Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1
Solvent: CCCCCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc(O)cc1

Procedure:
The title compound is prepared from 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-N-(4-methoxy-phenyl)-acetamide (Example 191) according to the method described in Example 192. Melting Point: 70-77° C. (hexane)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].COC1C=C(N2CCC[C@@H](C(O)=O)C2)C=CC=1[N+]([O-])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[O:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@@H](C(=O)O)C2)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCC[C@@H](C(=O)N3CCN(C)CC3)C2)ccc1[N+](=O)[O-]

Procedure:
[(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in an analogous fashion to) [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460b replacing (S)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid with (R)-1-(3-Methoxy-4-nitro-phenyl)-piperidine-3-carboxylic acid. [(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone was isolated as a yellow oil after described extractive workup and was used without further manipulation. LC: 88% pure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([CH:8]([CH:17]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18]1)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])=[O:6].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:25].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[C:2]([CH2:3][CH2:4][S:5]([CH:8]([CH:17]1[O:22][C:21](=[O:23])[CH2:20][CH2:19][CH2:18]1)[CH:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:7])([OH:25])=[O:1]
Reactant: O=C1CCCC(C(C=Cc2ccccc2)S(=O)(=O)CCCO)O1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCS(=O)(=O)C(C=Cc1ccccc1)C1CCCC(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 6-[1-(hydroxypropylsulphonyl)-3-phenyl-2-propenyl]tetrahydro-2H-pyran-2-one, (see Example 24) (1.0 g) and pyridinium dichromate (4.67 g) in dimethyl formamide (10 ml) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate to give 6-[1-(carboxyethylsulphonyl)-3-phenyl-2-propenyl]tetrahydro-2H-pyran-2-one as an oil. The lactone was hydrolysed and the disodium salt prepared, as described in Example 22(b) to give the disodium salt of the title compound, m.p. about 203° C.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([Si:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:13]=1[O:41]C.B(Br)(Br)Br.C(Cl)Cl.C[CH2:51][O:52]CC>O.CN(C=O)C>[OH:41][C:13]1[C:14]([Si:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[CH:51]=[O:52]
Reactant: CCOCC
Reactant: COc1c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2ccccc2c1Br
Agent: BrB(Br)Br
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(O)c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of 16.1 mL of tert-BuLi 1.5 M in pentane (24.10 mmol) was added dropwise to a stirred solution of 6.02 g of (4-bromo-3-methoxy-2naphtyl)-triphenylsilane (12.05 mmol) in 50 mL of Et2O at −78° C. The reaction mixture was stirred during 1.5 h at a given temperature and 30 min at 0° C. followed by addition of 0.94 mL of DMF. The resultant mixture was stirred overnight at room temperature and diluted with 200 mL of water. The organic part was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over MgSO4. The resultant solution was transferred to a Schlenk flask under argon and a solution of 24.1 mL of BBr3 1M in CH2Cl2 (24.1 mmol) was added dropwise at −78° C. The reaction mixture was stirred overnight at room temperature, then carefully hydrolysed with 500 mL of water. The organic part was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried over MgSO4, and evaporated. The crude residue was recrystallised from methanol and dried under vacuum to give 5.44 g of 1 (12.63 mmol) with a yield of 95%.
Reaction SMILES: Cl[Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[CH2:12]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CN=C1>CN(C=O)C>[CH2:12]([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][O:23][Si:2]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OC[C@H](O)COCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](O)COCc1ccccc1)(C(C)C)C(C)C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
Chloro(triisopropyl)silane (12.2 mL, 0.057 mol) was added dropwise at 20° C. to a stirred solution of diol 78 (9.52 g, 0.052 mol) and imidazole (5.33 g, 0.078 mol) in DMF (150 mL) and stirring was continued for 16 h. Most of the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic extract was washed well with water, then brine, and was evaporated to give an oil, which was chromatographed on silica. Elution with petroleum ether gave fore fractions, and then further elution with EtOAc/petroleum ether (1:19) gave (2R)-1-(benzyloxy)-3-[(triisopropylsilyl)oxy]-2-propanol (79) (13.80 g, 78%) as a colourless oil: [α]19 −0.78° (c, 8.93, CHCl3); 1H NMR (CDCl3) δ 7.41-7.27 (m, 5H), 4.55 (s, 2H), 3.90-3.84 (m, 1H), 3.79-3.72 (m, 2H), 3.59-3.51 (m, 2H), 2.52 (d, J=5.1 Hz, 1H), 1.13-1.03 (m, 21H). APCI MS m/z 339 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[NH2:19])[CH:12]=[CH:13][C:14]=1[F:15].OC(C(O)C([O-])=O)C([O-])=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>O1CCCC1>[F:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[NH:19][C:5](=[O:7])[CH3:6])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1C[C@H]1c1ccc(F)c(F)c1

