Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:30])[C@@H:10]([OH:29])[CH:11]=[CH:12][C:13]1[C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[Si:1]([O:8][C@@H:9]([CH3:30])[C@@H:10]([OH:29])[CH2:11][CH2:12][C:13]1[C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)C=Cc1cccc2oc(-c3ccc(Cl)cc3)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc2oc(-c3ccc(Cl)cc3)nc12
Reaction time: 0.33 h
Yield: 103.4 %

Procedure:
A mixture of (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)-4-benzoxazolyl]-1-penten-3-ol (P0005; 385 mg) and 10% Pd—C (77 mg) in EtOAc (19 ml) was stirred under hydrogen atmosphere at atmospheric pressure for 20 min. Pd—C was removed by filtration and the filtrate was evaporated to give a colorless oil of (3S,4S)-4-(tert-butyldimethylsilyloxy)-1-[2-(4-chlorophenyl)4-benzoxazolyl]pentan-3-ol (P0006; 0.40 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O-:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:26]([OH:31])=[CH:27][CH:28]=[C:29]([CH3:30])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[C:32]([O:31][C:26]1[C:8]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]=2[C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2C(=O)[O-])cc1
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCc1nc2c(C)ccc(OC(=O)CCC)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 60 from 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and butyric acid chloride in pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.[Li+].CC([N-]C(C)C)C.C(C1C=CC=CC=1)C.[CH3:35][C:36]([CH3:40])([CH3:39])[CH:37]=[O:38]>C1COCC1.CCCCCCC>[OH:38][CH:37]([C:36]([CH3:40])([CH3:39])[CH3:35])[CH2:17][C:8]1[C:7]2[CH:18]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:10][C:9]=1[C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C=O
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(C)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(O)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.23 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 10 mL anhydrous THF at −78° C. under nitrogen was added 0.93 mL 2 M LDA in heptane, THF, and ethylbenzene. After 15 minutes, 0.160 g trimethylacetaldehyde was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 30 minutes, evaporate the reaction mixture under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 75˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, J=9.2 Hz, 1H), 7.12 (dd, J=2.7 & 9.1 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 3.89 (s, 3H), 3.48˜3.52 (br m, 1H), 3.40 (br d, J=7.0 Hz, 1OH), 3.10˜3.16 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H). LC-MS: 4.23 min. (m/Z=245.2, 315.2, 355.2=M+Na, 259.1). A faster-eluting isomeric side-product was also isolated during purification: 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one. 1H NMR (CDCl3, 500 MHz) 7.34 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.5 & 9.0 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 4.53 (s, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.84 (s, 3H), 1.32 (s, 9H), 1.06 (s, 9H). LC-MS: 3.77 min. (m/Z=355.2=M+Na, 315.2). The structures of the isomers were further confirmed by COSY and NOESY spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH3:31])=[C:26]([NH2:32])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]>>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]3[N:30]([CH3:31])[C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][N:6]=4)=[N:32][C:26]=3[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Reactant: CNC(=O)c1cc(Oc2ccc(NC)c(N)c2)ccn1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(-c2n[nH]c4ccc(F)cc24)n3C)ccn1

Procedure:
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid methylamide as described above in Example 4. LC/MS (m/z) 417.4 (MH+), Rt 3.62 minutes.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29](O)=[O:30])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][S:52](=[O:55])[CH2:51][CH2:50]2)[CH2:45][CH2:44]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29](=[O:30])[N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:50][CH2:51][S:52](=[O:55])[CH2:53][CH2:54]4)[CH2:47][CH2:48]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: O=S1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCS(=O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 1.21 from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 77 μL (0.55 mmol) triethylamine and 47 mg (0.17 mmol) 4-piperidin-4-yl-thiomorpholine-1-oxide (used as the bis-hydrochloride salt).
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N+:51]([O-])=O)[CH2:39][CH2:38]3)=[N:32][CH:33]=1)([O-])=O>[Zn]>[NH2:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH:40]1[CH2:39][CH2:38][C:37]2[C:42](=[CH:43][CH:44]=[C:35]([O:34][C:31]3[N:32]=[CH:33][C:28]([NH2:25])=[CH:29][CH:30]=3)[CH:36]=2)[O:41]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2[N+](=O)[O-])O3)nc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2N)O3)nc1

