Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:17]([O:19][C:20](=[O:23])[CH:21]=O)[CH3:18]>C1(C)C=CC=CC=1>[CH2:17]([O:19][C:20](=[O:23])[CH:21]=[N:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:18]
Reactant: CCOC(=O)C=O
Reactant: C[C@@H](N)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=N[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1-phenyl-ethylamine (59 g, 0.49 mmol) dissolved in toluene (500 mL) was added sodium sulfate (173 g, 1.22 mmol) followed by oxo-acetic acid ethyl ester (134 g, 0.49 mmol, 50% in toluene) dropwise. The reaction mixture was stirred at RT for 1 h. The solid was filtered and the filtrate was concentrated under vacuum to provide ((R)-1-phenyl-ethylimino)-acetic acid ethyl ester, which was dissolved in DMF (300 mL) at RT. TFA (56 g, 0.49 mmol) was added dropwise at RT, followed after 10 min by cyclopenta-1,3-diene (65 g, 0.98 mmol) and water (0.25 ml). The mixture was stirred at RT overnight, concentrated under vacuum and the residue was poured into a 10% aqueous solution of NaHCO3 (500 mL). The solution was adjusted to pH 8 with solid Na2CO3, and extracted with EtOAc (3×80 mL). The combined organic layers were purified by silica gel chromatography (30:1-15:1 petroleum ether:EtOAc) to provide the title intermediate (35 g, 26% yield), as a colorless oil. (m/z): [M+H]+ calcd for C17H21NO2 272.16 found 272.2.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CCOCC>[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCCOCc1ccccc1
Reactant: Brc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: c1ccc(CCCCCOCc2ccccc2)cc1
Temperature: -5 °C
Reaction time: 2.5 h

Procedure:
Into a flask containing magnesium turnings (about 750 mg, about 31 mmol), ether (about 10 ml) was added, and then a small amount of iodine (about 1 mg˜about 5 mg) was added, and the resulting mixture was stirred for several min until it was colorless. Bromobenzene (about 100 ml, about 0.9 mmol) was added to the mixture and then heated to thus initiate the reaction. While the mixture was weakly refluxed, a mixture solution of bromobenzene (about 3.2 ml, about 30 mmol) and ether (about 50 ml) was added in droplets thereto for about 2.5 hours. The deeply browned mixture was stirred at ambient temperature for about 3 hours in a nitrogen atmosphere and then cooled in an ice-salt bath at about −5° C. To the mixture, a mixture solution of 5-benzyloxy-1-bromopentane (about 1.54 g, about 6 mmol) and ether (about 10 ml) was added in droplets. The resulting mixture was stirred for about 2 hours, cooled, heated to reflux for about 3 hours, and then cooled at ambient temperature. The above solution was poured onto ice water while being stirred, and hydrochloric acid (about 1 N) was added in droplets thereto. The pH thereof was maintained at about 4. The film was separated, after which the water-soluble film was extracted three times with methylene chloride. The organic layer was dried using MgSO4, filtered and concentrated to thus obtain brown oil, which was then subjected to column chromatography, yielding 5-phenylpentyl benzyl ether. A mixture of 5-phenylpentyl benzyl ether and methanol (about 50 ml) was blended with about 10% Pd/C catalyst, stirred for about 3 hours in a hydrogen atmosphere, and then filtered through a Celite pad. The filtrate was concentrated, thus obtaining 5-phenylpentylalcohol. Using 5-phenylpentylalcohol as a starting material, the same procedure as in Example 1 was performed, thereby obtaining the precursor compound 2 of the above formula.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10](O)[C:4]=2[CH:3]=1.S(Cl)([Cl:20])=O>CCOCC>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([Cl:20])[C:4]=2[CH:3]=1
Reactant: OC1c2ccccc2COc2ccc(Cl)cc21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1)C(Cl)c1ccccc1CO2
Temperature: 5 °C
Reaction time: 3 h