Procedure:
Acetic anhydride (0.31 ml) was added to a suspension of (1R-trans)-2-(3,4-difluorophenyl)cyclopropanamine, (R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described in International Patent Application WO 9905143) (700 mg) and potassium carbonate (1.0 g) in tetrahydrofuran (20 ml) and stirred for 20 h. Saturated ammonium chloride solution was added and the mixture was extracted with ether and the organic layers were dried (MgSO4) and evaporated to afford the sub-title compound (470 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][OH:14])[O:9]2)=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>C1COCC1>[OH:14][CH2:13][CH:8]1[O:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]3[NH:1][C:15](=[O:16])[NH:12][C:11]3=2)[CH2:6][CH2:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2c(c1N)OC(CO)CC2
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc3c(c2[nH]1)OC(CO)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a solution of (7,8-diamino-chroman-2-yl)-methanol (194 mg, 1 mmol) in THF (50 mL) was added 1,1′-carbonyidiimidazole (CDI) (81 mg, 1.5 mmol). The resulting solution was stirred for 8 hours at room temperature and the solvent was evaporated in vacuo to a residue. The residue was purified by chromatography (50% CH2Cl2-hexanes) to give 139 mg (63% yield) of the title compound: mp 240° C.; 1H NMR (400 MHz, CDCl3) δ1.65 (m, 1H), 2.01 (m, 1H), 2.70 (m, 2H), 3.55 (m, 1H), 3.63 (m, 1H), 4.05 (m, 1H), 4.68 (bs, 1H, OH), 6.41 (d, J=7.9, 1H), 6.60 (d, J=7.9, 1H), 10.36 (s, 1H), 10.37 (s, 1H); IR: 3250, 3080, 2980, 1700, 1500, 1210 cm−1; MS 220 [M]+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([CH3:34])([C:28]1[NH:32][C:31]([CH3:33])=[N:30][N:29]=1)[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:23][CH2:22][CH2:21][N:20]3[C:16](=[N:17][C:18]([C:24]([NH2:26])=[O:25])=[CH:19]3)[C:15]=2[CH:27]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][C:8]([CH3:34])([C:28]1[NH:32][C:31]([CH3:33])=[N:30][N:29]=1)[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[O:23][CH2:22][CH2:21][N:20]3[C:16](=[N:17][C:18]([C:24]([NH2:26])=[O:25])=[CH:19]3)[C:15]=2[CH:27]=1
Reactant: Cc1nnc(C(C)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)CO[Si](C)(C)C(C)(C)C)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nnc(C(C)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2CCO3)CO)[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 22.4 %

Procedure:
9-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-3-(5-methyl-4H-[1,2,4]triazol-3-yl)-but-1-ynyl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (120 mg, 0.2 mmol) was dissolved in THF (10 mL), TBAF (62.9 mg, 0.24 mmol) was added. The mixture was stirred at room temperature for 14 h. The mixture was purified via HPLC separation (0.1% HCOOH) to afford the titled compound (17.6 mg, 23.0%). 1H-NMR (DMSO-d6, 400 MHz): δ 114 (s, 1H), 8.45 (s, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.11 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 5.05 (s, 1H), 4.45 (s, 4H), 3.77 (s, 2H), 2.29 (s, 3H), 1.21 (s, 3H). LCMS: [M+H]+=393.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)(=O)=O>>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)OCc1ccc(OCc2ccccc2)cc1
Product: O=Cc1cn(Cc2ccc(OCc3ccccc3)cc2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 435 mg of indole-3-carbaldehyde and 4-benzyloxybenzyl methanesulfonate in place of the benzyl bromide used in Example 1 to give 626 mg of 1-(4-benzyloxybenzyl)indole-3-carbaldehyde as colorless crystals. The yield thereof was found to be 61%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O)[CH3:3].[H][H]>CO.[Ni]>[CH3:3][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:1]
Reactant: CC(C)Oc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)Oc1ccccc1N
Yield: 94.4 %