Procedure:
6-[2-(2-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 100 mg 5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine (Example 89(d)) and 700 mg of Zn. 1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, 1H, J 2.9 Hz), 7.15-7.18 (m, 1H), 7.05 (dd, 1H, J 8.6, 2.9 Hz), 6.98-7.00 (m, 1H), 6.77 (d, 1H, J 8.6 Hz), 6.73-6.75 (m, 2H), 6.66-6.71 (m, 2H), 6.56-6.61 (m, 1H), 5.11 (dd, 1H, J 10.4, 2.0 Hz), 5.01 (s, 2H), 4.99 (s, 2H), 2.94-2.99 (m, 1H), 2.66-2.74 (m, 1H), 2.06-2.13 (m, 1H), 1.88-1.95 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH2:24])=[C:19]([CH3:25])[CH:18]=1.O>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([NH:24][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:19]([CH3:25])[CH:18]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
3,3-Dimethylbutanoyl chloride (3.37 g, 3.5 mL, 25 mmol) and triethylamine (2.53 g, 3.5 mL, 25 mmol) were added to a solution of 4-bromo-2,6-dimethyl-phenylamine (5.0 g, 25 mmol) in acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was added to the mixture, and the precipitate which formed was collected to give the title compound as a powder (7.46 g, 100% yield).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:5]2)=[O:28])=[CH:30][CH:31]=1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc2c(c1)Cc1sccc1CN2
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(C(=O)N2Cc3ccsc3Cc3ccccc32)cc1

Procedure:
As described for Example 26, 4,10dihydro-5H-thieno[3,2-c][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[N:5]=1.[CH3:39]O>>[CH3:39][O:23][C:22]([C:16]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:8]3[CH:7]=[C:6]([NH:25][CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=4)[N:5]=[C:4]([O:3][CH3:2])[N:9]=3)[CH:11]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:24]
Reactant: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2cccc(-c3cc(NCCc4ccc(OC(F)(F)F)cc4)nc(OC)n3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane, 43.5 μL, 0.17 mmol) is added to a solution of N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid (45 mg, 0.09 mmol) in methyl alcohol (4 mL) and the reaction mixture is stirred overnight at 70° C. The reaction is cooled to room temperature, quenched with water. The volatiles are removed in vacuo. The aqeous is extracted twice with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluted with ethyl acetate/heptane to afford 4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester [86 mg, Example 84(b)]. LCMS: RT=2.48 minutes, MS: 532 (M+H). IC50=70 nM
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43](O)(=[O:45])[CH3:44]>O1CCCC1>[C:43]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:45])[CH3:44]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a stirred solution of 3β-hydroxy-5α-pregnan-20-one (4.5 g, 318.5 g/m, 14 mmol) in 150 mL of freshly distilled THF, triphenylphosphine (5.58 g, 262.3 g/m, 21 mmol), and acetic acid (1.22 mL) were added. To this stirred reaction mixture at room temperature was added a solution of diisopropylazidodicarboxylate (DIAD) (4.18 mL, 1.027 g/ml, 202.2 g/m, 21 mmol) in 75 mL of tetrahydrofuran dropwise over a period of 10 minutes. After 30 min., the reaction mixture was concentrated under reduced pressure and redissolved in 100 mL of chloroform and extracted twice with water. The chloroform extract was dried over magnesium sulfate and evaporated. The product residue was purified by flash chromatography on silica gel with a mixture of hexane/ethyl acetate (9:1). Fractions corresponding to the title compound were concentrated to give 4.95 g (97.5%) of 3α-acetoxy-5α-pregnan-20-one as a white solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:24]2[C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[O:30])=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.[C:46]1(O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:15]1([CH2:20][C:21]([N:23]2[CH2:27][C@H:26]([O:28][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:25][C@H:24]2[C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[CH:36][CH:37]=2)=[O:30])=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Oc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 60 °C
Yield: 2.2 %

