Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:17]([C:16]1[CH:15]=[C:14]([CH:21]=[CH:20][CH:19]=1)[O:13][C:4]1[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])=[O:18]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(C#N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)c1
Yield: 35.4 %

Procedure:
4-Methyl-2-nitrobenzonitrile (0.50 g, 3.1 mmol), 3-hydroxybenzaldehyde (0.38 g, 3.1 mmol) and cesium carbonate (1.00 g, 3.1 mmol) were heated with stirring in dry DMF (5 mL) at 80° C. for 28 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 0.1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-phenoxy)-4-methyl-benzonitrile (0.26 g, 36%) as a brown resin, and was carried forward without further purification.
Reaction SMILES: C1(COC2C=C(C3OC=C(C[NH:20][C:21](=[O:29])[C:22]4[C:27]([OH:28])=[CH:26][CH:25]=[CH:24][N:23]=4)N=3)C=CC=2OC)CC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH3:39].O>C(#N)C.C(OCC)(=O)C>[CH2:37]([O:28][C:27]1[C:22]([C:21]([NH2:20])=[O:29])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:38][CH3:39]
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3O)co2)cc1OCC1CC1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOc1cccnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 g of N-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-hydroxypicolinamide obtained in Example 45 and 0.16 g of cesium carbonate were dissolved in 4 ml of acetonitrile, and 0.2 g of 1-bromopropane was added thereto and stirred overnight at room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water once, and further washed with saturated aqueous citric acid once. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, yielding 72 mg of white powdery N-2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-ylmethyl]-3-propoxypicolinamide.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.ClC1C=CC(C(N2C3C(=CC(OC)=CC=3)C(CC(O)=O)=C2C)=[O:24])=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:10]1([NH:9][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DCC (1.0 g, 4.84 mmol) was added to a stirred solution of the product of Example 13d (0.9 g, 4.40 mmol), 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2 methylindol-3-yl}acetic acid (1.57 g, 4.40 mmol), and DMAP (0.05 g) in CH2Cl2 (30 mL) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was removed by filtration and washed with CH2Cl2 (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 5:95 MeOH:CH2Cl2 to afford a green solid (contaminated with dicyclohexyl urea). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (1.85 g, 77%) as a viscous green oil. 1H NMR (300 MHz, CDCl3) δ 7.47-7.65 (mult, 4H), 6.84-6.91 (mult, 2H), 6.65 (dd, J=2.5 and 9.0 Hz, 1H), 4.29 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 3.61 (s, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.10-2.70 (mult, 10H); 13C NMR (75 MHz, CDCl3) δ 170.5, 168.2, 156.1, 139.2, 135.9, 133.9, 131.1, 130.7, 130.6, 129.1, 114.9, 112.2, 111.6, 101.3, 61.3, 57.5, 55.7, 51.4 (2C), 46.1, 36.6, 30.3, 13.3; mass spectrum (API-TIS) m/z 544 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:33][CH2:32]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:34]2[CH2:35][CH2:36][CH2:37][N:31]([C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:32][CH2:33]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(CS(C)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylsulfinylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH:7]([C@@H:9]1[C@@H:11]([C:12]([O:14][CH2:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([CH3:24])=[C:18]([F:25])[C:17]=2[F:26])=[O:13])[C:10]1([CH3:28])[CH3:27])=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH3:27][C:10]1([CH3:28])[C@H:9](/[CH:7]=[CH:1]\[CH3:2])[C@H:11]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([CH3:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]
Reactant: CC(C)(C)[O-]
Reactant: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=O)C2(C)C)c(F)c1F
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C\[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
A mixture of 1.1 g of ethyltriphenylphosphonium bromide and 30 ml of terahydrofuran was cooled by ice and 0.23 g of potassium tert-butoxide was added to the mixture under stirring. After 15 minutes, a tetrahydrofuran (5 ml) solution containing 0.32 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-3-formyl-2,2-dimethylcyclopropanecarboxylate was added to the mixture. After 30 minutes, the reaction mixture was filtered with celite and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give 0.22 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl(1R)-trans-2,2-dimethyl-3-((Z)-1-propenyl)cyclopropanecarboxylate
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1>>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH:48]2[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN1CCC(=O)CC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C2CCN(C)CC2)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound 60 (72.0 mg, 62.0%) was obtained in the same manner as that in Example 10, by using compound 1 (100 mg, 0.167 mmol) obtained in Example 1, and 1-methylpiperidin-4-one (Aldrich; 0.205 mL, 1.67 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1.[H-].[Al+3].[H-].[H-].C1C[O:34]CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[O:34])=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Agent: [Al+3]
Agent: [H-]
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C=O)cc3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-[6-amino-8-methoxy-2-(2-methoxyethoxy)purin-9-ylmethyl]benzonitrile (100 mg) is dissolved in dry THF (3 mL) and cooled to 0° C. under argon. The aluminum hydride reagent generated above (0.72 mL) is added to the reaction flask and the mixture is stirred at 0-5° C. for 1 hour and then quenched by addition of 3 M HCl. The mixture is then extracted with ethyl acetate and then dichloromethane and concentrated in vacuo to yield 85 mg. NMR is consistent with structure assignment.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH3:11][C:12]([CH3:23])([CH3:22])[CH2:13][CH2:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17].[SiH4]>C(O)C.O1CCCC1>[CH2:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Si:15]([CH2:14][CH2:13][C:12]([CH3:23])([CH3:22])[CH3:11])([O:18][CH3:19])[O:16][CH3:17])[CH3:10]
Reactant: CCc1ccccc1Br
Reactant: CO[Si](CCC(C)(C)C)(OC)OC
Agent: [Mg]
Agent: [SiH4]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccccc1[Si](CCC(C)(C)C)(OC)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
Under an atmosphere of dry nitrogen a magnetically stirred suspension of anhydrous tetrahydrofuran (Aldrich, 300 mL) and magnesium turnings (Aldrich, 1.2 g, 49 mmol) was treated dropwise at room temperature with 1-bromo-2-ethylbenzene (Aldrich, 6.1 mL, 44 mmol). After minutes the reaction mixture began to reflux mildly. After the addition was complete the reaction mixture was heated to reflux overnight (18 h). A separate flask was flushed with dry nitrogen and then charged with anhydrous tetrahydrofuran (Aldrich, 100 mL) and 3,3-dimethylbutyl-trimethoxysilane (Huls, 11.4 mL, 49 mmol). The Grignard solution was cooled to room temperature and then added to the silane solution at room temperature via stainless steel cannula. The reaction mixture stirred at room temperature overnight (18 h). Ethyl alcohol (Aldrich, 5 mL) was added to quench any remaining Grignard. The reaction mixture was concentrated on a rotary evaporator and distilled in vacuum to give 3.7 g (30%) of the title compound as a colorless oil (b.p. 107–108° C. at 0.5 mm Hg, 99% GC-purity): C16H28O2Si (Mw=280).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:16][C:17]([NH:20][C:21](=[O:29])[C@@H:22]([NH:27][CH3:28])[CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)[CH2:36][CH:37]([CH3:39])[CH3:38].[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:30][CH:31]=[C:32]([CH3:33])[CH3:34])[CH2:16][C:17]([NH:20][C:21](=[O:29])[C@@H:22]([N:27]([CH3:43])[CH2:28][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:23][CH:24]([CH3:26])[CH3:25])([CH3:19])[CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN[C@@H](CC(C)C)C(=O)NC(C)(C)CN(CC=C(C)C)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)CC=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=CCN(CC(C)(C)NC(=O)[C@H](CC(C)C)N(C)CCC(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid {2-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-1,1-dimethyl-ethyl}-amide (XIa, 0.67 mmol) was dissolved in CH2Cl2 (10 mL), treated with isovaleraldehyde (60.2 mg, 0.7 mmol), and stirred for 30 minutes. The reaction was cooled to 0° C. and NaBH(OAc)3 (212 mg, 1 mmol) was added. The mixture was stirred at room temperature for 15 hours, then washed with saturated sodium bicarbonate solution and concentrated. The residue was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Temperature: -25 °C
Reaction time: 4.5 h
Yield: 115.9 %

