Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:26])[C:5](=[N:10][N:11]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:12](=[O:19])[CH2:13][C:14]([O:16]CC)=O)[C:6]([CH3:9])([CH3:8])[CH3:7])C.C1CCN2C(=[N:31]CCC2)CC1.C(C(C(Cl)=O)C(Cl)=O)C.Cl.CC[O:50][C:51]([CH3:53])=[O:52]>O1CCCC1.O>[CH:20]1([N:11]2[C:12](=[O:19])[C:13]([C:14]([NH:31][CH2:53][C:51]([OH:50])=[O:52])=[O:16])=[C:4]([OH:26])[C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:10]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CC(=O)N(N=C(C(=O)OCC)C(C)(C)C)C1CCCCC1
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nn(C2CCCCC2)c(=O)c(C(=O)NCC(=O)O)c1O
Reaction time: 0.17 h

Procedure:
Ethyl-2-{cyclohexyl[3-(ethyloxy)-3-oxopropanoyl]hydrazono}-3,3-dimethylbutanoate. DBU (0.21 ml, 1.393 mmol) was added to a solution of the compound from example 99a) (0.323 g, 1.270 mmol) in Tetrahydrofuran (THF) (1 ml) at 0° C. The reaction was brought to room temperature and stirred for 10 minutes. The temperature was then reduced to 0° C. and ethyl malonyl chloride (0.19 ml, 1.410 mmol) was added. The reaction stirred for 2.5 h at room temperature followed by the addition of 1N HCl. The solution was diluted with H2O and EtOAc and the layers separated. The aqueous phase was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 5-25% EtOAc/Hexanes) to give a mixture of the title compound and the cyclized product 56c) (197 mg, 42%). LCMS (ES+) m/z 369.0, 323.0 (MH+).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](#[N:13])[CH2:11][CH3:12].[OH-].C[N+](C)(C)C>O>[CH3:12][C:11](=[C:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10]#[N:13]
Reactant: CCCCCCC(C)=O
Reactant: CCC#N
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: CCCCCCC(C)=C(C)C#N

Procedure:
Into a 100 ml. flask, equipped with magnetic stirrer, thermometer, condensor and static nitrogen head, was placed 23.6 g. of 2-octanone (0.18 m), 22 g. of propionitrile (0.4 m), 7 g. of Ca(OH)2 (0.09 m), 7 g, of CaO (0.12 m), and 0.6 g. of 25% tetramethyl ammonium hydroxide in water. The solution was held at reflux for 64 hours, whereupon a gas chromatographic analysis of a sample of the reaction mixture showed 10.7% conversion of the ketone to the product nitrile.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[CH3:15][C:16]([CH3:18])=[O:17].[OH2:19]>C(O)(=O)C.Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:9]/[C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]2[CH:8]=[CH:18][C:16]([OH:17])=[C:15]([O:19][C:11]([F:12])([F:13])[F:14])[CH:6]=2)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: O=Cc1ccc(O)c(OC(F)(F)F)c1
Reactant: O
Reactant: CC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(/C=C/c1ccc(O)c(OC(F)(F)F)c1)/C=C/c1ccc(O)c(OC(F)(F)F)c1
Temperature: 27.5 °C
Reaction time: 36 h
Yield: 50 %

Procedure:
A mixture of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (600 mg, 2.9 mmol) in acetone (107 μL, 1.5 mmol) was dissolved in glacial acetic acid (8 mL), saturated with anhydrous HCl and heated to 25-30° C. for 2 h. The red solution was stirred for 36 h and treated with cold water. The red suspension turned dark green. The resulting precipitate was filtered, washed with water and dried in vacuo to afford NW317 as a yellow-green solid (314 mg, 50%). mp: 103-105° C. 1H NMR (300 MHz, CD3OD) δ (ppm): 7.72 (d, 3J=15.9 Hz, 2H, Hvin), 7.62 (s, 2H, HAr), 7.58 (dd, 3J=8.5 Hz, 4J=2.0 Hz, 2H, HAr), 7.13 (d, 3J=15.9 Hz, 2H, Hvin), 7.03 (d, 3J=8.4 Hz, 2H, HAr). 13C NMR (75 MHz, CD3OD) δ (ppm): 191.2 (C), 153.8 (C), 143.8 (CH), 138.4 (C), 130.1 (CH), 128.4 (C), 125.0 (CH), 124.4 (CH), 120.5 (CH). MS (FAB) m/z: 435.2 (M+). Light-sensitive!
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([Cl:24])=[O:23])=[CH:17][CH:16]=1>C(N(CC)CC)C>[ClH:24].[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:8]2[CH2:9][CH2:10][S:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:23])=[CH:17][CH:16]=1
Reactant: CSc1ccc(CC(=O)Cl)cc1
Reactant: C1CCN(CC2CSCCN2)C1
Solvent: CCN(CC)CC
Product: CSc1ccc(CC(=O)N2CCSCC2CN2CCCC2)cc1
Product: Cl