Procedure:
2-Chloro-11-hydroxy-6,11-dihydrodibenz[b,e]oxepin (12.75 g; 0.051 mole) is dissolved in dry ether (220 ml) and cooled to 5° C. under a dry nitrogen atmosphere. Thionyl chloride (6.76 g; 0.056 mole) in ether (20 ml) is slowly added dropwise while maintaining the temperature below 5° C. Upon completion of the addition, the reaction is brought to ambient temperature and stirred for three hours. Upon removal of the solvent in vacuo, the resulting solid is recrystallized from cyclohexane to give crystals of 2,11-dichloro-6,11-dihydrodibenz[b,e]oxepin, m.p. 125°-127° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>>[Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][CH2:16][O:17][C:21]2[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=2)[CH2:11][CH2:12][CH2:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CCCO)CCC1
Reactant: Clc1ccnc(Cl)n1
Product: CC(C)(C)[Si](C)(C)OCC1(CCCOc2ccnc(Cl)n2)CCC1

Procedure:
The title compound was prepared from 3-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]-1-propanol and 2,4-dichloropyrimidine using the same experimental procedure as in example 25a. 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=6 Hz, 1H), 6.59 (d, J=6 Hz, 1H), 4.33 (t, J=6 Hz, 2H), 3.44 (s, 2H), 1.81-1.51 (m, 8H), 1.21 (m, 2H), 0.84 (s, 9H), −0.002 (s, 6H). GC-MS m/z 371 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30][CH2:29]2>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH:11]1[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]1)[CH2:31][CH2:30][CH2:29]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(Cl)ccc43)CC2C)cc1OC
Yield: 37.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 6-chloro-1,2,3,4-tetrahydroquinoline (614 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (216 mg, yield: 37%) as a colorless oil. (cis:trans=3.4:1)
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22]C=C)[C@@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([CH2:22][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:52])([F:25])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:46])([F:47])[F:45])[C:30]([OH:32])=[O:31])[C@@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[C@H]1c2ccc(OC)cc2SC[C@@]1(C)c1ccc(OC)cc1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@@H]1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3R,4R)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman resolved as Peak 2 in Example 17 and the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared in Example 3, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3R,4R)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[K+].[Br-].[O-]Cl.[Na+].O.C([O-])(O)=[O:16].[Na+].[OH-].[Na+]>C(Cl)Cl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CC1(C)N([O])C(C)(C)CCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:16])=[O:8]
Reactant: O=C([O-])O
Reactant: OCC1CCCCO1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.4 %

Procedure:
A solution of tetrahydropyran-2-methanol (15.63 g, 135 mmol) in DCM (280 mL) are cooled to 0° C. TEMPO (0.25 g, 1.59 mmol) is added, followed by Aliquat 336 (2.8 g, 6.93 mmol) and 0.5 M aqueous KBr solution (27 mL, 13.5 mmol). Under vigorous stifling a solution of NaOCl/water (pH 8.6, 960 mL) and NaHCO3 (57.6 g) is added dropwise. The reaction is allowed to warm to room temperature and stirred for 18 h. Sodium hydroxide (15 g) is added and the reaction mixture is washed with DCM (2×100 mL). The basic aqueous layer is carefully acidified with concentrated aqueous HCl solution (150 mL) and then extracted with ethyl acetate (8×250 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give a pale yellow oil, which is purified by distillation under reduced pressure (bp 144-146° C., 25 Torr) to give 6.74 g of tetrahydro-pyran-2-carboxylic acid. Yield: 35%; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.45-1.77 (4 H, m), 1.79-2.19 (2 H, m), 3.44-3.67 (1 H, m), 3.93-4.18 (2 H, m), 9.62 (1 H, br. s.)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:53](=[O:54])[C@H:49]([CH:50]([CH3:51])[CH3:52])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (679 mg) and N-(9-fluorenylmethoxycarbonyl)-L-valine (865 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH:14]=[C:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(O)=O>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH2:19][CH3:20])[CH2:14][CH:13]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Agent: [Pd]
Solvent: O=CO
Product: CCN1CC(Cc2ccc(C(=O)OC)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Temperature: 80 °C
Yield: 73.7 %