Procedure:
Diisopropylazodicarboxylate (0.111 mL, 0.551 mmol) was added to a flask charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (233 mg, 0.551 mmol), prepared as in Reference 11, phenol (52 mg, 0.55 mmol), triphenylphosphine (145 mg, 0.551 mmol) and THF (3 mL). The reaction mixture was heated at 60° C. for 30 minutes and then concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 259, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-phenoxypyrrolidine-2-carboxamide (15 mg, 0.012 mmol, 5% yield), as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.17 (s, 1H), 8.45 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.37-7.32 (m, 2H), 7.21-7.17 (m, 2H), 7.04-6.95 (m, 7H). MS (EI) for C27H24FN5O4. found 502.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1nccn1CC(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccn1CC(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
A cooled (ice-bath) solution of 1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethanone (9.0 g, 41.3 mmol) in methanol (60 ml) was treated portionwise with sodium borohydride (1.56 g; 41.3 mmol) and the mixture stirred at ambient temperature for 16 hours. Most of the methanol was removed and water and ethyl acetate added. The organic layer was separated, the aqueous extracted with ethyl acetate (2×) and the combined organic extracts washed with water, brine, dried filtered and evaporated to give a residue which was triturated with diethyl ether to give 1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethanol (7.7 g, 84%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8].C(OCC)(=O)[CH2:17][C:18]([O:20]CC)=[O:19].[H-].[Na+].Cl>O1CCCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][CH2:17][C:18]([OH:20])=[O:19])=[C:7]([CH3:8])[O:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1CCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
4-Chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (1.21 g) was dissolved in tetrahydrofuran (50 ml) and added to a mixture of diethyl malonate (1.20 g), sodium hydride (60%, oil, 0.21 g) and tetrahydrofuran (20 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-chlorophenyl)-5-methyl-4-isoxazolyl]propionic acid (1.20 g, yield 90%). The crystals were recrystallized from ethanol. melting point: 187–188° C.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>>[CH3:30][NH:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 67 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 67%) was obtained as colorless crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[Cl:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)=[O:9]>CO>[Cl:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([C:17](=[N:2][OH:3])[NH2:18])=[CH:15][CH:16]=1)=[O:9]
Reactant: NO
Reactant: N#Cc1ccc(NC(=O)CCl)cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.16 g, 2.3 mmol) was added to a solution of potassium hydroxide (0.152 g, 2.3 mmol) in methanol and the mixture was stirred for 30 minutes and filtered. To the filtrate, compound of example 3 (0.3 g, 1.53 mmol) was added and reaction mixture was refluxed for 4 hours. After completion of reaction the mixture was cooled, concentrated and triturated with diethyl ether to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][O:8][C:4]=2[CH:3]=1.[N:17]1C=CC=C[CH:18]=1>Cl>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][O:8][C:4]=2[CH:3]=1)#[N:17]
Reactant: Clc1ccc2c(-c3ccccc3)coc2c1
Reactant: c1ccncc1
Agent: Cl
Product: N#Cc1ccc2c(-c3ccccc3)coc2c1
Temperature: 200 °C

Procedure:
A mixture of 76.2 g of 6-chloro-3-phenylbenzofuran, 34.1 g of cuprous cyanide and 28 ml of pyridine is heated for about 125 hours at a temperature of 200° C. The mixture is then poured into a solution of 100 g of ferric chloride in 60 ml of concentrated hydrochloric acid and 300 ml of ice water. The mixture is extracted twice with diethyl ether, the ether extracts are washed with saturated sodium chloride solution and dried. The solvent is evaporated to provide the desired product, 6-cyano-3-phenylbenzofuran.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1ccccc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1CNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
25 g (0.177 mole) of 1-Flouro-2-nitrobenzene is added to a 500 ml round bottom flask containing a solution of 200 ml of anhydrous DMF and 24.28 g (0.177 mole) of 2-Methoxybenzylamine. 73.27 g (0.531 mole) of K2CO3 is added and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered through celite and washed with 400 ml of ethyl acetate. The filtrate is then washed twice with 200 mL saturated brine and twice with 200 mL water. The organic layer is dried over anhydrous Na2SO4 concentrated in vacuo to afford 32 g (0.13 mole, 76%) of (2-methoxy-benzyl)-(2-nitro-phenyl)-amine (1). 1H NMR (400 MHz, DMSO) 8.6 (m, 1H), 8.0 (m, 1H), 7.4 (m, 1H), 7.2 (m, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 6.6 (m, 1H) 4.6 (m, 2H), 3.8(s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:25])[N:9]=2)=[CH:4][CH:3]=1.F[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:25][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(-c2nc3cccc(N)c3nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc3cccc(Nc4ccc([N+](=O)[O-])cc4)c3nc2-c2ccc(C)cc2)cc1
Reaction time: 20 h

Procedure:
While agitating 3.0 g (9.2 mmol) of 2,3-di(4-methyl-phenyl)-5-aminoquinoxaline, 1.4 g (9.9 mmol) of 4-fluoronitrobenzene and 100 ml of dimethylsulfoxide, 3.4 g (30.3 mmol) of t-butoxy potassium was gently added. After completion of the addition, the reaction container was purged with nitrogen, followed by agitation at room temperature for 20 hours. After completion of the reaction, 100 ml of water was added while cooling, and an organic phase was extracted by use of a chloroform solvent, followed by concentration to obtain the intended product.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=[N:20][OH:21])[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[C:13]12[CH2:12][N:4]([C:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11])[CH2:1][CH:2]1[CH2:3][O:21][NH:20]2
Reactant: C=CCN(CC(=NO)c1cnccn1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CONC2(c2cnccn2)C1
Yield: 77.7 %

Procedure:
A solution of tert-butyl N-allyl-N-(2-hydroxyimino-2-pyrazin-2-yl-ethyl)carbamate (6.6 g, 22.58 mmol) in toluene (80 mL) is stirred at 120° C. for 22 hours. The reaction is cooled and the solvent is evaporated under reduced pressure. The crude product is purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (5.13 g, 74%). ES/MS (m/e): 293 (M+1).