Procedure:
1-(1-methylethoxy)-2-nitrobenzene, 45.26 g (0.25 mol) is dissolved in 500 ml of methanol, 4 g Raney nickel is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The methanol solution is filtered and concentrated in vacuo and the residue distilled to give 35.7 g (94.4%) of 2-(1-methylethoxy)benzenamine; bp 100-102 (at 4 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([O:28][CH2:29][CH3:30])[N:23]=[C:22]([NH2:31])[CH:21]=1>C(Cl)Cl.N1C=CC=CC=1.O>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([O:28][CH2:29][CH3:30])[N:23]=[C:22]([NH:31][C:10](=[O:12])[CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:21]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: CCOc1nc(N)cc(N)c1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(NC(=O)Cc2cccc(OC)c2)cc(N)c1C#N
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
To a solution of 28 mg (0.17 mmol) of (3-methoxyphenyl)acetic acid in 0.5 mL of CH2Cl2 (or the minimum amount necessary for dissolution) was added 20 μL (0.22 mmol) of oxalyl chloride. The solution was swirled, allowed to stand for 5 minutes at ambient temperature, then added to a solution of 30 mg (0.14 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 0.5 mL of pyridine. The mixture was shaken for 15 minutes, diluted with 1 mL of water and concentrated under reduced pressure. The residue was taken up in 3 mL of ethyl acetate, and extracted with water (2×1 mL), 1M HCl(aq.) (1×1 mL), saturated NaHCO3(aq.) (2×1 mL), and brine (1×1 mL), dried over MgSO4, filtered, and concentrated to a solid. This was recrystallized from 1 mL of methanol to provide 9 mg (16%) of a colorless solid. 1H NMR (300 MHz, d6-DMSO) 610.28 (s, 1H), 7.22 (m, 1H), 7.16 (m, 1H), 6.89 (m, 4H), 6.81 (m, 1H), 4.34 (q, 2H, J=7.1 Hz), 3.74 (s, 3H), 3.67 (s, 2H), 1.31 (t, 3H, J=7.1 Hz); MS (ESI) m/e=299 (M−Et+H)+, 327 (M+H)+, 349 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[F:20].S(Cl)(Cl)=O>CN(C)C=O.C1CCCCC1>[Br:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([O:18][CH2:7][CH2:8][N:9]([CH3:14])[CH3:10])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[F:20]
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: C1CCCCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)OCCN(C)C)cn1c23

Procedure:
A mixture of 3.0 g of 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 25 ml of thionyl chloride and 2 drops of N,N-dimethylformamide was heated on a steam bath for 15 minutes. The excess thionyl chloride was removed by evaporation. The residue of solid 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxyl chloride was suspended in 100 ml of dichloromethane, the mixture was stirred and 10 ml of dimethylaminoethanol was added. After 10 minutes of stirring the solution was washed with sodium bicarbonate solution, then dried over magnesium sulfate. The solution was treated with decolorizing charcoal, filtered and concentrated to provide an oil. When cyclohexane was added, tan solid N,N-dimethylaminoethyl 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate formed. This product was dissolved in 50 ml of hot isopropanol, treated with decolorizing charcoal and filtered. A solution of isopropanol saturated with hydrogen chloride gas was added until the mixture became acidic. The white precipitate that formed was N,N-dimethylaminoethyl 8-bromo-6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate hydrochloride, m.p. 250° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([Cl:13])[C:3]=1[CH:4]=[O:5].[C:14]([C:18]([Zn]Cl)([Cl:20])[Cl:19])([F:17])([F:16])[F:15].C(C(Cl)(Cl)Cl)(F)(F)F.O>CN(C=O)C.C1COCC1.[Zn]>[Cl:19][C:18]([Cl:20])([C:14]([F:17])([F:16])[F:15])[CH:4]([C:3]1[C:2]([Cl:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=1[Cl:13])[OH:5]
Reactant: O=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: FC(F)(F)C(Cl)(Cl)[Zn]Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c(C(O)C(Cl)(Cl)C(F)(F)F)c(Cl)c1
Temperature: 50 °C

