Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-hydroxybenzoic acid (15.0 g) in methanol (150 mL) was added dropwise thionyl chloride (10.1 mL) under ice-cooling. The reaction solution was stirred at 70° C. overnight under argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27]C(=O)OC(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>O1CCOCC1>[NH2:27][C@H:22]1[C:23]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Temperature: 55 °C
Yield: 80.9 %

Procedure:
To (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate (12.8 g, 27.8 mmol) in dioxane (200 mL) was added 4N HCl in dioxane (69 mL). The solution was heated to 55° C. for 1 h, and product precipitated. Dioxane was removed and the resulting solid suspended in ether and collected. The material was recrystallized from MeOH (200 mL) to produce 8.11 g (81%) of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 as the HCl salt. LCMS-ESI (m/z): calcd for: C21H20N4O2: 360.4. found 383.2 [M+Na]+, tR=2.49 min. Elemental Analysis and NMR spectra determined for C21H21N4O2Cl*0.5 H2O; C calculated=62.14%. found=62.25%. H calculated=5.46%. found=5.30%. N calculated=13.80%. found=13.84%. Cl calculated=8.73%. found=8.34%. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 3H), 8.49 (d, J=2.3, 1H), 8.39 (dd, J=9.0, 2.3, 1H), 8.11 (d, J=7.6, 1H), 7.91 (d, J=7.6, 1H), 7.55 (t, J=8.5, 2H), 4.97 (hept, J=6.1, 1H), 4.80 (s, 1H), 3.47 (ddd, J=17.4, 8.7, 5.3, 1H), 3.23 (ddd, J=17.4, 8.6, 6.4, 1H), 2.55 (ddd, J=13.7, 8.3, 3.2, 1H), 2.22-1.97 (m, 1H), 1.38 (d, J=6.0, 6H). 13C NMR (101 MHz, CDCl3) δ 173.28, 167.98, 162.53, 143.69, 141.29, 134.59, 133.80, 128.93, 128.11, 127.55, 122.72, 115.87, 115.24, 114.91, 102.46, 72.54, 54.38, 31.51, 29.91, 21.47. Chiral HPLC of the free base: (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile was eluted using 15% i-PrOH in hexanes plus 0.3% DEA: >99.9% ee, tR=30.80 min. (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy-benzonitrile 50 was prepared in an analogous fashion from (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate: >99.9% ee, tR for (S)-enantiomer=28.58 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:26]2([CH3:29])[CH2:28][CH2:27]2)[N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.CC(O)C.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O-])(O)=O.[Na+]>O.N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:26]2([CH3:29])[CH2:27][CH2:28]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: CC1(c2nc(Br)c(-c3ccnc(NCCC#N)n3)n2COCC[Si](C)(C)C)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CC1(c2nc(Br)c(-c3ccnc(NCCC#N)n3)[nH]2)CC1
Temperature: 90 °C
Yield: 78.8 %

Procedure:
To a 200 mL round-bottom flask containing 3-(4-(4-bromo-2-(1-methylcyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (2.46 g, 5.2 mmol) were added 2-propanol (10 mL) and PPTS (1.94 g, 7.7 mmol). The reaction was heated to 90° C. in an oil bath for 3 hours, LCMS indicated 90% conversion. Additional pyridine (100 μL) and the reaction was maintained at 90° C. for another 5 hours. The reaction was allowed to cool to room temperature and to an yellow gum. Added water (100 mL), adjusted to pH 7 with saturated aqueous NaHCO3 solution, and extracted with EtOAc (2×100 mL). Combined EtOAc, washed with saturated NaHCO3 (1×100 mL), brine (1×100 mL), dried (Na2SO4), filtered, and concentrated to obtain tacky yellow solids. The residue was triturated in EtOAc-Et2O (1 mL, 10 mL) to furnish 3-(4-(4-bromo-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propanenitrile (1.50 g, 4.10 mmol, 95% purity by LCMS) as off-white solids: LCMS (m/z) 347.0 (MH+), tR=0.59 minute; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=6.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 3.88 (t, J=6.3 Hz, 2H), 2.75 (t, J=6.5 Hz, 2H), 1.47 (s, 3H), 1.22 (m, 2H), 0.84 (m, 2H).
Reaction SMILES: N#N.[CH3:3][C:4]1([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:5]1>[Pd].CO>[NH2:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[N:6]1[CH2:7][CH2:8][CH2:9][C:4]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:3])[CH2:5]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2ccncc2[N+](=O)[O-])C1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2ccncc2N)C1