Procedure:
The procedure described in Example 17 was repeated, but using 1.0 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 1.38 ml of triethylamine and 1.2 of 4-methylthiophenylacetyl chloride, to afford 1.36 g of the title compound, melting at 162°-166° C. (dec.).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:4]=1)[NH2:2].[CH:27]([CH:29]([CH:35]=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=O.C(N(C(C)C)CC)(C)C>C(O)C>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][CH:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([N:1]1[CH:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:2]1)=[N:4][C:5]=2[NH:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(C=O)C=O
Reactant: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C

Procedure:
(4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (0.2 mmol) and ethyl 2,2-diformylacetate (0.28 mmol) were suspended in 3 mL of ethanol and to the suspension was added 5 mmol of diisopropylethylamine. The mixture was heated at reflux for 3 hours. Upon cooling to room temperature, the precipitate thus formed was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:44]1[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:49][CH:46]3[CH2:47][CH2:48][O:44][CH2:45]3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: NC1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NC1CCOC1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), tetrahydro-furan-3-ylamine (23 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C15H20ClN6O3, 354.13. found 354.2.
Reaction SMILES: [NH2:1][C@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.Cl.Cl[CH2:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1>>[NH2:1][C@H:2]([CH3:24])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2
Reactant: ClCc1cscn1
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 65 %

Procedure:
The procedure described in Example 65 (preparation of starting materials) was repeated using 4-[(5-{[(2R)-2-aminopropyl]oxy}quinazolin-4-yl)amino]-2-chlorophenol and 4-(chloromethyl)-1,3-thiazole hydrochloride give 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine in 65% yield; NMR spectrum (DMSO-d6) 1.17 (d, 3H), 3.33-3.45 (m, 1H), 4.00 (dd, 1H)), 4.24 (dd, 1H), 5.32 (s, 2H), 7.11 (d, 1H), 7.30 (d, 1H), 7.33 (d, 1H), 7.67-7.82 (m, 3H), 8.23 (d, 1H), 8.51 (s, 1H), 9.14 (d, 1H); Mass spectrum MH+ 441.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14](C=O)=[CH:13][N:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][N:24]([CH2:32][CH2:33][NH:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[BH3-][C:37]#N.[Na+].O>CO.[Cl-].[Cl-].[Zn+2]>[CH3:23][N:24]([CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][C:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[N:11][N:12]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:13]=1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: O=Cc1cn(C2CCCCO2)nc1-c1ccc([N+](=O)[O-])cc1
Reactant: [BH3-]C#N
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1-c1ccc([N+](=O)[O-])cc1
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
To a solution of 3-(4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde (0.550 g, 0.00182 mol) in methanol (10 mL) at room temperature were added TEA (221 mg, 0.00913 mol), ZnCl2 (0.025 g, 0.000182 mol) and tert-butyl methyl(2-(methylamino)ethyl)carbamate (0.410 g, 0.00219 mol) and stirred for 45 min. NaCNBH3 (0.580 g, 0.00913 mol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction was poured into water (70 mL) and extracted with EtOAc (70 mL×2). The combined extracts were washed with brine (100 mL), dried over sodium sulphate and concentrated under vacuum. The residue was purified by SGC using DCM:MeOH (0%-4%) as eluent to obtain tert-butyl methyl(2-(methyl((3-(4-nitrophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (0.770 g, Yield: 86.71%). LCMS (ESI): RT=2.00 min, m/z=474.8 [M+F1]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([N:21]1[CH2:25][C@@H:24]([O:26][C:27](=[O:29])[CH3:28])[CH2:23][C@@H:22]1[C:30]1[CH:35]=[C:34]([N+:36]([O-])=O)[C:33]([NH:39][C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=O)=[CH:32][C:31]=1F)(=[O:20])[CH3:19].O.O.[Sn](Cl)Cl>C(OCC)(=O)C.CN(C)C=O>[C:27]([O:26][C@@H:24]1[CH2:25][N:21]([C:18](=[O:20])[CH3:19])[C@@H:22]([C:30]2[C:31]([O:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:32][C:33]3[N:39]=[C:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[NH:36][C:34]=3[CH:35]=2)[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)O[C@H]1C[C@H](c2cc([N+](=O)[O-])c(NC(=O)c3ccccn3)cc2F)N(C(C)=O)C1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)O[C@H]1C[C@H](c2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccc(S(C)(=O)=O)cc2)N(C(C)=O)C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
10 mg of 4-methanesulfonyl-phenol and 20 mg of cesium carbonate were added to a dimethylformamide (0.5 ml) solution of 21 mg of trans-1-acetyl-2-(5-nitro-2-fluoro-4-((pyridin-2-carbonyl)-amino)-phenyl)-4-acetoxy-pyrrolidine, and the reaction liquid was stirred at 90° C. for 1 hour. 100 mg of tin(II) chloride dihydrate was added to it, and the reaction liquid was stirred at 90° C. for 5 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [OH:1][C@@:2]1([C:9]#[C:10][C:11]2[N:19]=[C:18]3[C:14]([NH:15][CH:16]=[N:17]3)=[C:13]([NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[N:12]=2)[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.Cl.ClC[C:29]1[N:30]=[C:31]([CH3:34])[S:32][CH:33]=1.[CH3:35]N(C=O)C>>[OH:1][C@@:2]1([C:9]#[C:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH2:35][C:33]3[S:32][C:31]([CH3:34])=[N:30][CH:29]=3)=[C:13]([NH:20][CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[N:12]=2)[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: Cc1nc(CCl)cs1
Reactant: CCC(CC)Nc1nc(C#C[C@]2(O)CCC[C@@H](C)C2)nc2nc[nH]c12
Reactant: CN(C)C=O
Agent: Cl
Product: CCC(CC)Nc1nc(C#C[C@]2(O)CCC[C@@H](C)C2)nc2c1ncn2Cc1cnc(C)s1