Procedure:
Palladium-on-carbon (10% w/w, 0.5 g.) was added to a mixture of methyl 4-[5-(2-cyclopentylacetamido)-1-ethylindol-3-ylmethyl]-3-methoxybenzoate (0.5 g., prepared as described in Example 80), and formic acid (99%, 20 ml.), under an atmosphere of nitrogen. The mixture was vigorously stirred and heated at 80° C. for one hour. The cooled mixture was filtered through a pad of diatomaceous earth, the filter cake washed with methanol, and the filtrate evaporated. The resulting oil was dissolved in ethyl acetate (30 ml.) washed with water, brine, then dried (MgSO4) and evaporated. The product was purified by flash chromatography on silica gel (4 cm. diameter column), eluting with 2:3 v/v ethyl acetate:hexane, to give the title compound (0.37 g., 80%) as a foam; NMR (250 MHz, DMSO-d6): 1.04(t,3H, --CH2CH3); 1.15(m,2H, cyclopentyl ring); 1.4-1.8(m,6H, cyclopentyl ring); 2.2(m,3H); 2.7(dd,1H); 2.85-3.2(m,5H); 3.45(m,1H); 3.86(s,3H, OCH3); 3.87(s,3H, OCH3) 6.43(d,1H); 7.20 (m,2H); 7.30(d,1H); 7.50(m,2H); 9.47(s,1H, NH).
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].Br[C@H:21]1[O:38][C@H:37]([C:39]([O:41][CH3:42])=[O:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25]>>[C:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:7]=[N:6][C:5]=1[O:19][C@@H:21]1[O:38][C@H:37]([C:39]([O:41][CH3:42])=[O:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]1[O:23][C:24](=[O:26])[CH3:25])(=[O:3])[NH2:2]
Reactant: COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Product: COC(=O)[C@H]1O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Following a procedure similar to that of Example 1 but using 1.442 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 4.37 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranuronate there was obtained methyl 1-O-[5-carbamoyl-1-(4-nitrobenzyl)imidazole-4-yl]-2,3,4-tri-O-acetyl-β-D-glucopyranuronate. The resulting product as such was used as the starting compound in the following Example 19.
Reaction SMILES: [O-]CC.[Mg+2].[O-]CC.[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([OH:12])=O.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+:44]>CO.C(OCC)(=O)C.C1COCC1>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:10]([O-:12])=[CH:9][C:8]([O:14][CH2:15][CH3:16])=[O:13].[Na+:44]
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: CCOC(=O)CC(=O)O
Agent: CC[O-]
Agent: C[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C=C([O-])c1cc(OC)ccc1OC
Temperature: 45 °C
Reaction time: 20 h

Procedure:
A 20-L reaction vessel was charged with magnesium ethoxide (3.61 moles; 413.52 g) and THF (6.6 L), and the resulting mixture was stirred as ethyl hydrogen malonate (7.23 moles; 888.89 mL; 994.67 g; diluted with 20 mL of THF) was added and the mixture was heated at 45° C. for 4 hours. Meanwhile, a 20 L reactor was charged with 2,5-dimethoxybenzoic acid (3.29 moles; 600.00 g) and THF (3.6 L). To this mixture stirring at room temperature was added 1,1′-carbonyldiimidazole (3.61 moles; 585.98 g) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45° C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (6 L) followed by 2 N HCl (3 L). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (3 L), saturated sodium bicarbonate (3 L), and water (3 L). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (6 L) and concentrated again to afford an oil, which was transferred to a 20 L reaction vessel with 5 L of ethyl acetate and treated with sodium methoxide (3.45 moles; 793.00 mL of a 4.35 M solution in methanol). After stirring at room temperature for 3 hours, an additional 6 L of ethyl acetate was added and the solid collected by vacuum filtration and dried overnight in a vacuum oven at 40° C. to give 661 grams of the title product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:12][N:13]([CH3:17])[CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:25][C:20]1[CH:19]=[C:18]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:28]#[N:29])=[CH:8][CH:9]=3)[CH2:14][N:13]([CH3:17])[CH2:12]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cc(-c3ccccc3C#N)ccc2C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 90 °C
Yield: 63 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (100 mg, 0.23 mmol) which was prepared in Step G of Example 11, 2-cyanophenylboronic acid (51 mg, 0.35 mmol) and cesium carbonate (225 mg, 0.69 mmol) in water (1 mL) and N,N-dimethylformamide (2 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (8 mg, 0.01 mmol) was added. The mixture was degassed again and then heated to 90° C. for 3 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was partially purified by preparative thin-layer chromatography (1:4 hexanes/ethyl acetate) to give 2-(4-(3,4-dichlorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)benzonitrile (57 mg, 63%) as a brown solid: ESI MS m/z 393, 395 [M+H]+.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([OH:35])=O)[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([NH:2][CH3:1])=[O:35])[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]
Reactant: COc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
HATU (0.606 g, 1.594 mmol) was added to a solution of 6-methoxy-5-nitropicolinic acid (Preparation 190, 0.243 g, 1.226 mmol), DIPEA (0.320 mL, 1.840 mmol) and 2M methylamine solution in THF (1.2 mL, 2.453 mmol) in THF (3.3 mL). The reaction mixture was stirred at room temperature for 3 hours. Further methylamine (0.6 mL) was added and the mixture was stirred for 18 hours. The reaction was quenched with water and concentrated in vacuo. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed twice with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 99/1 to 90/10 to afford the title compound as a yellow solid (182 mg, 70%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1>O1CCCC1>[N:17]1[N:16]=[C:15]([NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[NH:19][CH:18]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: Nc1nc[nH]n1
Solvent: C1CCOC1
Product: O=C(Nc1nnc[nH]1)c1ccc2ccccc2c1
Yield: 63 %