Procedure:
10% Palladium on carbon (0.1 eq) was added to a N2-flushed solution of tert-butyl 3-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (1 eq) in MeOH (0.2 M). The reaction was purged with H2 under atmospheric pressure for 16 h at it. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with EtOAc and MeOH, then concentrated in vacuo. The crude residue was dissolved in CH2Cl2, loaded onto a SiO2 column, and purified by flash chromatography (1:2 EtOAc in hexanes+5% MeOH) to give tert-butyl 1-(3-aminopyridin-4-yl)-3-methylpiperidin-3-ylcarbamate. LC/MS (m/z): 307.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:34])[CH:20]([CH2:35][OH:36])[CH2:19]1)[CH2:11]2)(C)(C)C>Cl.O1CCOCC1.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=4[N:26]=[C:25]3[CH3:34])[CH:20]([CH2:35][OH:36])[CH2:19]1)[CH2:11]2
Reactant: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(CC2Cc3ccc(N)cc3C2)CC1CO
Reaction time: 1 h

Procedure:
{2-[4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxymethyl-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester (191 mg) was dissolved in 4M HCl in dioxane and stirred for 1 h after which all volatiles were removed under reduced pressure to yield a heavy oil which was suspended in CH2Cl2 and washed with 0.1 M NaOH. The organic phase was dried over Na2CO3. Filtration and removal of volatiles yielded [1-(5-amino-indan-2-ylmethyl)-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidin-3-yl]-methanol as a heavy oil (86 mg; 59%)
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:15]#[CH:16]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[CH2:8][O:9][C:10]=2[C:2]=1[C:16]#[C:15][CH2:14][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: COc1ccc2c(c1I)OCC2=O
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C#CCC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A solution of 7-iodo-6-methoxybenzofuran-3(2H)-one (0.348 g, 1.20 mmol) synthesized in Example B46, Step 2 in triethylamine (10 mL) was added with tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.269 g, 1.20 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.0842 g, 0.120 mmol) and copper(I) iodide (0.0114 g, 0.0600 mmol), and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated, and then added with water, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)prop-2-ynyl]piperidine-1-carboxylate (0.281 g, 61%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CO.[BH4-].[Na+].[Cl-].[NH4+]>O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CCC(O)CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 68.5 parts of ethyl 4-oxo-1-piperidinecarboxylate in 240 parts of methanol was added portionwise 3.8 parts of sodium borohydride at a temperature between 20°-30° C. (the reaction mixture was cooled if necessary in a water-bath). After the addition was complete, the whole was stirred for 30 minutes. The reaction mixture was then poured into a mixture of 53.5 parts of ammonium chloride and 400 parts of water. The methanol was evaporated. The product was extracted with trichloromethane. The extract was dried and evaporated. The oily residue was distilled in vacuo, yielding 60 parts of oily ethyl 4-hydroxy-1-piperidinecarboxylate; bp. 140° C. at 1.4 mm. pressure; nD20 : 1.4796; d2020 : 1.1166 (3).
Reaction SMILES: C(OC1C=CC(N2CCN(CCCC3CCCCC3)CC2)=CC=1Cl)C1C=CC=CC=1.C([O:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:47][CH2:46]2)=[C:41]([Cl:59])[CH:40]=1)C1C=CC=CC=1>>[Cl:59][C:41]1[CH:40]=[C:39]([OH:38])[CH:44]=[CH:43][C:42]=1[N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:47][CH2:46]1
Reactant: Clc1cc(OCc2ccccc2)ccc1N1CCN(CCc2ccccc2)CC1
Agent: Clc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Product: Oc1ccc(N2CCN(CCc3ccccc3)CC2)c(Cl)c1
Yield: 57.3 %