Procedure:
3 g of 2,6-dichloro-4-nitro benzaldehyde were reacted, in 20 ml of anhydrous DMF under a nitrogen atmosphere, with CF3CCl2ZnCl prepared from 5 g of CF3CCl3 and 2.2 g of Zn in 10 ml of THF at 60° C. for 1 hour. The mixture was heated at 50° C. for 2 hours and at the end of the reaction it was poured into acidulated water and extracted repeatedly with ethyl ether.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:18])=[O:14])[CH:10]=[CH:11][CH:12]=1)[NH2:5])#[N:2]>CO.C1COCC1.[OH-].[Na+]>[NH2:5][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:14])[CH:10]=[CH:11][CH:12]=1)=[N:3][C:1]#[N:2]
Reactant: N#CN=C(N)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)OCc2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CN=C(N)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a stirred solution of the compound from Example 134 (285 mg) in methanol (3 ml) and THF (3 ml), 1N sodium hydroxide (3 ml) was added. The reaction mixture was stirred at room temperature for 2 hours, evaporated and the residue dissolved in water. The resulting solution was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate/MeOH. The organic extracts were washed with water, dried (Na2SO4) and evaporated to afford an off white solid. The crude product was further purified by reverse phase HPLC on a C18 column (eluant:0.5% TFA-water/acetonitrile) and lyophilized to afford the title compound (65 mg) as a white solid.
Reaction SMILES: C[Si](C)(C)CCOC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CS(C)=O>[CH:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=2)=[CH:16][CH:17]=1)([CH3:25])[CH3:24]
Reactant: CC(C)OCc1ccc(Cc2ccc(NC(=O)OCC[Si](C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)OCc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a solution of 4-(4-isopropoxymethylbenzyl)phenyl carbamic acid 2-trimethylsilanyl-ethyl ester (734 mg, 1.84 mmol) in dry dimethyl sulfoxide at 20° C. under argon atmosphere was added tetra-n-butylammonium fluoride in tetrahydrofuran (5.52 mL, 5.52 mmol). After the mixture was stirred for 1 hour, the solution was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous phase was extracted with diethyl ether (2×20 mL), and the combined organic layers were washed with water and brine, dried (Mg2SO4), and evaporated in vacuo. The crude product was purified by flash chromatography to give pure 4-(4-isopropoxymethyl-benzyl)-phenylamine (405 mg, 86%) as a clear oil.
Reaction SMILES: [ClH:1].C(O[N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:16][C:17]2[N:18]=[N:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=2)[CH2:14][CH3:15])[CH2:9][CH2:8]1)(C)(C)C>CCOC(C)=O>[ClH:1].[CH2:22]([N:20]1[N:19]=[N:18][C:17]([CH2:16][N:13]([CH:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)[CH2:14][CH3:15])=[N:21]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCN(OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(Cc1nnn(Cc2ccccc2)n1)C1CCNCC1
Reaction time: 0.67 h

Procedure:
To 4 ml of a saturated solution of hydrogen chloride in EtOAc was added 204 mg of 1-t-butyloxy-4-(N-(2-benzyl-2H-tetrazol-5-yl)methyl-N-ethylamino)-piperidine (from Step C). After 40 minutes, the solvent was evaporated under reduced pressure to give 170 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.N.[CH:28](Cl)(Cl)Cl.[K+].[Br-]>>[CH3:28][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1C=CC2=CN=C(c3ccc(C4CCNCC4)cc3)N3CCC(=C23)N1
Reactant: ClC(Cl)Cl
Agent: N
Agent: [Br-]
Agent: [K+]
Product: CN1CCC(c2ccc(C3=NC=C4C=CC(=O)NC5=C4N3CC5)cc2)CC1