Procedure:
2-{2-[1-(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine (56 mg, 0.1640 mmol) and 4-chloromethyl-2-methylthiazole hydrochloride (127 mg, 0.6899 mmol) were stirred in DMF (8 mL) at 150° C. for 22 h. The reaction mixture was adhered to silica and purified by column chromatography, eluting with a gradient of DCM/MeOH (0–6%) to afford pure 31 as an off white solid: yield 2 mg, 3%. 1H NMR (CD3OD) δ 8.12 (s, 1H), 7.29 (s, 1H), 5.44 (s, 2H), 4.22 (m, 1H), 2.65 (s, 3H), 2.14–2.05, 1.94–1.37, 0.99–0.80 (3×m, 21H), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI (M+H+) 453.2.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:25][O:26][CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: COCc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 38.4 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.75 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.43 g, 39%) was obtained as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:23])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1.[OH-:24].[Na+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl>O1CCCC1.C(O)C>[CH3:23][C:10]1[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[C:4]2[N:3]=[C:2]([N:3]3[CH2:4][CH2:11][O:24][CH2:7][CH2:2]3)[CH:7]=[C:6]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:5]2[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nn2c(N3CCOCC3)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To the solution of 5,7-dichloro-2-methyl-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.584 mmol) in Tetrahydrofuran (THF) (5 mL) was added sodium hydroxide (2.045 mL, 4.09 mmol). The reaction was stirred at rt for 18 h. The reaction was acidified. The reaction was extracted with EtOAc (80 mL×2). The organic phases were combined, washed with Brine, dried and concentrated. The mixture was transferred to 5 mL MW vial. Morpholine (0.509 mL, 5.84 mmol) and Ethanol (1 mL) was added in. The reaction mixture was subjected to MW irradiation at 150° C. for 3 h. 6 N HCl was added to the reaction to acidify the solution. The reaction mixture was extracted with EtOAc (50 mL×2). The organic phases were combined, washed with Brine, dried and concentrated. The residue was purified by reversed phase HPLC (25˜55% CH3CN (0.1% TFA)/Water (0.1% TFA)) to give the product (30 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.17 (s, 3H) 3.52-3.64 (m, 8H) 3.66-3.73 (t, J=4.63 Hz, 4H) 3.74-3.82 (t, J=4.44 Hz, 4H) 4.30 (s, 2H) 5.78 (s, 1H) 7.31 (d, J=6.57 Hz, 1H) 7.37-7.43 (m, 1H) 7.43-7.53 (m, 2H) 7.75 (d, J=8.08 Hz, 1H) 7.84-7.94 (m, 1H) 8.46-8.56 (m, 1H); LC/MS: MS (ES+) m/e 444.2 [M+H]+.
Reaction SMILES: [P:1]([Cl:6])([Cl:5])([O:3][CH3:4])=[O:2].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[P:1]([Cl:6])([Cl:5])([O-:3])=[O:2].[CH3:4][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccncc1
Reactant: COP(=O)(Cl)Cl
Product: C[n+]1ccccc1
Product: O=P([O-])(Cl)Cl
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Anhydrous pyridine (10 mL, Aldrich, Milwaukee, Wis.) was cooled in an ice bath and methyl dichlorophosphate (1.488 g, 10 mmol, Aldrich, Milwaukee, Wis.) was added dropwise. The mixture was kept cold for a further 15 min. During this period a precipitate of N-methylpyridinium dichlorophosphate formed. 1-Adamantane ethanol (4.758 g, 26.4 mmol, Aldrich, Milwaukee, Wis.) was added, and the sealed mixture was stirred overnight at room temperature. It was then poured into 10% NaHCO3 solution (50 mL) and the pyridine was evaporated under vacuum. The slightly yellow solid was dissolved in 1 L of water and extracted with ether (three 150 mL portions). The aqueous phase was acidified with 2 N HCl to pH 1, and then extracted with three 150 mL portions of CHCl3:n-BuOH (7:3). The combined organic layer (ether and CHCl3:n-BuOH) was washed with water and a slightly yellow precipitate was formed in the mixed solvents, at which point the solvents were evaporated under vacuum A slightly yellow solid was formed and was recrystallized from acetone/hexane. The solid was dried under vacuum, yield 60%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12]C(=O)OC(C)(C)C)[CH2:6]2)#[N:2].[ClH:20]>O1CCOCC1.CCOCC>[ClH:20].[NH2:12][CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C#N)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CC(N)C2