Procedure:
Production Example 30 was repeated except that 1-(4-benzyloxy-3-chlorophenyl)-4-(3-cyclohexylpropyl)piperazine was replaced with 1-(4-benzyloxy-2-chlorophenyl)-4-phenethylpiperazine (65 mg). Thus obtained crude product was purified on TLC (developer, chloroform: methanol=17:1) to provide 3-chloro-4-(4-phenethylpiperazin-1-yl)phenol (29 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=O)=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([CH3:39])[C@@H:36]([O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:43])[CH3:42])[C@H:35]([NH:48][C:49]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:55])[CH2:34]3)=[O:25])=[N:14]2)=[CH:19][CH:18]=1
Reactant: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
A mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl ((3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (0.54 g, 1.2 mmol), and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL) and DIPEA (0.65 mL, 3.7 mmol) was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.565 g, 55%). LCMS calc. for C40H52BrN6O6Si [M+H]+: m/z=919.3. found: 819.4.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)[CH2:5][C:6](OC)=[O:7]>CO>[NH2:3][C@H:4]([C:10]1[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)C[C@H](N)c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc([C@@H](N)CCO)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
Sodium borohydride (1.039 mL, 29.48 mmol) was added portionwise to (S)-methyl 3-amino-3-(4-cyanophenyl)propanoate (2.23 g, 10.92 mmol) in methanol (20 mL) at 0° C. over a period of 5 minutes. The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was quenched with saturated NaHCO3 (50 mL), extracted with EtOAc (3×100 mL), the organic layer was washed with saturated brine (75 mL), dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 8% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-(1-amino-3-hydroxypropyl)benzonitrile (0.368 g, 19.13%) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])[CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)ccc1F
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
5-Bromo-2-fluoro-benzaldehyde (5.0 g, 24.6 mmol), malonic acid (5.6 g, 53.7 mmol), and piperidine (0.5 mL, 4.9 mmol) were added to pyridine (11.4 mL). The reaction mixture was stirred at 100° C. for 3 hours and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was recrystallized from ethanol to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:41]([N:44]=C=O)([CH3:43])[CH3:42]>O>[CH:41]([NH:44][C:20]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)[CH2:15][CH2:16]1)=[O:21])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: CC(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)NC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A mixture of tert-butyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 306 (140 mg, 0.38 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (3 ml), then neutralized with triethylamine (2 ml, 14.35 mmol). To the solution, isopropylisocyanate (75 μl, 0.76 mmol) was added followed by stirring at room temperature for 1 hour, then diluted with water. The solution was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid isopropylamide (90 mg, yield 67%) as a white powder.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])[CH3:5]>C(OCC)C>[CH2:4]([C:6]1[CH:7]=[C:8]([NH:9][C:2]#[N:1])[CH:10]=[CH:11][CH:12]=1)[CH3:5]
Reactant: CCc1cccc(N)c1
Reactant: N#CBr
Solvent: CCOCC
Product: CCc1cccc(NC#N)c1
Temperature: 24 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
A solution of cyanogen bromide (11.36 g, 107 mmol) in anhydrous diethylether (50 mL) was added slowly to a stirred solution of 3-ethylaniline (20.8 g, 171 mmol) in diethylether at 4° C. After the addition, the reaction mixture was stirred at 24° C. for 12 hours and it became a brown solution with a white precipitate. The precipitate was filtered off; the filtrate was washed with aqueous HCl (1N, 3×150 mL) and brine (60 mL). Then the etherate solution was dried over MgSO4, filtered, and concentrated to yield a thick liquid. The crude product was further purified by chromatography (SiO2, hexanes, hexanes/CH2Cl2, CH2Cl2) to afford 3-ethylphenylcyanamide (11.6 g, 76% in yield) as a liquid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH3:29][C:30]1[C:34]([CH:35]=O)=[C:33]([CH3:37])[N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:31]=1>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:35][C:34]1[C:30]([CH3:29])=[N:31][N:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:33]=1[CH3:37]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nn(-c2ccccc2)c(C)c1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1c(C)nn(-c2ccccc2)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To an ice-cold suspension of methoxymethyltriphenylphosphonium chloride (26.2 g, 74.9 mmol) in 300 mL tetrahydrofuran was added n-butyllithium (31 mL, 2.5 M in hexane). The mixture was stirred at 0° C. for 15 minutes and treated with 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbaldehyde (7.5 g, 37.5 mmol, suspended in 150 mL tetrahydrofuran). The mixture was slowly warmed to room temperature over 2 hours and quenched by slow addition of a saturated aqueous sodium chloride solution. The resulting white precipitate was removed by filtration and the filtrate was extracted several times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to an oil, which was purified via silica gel column chromatography (0-20% ethyl acetate in heptane) to provide the title compound as a yellow oil (7.09 g, 31.1 mmol, 83% yield) as a mixture of E:Z isomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:8]2[CH:7]=[CH:6][C:5]([S:10]([NH:13][C:14]3[S:15][CH:16]=[CH:17][N:18]=3)(=[O:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])=[C:22]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=2)[CH:21]=1
Reactant: Cn1nccc1-c1cc(Cl)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(Cl)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N

