the resulting oil chromatographed on silica gel, eluting with 95:5 dichloromethane:methanol to give the title compound as a mixture of diastereomeric diols as a foam (31.7 g) which was used without further purification.