Procedure:
A mixture of 2-naphthyl carboxylic acid (3.0 g, 17 mmol) and N,N'-carbonyldiimidazole (3.1 g, 19 mmol) in dry tetrahydrofuran (75 ml) was stirred at reflux temperature for 1 h. To the cooled reaction mixture was added 3-amino-1,2,4-triazole (1.5 g, 17 mmol) and the resulting mixture was refluxed for 2.5 h. The cooled reaction mixture was quenched with water (150 ml) and the precipitate was filtered off and washed with water (2×20 ml), heptane (2×20 ml) and diethyl ether (2×20 ml), dried in vacuo at 50° C. affording 2.55 g (61%) of the title compound as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)=[N:12][C:11]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.OO.C(=O)([O-])[O-:32].[K+].[K+]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:19]([NH2:20])=[O:32])=[CH:21][CH:22]=4)=[N:12][C:11]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(-c2nc(-c3ccccn3)c(-c3ccc4c(c3)OCO4)o2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: NC(=O)c1ccc(-c2nc(-c3ccccn3)c(-c3ccc4c(c3)OCO4)o2)cc1
Yield: 44 %

Procedure:
Prepared from 4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-oxazol-2-yl)-benzonitrile using hydrogen peroxide and methanolic potassium carbonate according to Example 16 and isolated in 44% yield. 1H NMR (DMSO) δ: 6.15 (2H, s), 7.08-7.16 (2H, m), 7.45-7.54 (2H, m), 7.95-7.99 (1H, m), 8.02 (1H, br. s), 8.08 (1H, br. s), 8.12-8.15 (2H, m), 8.22 (1H, dd, J=7 and 1 Hz), 8.48 (1H, d, J=8 Hz), 8.74 (1H, d, J=8 Hz); m/z (API) 386 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([CH3:29])=[N:20][O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)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>[CH3:29][C:19]1[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:21][N:20]=1
Reactant: Cc1noc(-c2ccccc2)c1Br
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)noc3-c3ccccc3)c(C)nc12
Temperature: 130 °C
Yield: 19.3 %

Procedure:
Using the procedure analogous to Example 257, 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90 mmol), 4-bromo-3-methyl-5-phenyl isoxazole (430 mg, 1.8 mmol), cesium carbonate (880 mg, 2.70 mmol) and PdCl2(PPh3)2 (25 mg) in DMF (5 ml) are combined and heated at 130° C. for 5 hrs to give the title compound (65 mg, 23% yield). ES-MS (m/z): calc'd for C23H26N4O: 374.5. found 375.1 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.50 (d, 2H), 7.31 (m, 3H), 6.69 (s, 1H), 3.39 (m, 1H), 2.48 (s, 3H), 2.20 (s, 6H), 2.33 (s, 3H), 1.84 (m, 4H), 0.88 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]=1[C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH3:2].Cl.[NH2:18][OH:19].C[O-].[Na+]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[C:7]=1[C:8]([CH3:12])([CH3:11])[C:9](=[N:18][OH:19])[NH2:10])[CH3:2]
Reactant: CCc1oc2ccccc2c1C(C)(C)C#N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1oc2ccccc2c1C(C)(C)C(N)=NO
Yield: 41 %

Procedure:
The above-named compound was prepared from 2-(2-ethyl-3-benzofuranyl)-2-methyl-propionitrile by the procedure described in Example 1(a), but using 1.5 mol of hydroxylamine hydrochloride and sodium methylate for each mole of 2-(2-ethyl-3-benzofuranyl)-2-methylpropionitrile and continuing the reaction for 72 hours. Yield: 41%; m.p. 118°-120° C. after recrystallization from a mixture of ethyl acetate and light petroleum ether.