Procedure:
3-Cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide, (Preparation 46, 500 mg, 0.00176 mol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol, (Preparation 89, 370 mg, 0.00177 mol) and potassium carbonate (700 mg, 0.00287 mol) were stirred in dimethylformamide (5 mL) at 80° C. for 24 hours. The reaction mixture was cooled and partitioned between ethyl acetate (150 mL) and aqueous hydrochloric acid (80 mL of 2 molar), the organic layer was dried over anhydrous sodium sulphate, filtered and the solvents removed in vacuo to give an orange solid. The solid was triturated with diethyl ether (20 mL) to give the title compound as an orange powder, (680 mg).
Reaction SMILES: [N+]([CH:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][N:6]([C:17]2[CH:22]=[CH:21]C=CN=2)[CH2:5]1)([O-])=O>C(OCC)(=O)C.[Pd]>[C:13]([O:12][C:10]([N:9]1[CH2:4][CH2:5][N:6]([C:17]2[CH:22]=[CH:21][N:6]=[CH:5][C:4]=2[NH2:9])[CH2:7][CH2:8]1)=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccn2)CC1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2N)CC1
Reaction time: 8 h

Procedure:
3-Nitro-4-boc piperizinyl pyridine was dissolved in ethyl acetate and few drops of acetic acids was added. The resulting solution was subjected Pd/C(10%, 10 mol %) and was kept under hydrogen atmosphere at room temperature. Overnight stirring and monitored the reaction progress until the reaction is complete. The reaction solution was filtered through celite and concentrated to give the product, 4-(3-Amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in good yield (80%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:6]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 63.5 %

Procedure:
In a manner similar to that described in Example 3, 2-methoxy-benzoyl chloride (0.060 g, 0.00035 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.052 g of 4-[4-(2-methoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+328.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[CH3:12][C:6]1([CH3:13])[C:5]2[C:10](=[CH:11][C:2]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)[O:9][CH2:8][CH2:7]1
Reactant: CC1(C)CCOc2cc(Br)ccc21
Reactant: CCCCCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCC(=O)c1ccc2c(c1)OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 7-bromo-4,4-dimethyl-chroman (1.0 g, 4.15 mmole) in 20 mL of THF at −78° C., was treated with 1.91 mL of 2.5M butyllithium. After 30 minutes at −78° C. a solution of hexanoic acid methoxy-methyl-amide (0.726 g, 4.56 mmole) in 5 mL of THF was added. The reaction mixture was stirred at −78° C. for 30 minutes, warmed to room temperature, quenched by the addition of 25 mL saturated aqueous ammonium chloride solution and extracted with three 25 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.516 g of 1-(4,4-dimethyl-chroman-7-yl)-hexan-1-one as a colorless oil.