Procedure:
The product was prepared from 1-(4-piperidin-4-yl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (Example 137) following the procedure for Example 132 a white solid (77%): mp >240° C. (dec); Rf=0.21 (10% methanolic ammonia/CHCl3); IR (KBr) 1662, 1473, 1379, 1304 cm−1; 1H NMR (DMSO-d6) δ 1.69-1.81 (m, 4H), 2.00-2.07 (m, 2H), 2.23 (s, 3H), 2.53-2.58 (m, 1H), 2.89-2.93 (m, 2H), 3.51-3.52 (m, 2H), 4.45-4.47 (m, 2H), 7.34 (t, 1H, J=7.8 Hz), 7.45 (d, 2H, J=8.2 Hz), 7.79 (d, 2H, J=8.3 Hz), 7.84-7.90 (m, 2H), 8.44 (t, 1H, J=5.6 Hz). HRMS calcd for C22H24N4O 360.1950 (M+), found 360.1944. Anal. (C22H24N4O.0.25H2O) C, H, N.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([C:8](OC)=[O:9])[CH2:5][CH:4]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH:4]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH3:2]
Reactant: CCC1CC(C(=O)OC)CC1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC1CC(CO)CC1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 3-tert-butyl 1-methyl 4-ethylcyclopentane-1,3-dicarboxylate (3.88 g, 15.1 mmol, Preparation #11, Step B) in Et2O (150 mL) was cooled to about −40° C. LAH (2 N in THF, 8.32 mL, 16.6 mmol) was added dropwise. The reaction mixture was stirred at about −40° C. for about 1 hour. The reaction mixture was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (3×50 mL). The combined organic extracts were concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc/heptane to give tert-butyl 2-ethyl-4-(hydroxymethyl)cyclopentanecarboxylate (1.00 g, 29%) as a brown oil: LC/MS (Table 1, Method a) Rt=2.37 min; MS m/z: 229 (M+H)+.
Reaction SMILES: C(Br)C.[Mg].[OH:5][C:6]([CH3:16])([CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14])[C:7]#[CH:8].[CH3:17][C:18]1([CH3:26])[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[C:19]1=[O:25].[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[OH:5][C:6]([CH3:16])([C:7]#[C:8][C:19]1([OH:25])[CH:20]([CH3:24])[CH2:21][CH2:22][CH2:23][C:18]1([CH3:26])[CH3:17])[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=[CH2:14]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: C#CC(C)(O)C=CC=C(C)C=C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=CC(C)=CC=CC(C)(O)C#CC1(O)C(C)CCCC1(C)C

Procedure:
A solution of ethyl bromide (1.75 g.) in diethyl ether was added to a suspension of magnesium (0.385 g.) in ether and the mixture was heated to reflux for 30 minutes. A solution of the alcohol, 3-hydroxy-3,7-dimethyl-nona-4,6,8-trien-1-yne, (1.0 g.) in dry benzene was added and the mixture refluxed 30 minutes. A solution of 2,2,6-trimethylcyclohexanone (1.12 g.) in benzene was added and the mixture refluxed for 15 minutes and poured into saturated aqueous ammonium chloride solution. The organic phase was washed with brine dried and concentrated to give 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethylcyclohexyl)-nona-1,3,5-trien-8-yne which was chromatographed on activity III alumina to give pure 7-hydroxy-3,7-dimethyl-9-(1-hydroxy-2,2,6-trimethylcycohexyl)-nona-1,3,5-trien-8-yne.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9])=[O:3].[CH:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH:12]1([CH2:18][CH2:19][NH:20][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: NCCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCCC(=O)NCCC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 5-[chloroformyl]pentanoate (4.2 g) in dry dichloromethane (20 ml) was added dropwise to a stirred solution of 2-cyclohexylethylamine (3 g) and triethylamine (3.3 ml) in dry dichloromethane (40 ml) under a N2 atmosphere. The mixture was stirred at room temperature for 16 hours and heated under reflux for 1.5 hours.