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl (5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (1.85 g, 7.18 mmol) in dioxane (30 mL) at room temperature was added HCl in dioxane (18 mL of a 4.0 M solution; 72 mmol). The mixture was stirred for ca. 18 hr and diluted with ether. Solids were collected by filtration and rinsed thoroughly with ether, affording the title compound as a tan solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.65 (s, 1H), 7.59 (d, 1H, J=7.9 Hz), 7.46 (d, 1H, J=7.9 Hz), 4.14 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.04 (m, 1 H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 1,4-diiodobenzene (24.7 g), propargyl alcohol (1.68 g), BTPC (0.21 g) and CuI (28 mg) in diethylamine (180 ml) was stirred at room temperature under nitrogen for 18 h. The solvent was evaporated in vacuo at 35°, the residual solid taken up in MC (200 ml) and the solution washed with 2N hydrochloric acid (150 ml). The aqueous phase was extracted with further MC (75 ml), the organic layers combined, dried and purified by FCC eluting with EA-CX (1:6) and then EA-CX (1:3) to yield the title compound as fawn crystalline solid (4.9 g) m.p. 101°-102°.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].CC([O:19]O)(C)C.[OH-].[Na+].CCOCC.O>CO>[CH:2]([C@@H:3]1[O:19][C@H:4]1[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:1]
Reactant: COC(=O)c1cccc(/C=C/C=O)c1
Reactant: CC(C)(C)OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc([C@@H]2O[C@H]2C=O)c1
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
Methyl 3-(3-oxo-1E-propenyl)benzoate (0.67 g, 3.52 mmol) and 10 ml of methanol was added dropwise to 0.58 ml of 70% 1,1-dimethylethylhydroperoxide (4.2 mmol) in 5 ml of methanol. The pH was maintained at pH 8.0-8.5 throughout with 1N sodium hydroxide. The mixture was stirred at about 35° C. for 1.5 hrs. The reaction mixture was poured into ether/water and the ether layer was washed 3× with water and 1× with brine, dried over sodium sulfate, and concentrated. Flash chromatography using 10:1 followed by 2:1 hexane/ethyl acetate provided the product, methyl trans-3-(3-formyloxiranyl)benzoate as the pure trans epoxide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1.[CH3:30]C1N=C(C2C=C(C)C=CC=2)NC=1C=O.CC1N=C(C2C=CC=CC=2)NC=1C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][CH:25]=3)[NH:21][C:22]=2[CH3:23])[CH2:13][CH2:12]1
Reactant: Cc1cccc(-c2nc(C)c(C=O)[nH]2)c1
Reactant: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Nc2nc3ccccc3o2)CC1
Agent: Cc1nc(-c2ccccc2)[nH]c1C=O
Product: Cc1cccc(-c2nc(CN3CCC(Nc4nc5ccccc5o4)CC3)c(C)[nH]2)c1

Procedure:
The title compound was prepared according to the procedure described for the synthesis of example 325 (benzooxazol-2-yl-[1-(5-methyl-2-phenyl-1H-imidazol-4-ylmethyl)-piperidin-4-yl]-amine) using 5-methyl-2-m-tolyl-3H-imidazole-4-carbaldehyde ([CAS RN 68283-20-5] prepared as described in U.S. Pat. No. 4,107,307 (American Cyanamid Company)) instead of 5-methyl-2-phenyl-3H-imidazole-4-carbaldehyde. MS (ESI): 402.5 [M+H]+.
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>O.C(Cl)Cl>[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#CC=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (8.61 g, 22.54 mmol) and NaOH (1.127 g, 28.2 mmol) in water (24 mL) and DCM (12 mL) was added 4-(3-(trifluoromethyl)phenoxy)benzaldehyde (5 g, 18.78 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.07 g, 17.26 mmol, 92% yield) as pale yellow oil (slowly solidify to white solid). LCMS: rt=1.67 min, [M+H+]=290