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonium fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 minutes. It is filtered through Celite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine is added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO, and 1.6 g (10 mmol) of pyridine SO3.complex is added in portions over 10 minutes. It is stirred over 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-(trifluoromethyl)benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclobutylethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.81, 7.66, 7.51, 7.34, 3.86-3.66, 3.40-3.34, 2.33, 2.03, 1.86-1.57. 13C NMR (75 MHz, CDCl3) δ 166.0, 162.8, 159.8, 145.5, 138.9, 135.9, 129.8, 128.5, 127.5, 127.3, 125.6, 125.2, 112.7, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 496.5 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[OH:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1O
Reaction time: 24 h
Yield: 42.4 %

Procedure:
2-Benzyloxyphenol (5.00 g, 25.0 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (2.30 g, 27.5 mmol). The addition of sulfuric acid (3 l mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (2.6 g, 43%). 1H NMR (CD3COCD3): d 7.70 (d, 1H), 7.50-7.28 (m, 5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:25]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C1CC1(F)F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CC3(F)F)ncc2c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (103.2 mg, 0.4090 mmol), 2,2-difluorocyclopropanecarboxylic acid (79.6 mg, 0.652 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (326.5 mg, 0.6298 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.055 mmol). The reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, and filtered through a plug of silica gel, which was rinsed with ethyl acetate, and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 106.4 mg (73%) of 2,2-difluoro-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=5.701, M+H=357.1, Method=E; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.7 Hz, 2H), 3.07 (d, J=10.0 Hz, 1H), 2.25 (s, 3H), 2.07 (s, 2H).
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[CH3:22][N:23]([CH2:24][CH2:25][S:1][C:2]1[S:6][C:5]([S:7][CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:10]2(=[O:12])=[O:11])=[N:4][N:3]=1)[CH3:27]
Reactant: CN(C)CCCl
Reactant: O=C1c2ccccc2S(=O)(=O)N1CSc1nnc(S)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCSc1nnc(SCN2C(=O)c3ccccc3S2(=O)=O)s1
Yield: 57.6 %

Procedure:
Following a procedure similar to that described in Example 33A above, 1.72 g (0.005 mol) of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with 1.44 g (0.01 mol) of 2-dimethylaminoethyl chloride hydrochloride in 10 ml of DMF in the presence of 1.72 g (0.017 mol) of triethylamine to give 1.2 g (58%) of 2-(5-[2-(N,N-dimethylamino)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin, mp 90.5°-91.5° C. (from ethyl acetate).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Se](=O)=O.[CH:13]1[CH:18]=[C:17]([C:19]([OH:21])=O)[C:16](O)=CC=1.[C:23](OO)(C)([CH3:25])[CH3:24]>ClCCl.C1C=CC=CC=1>[OH:21][CH2:19]/[C:17](/[CH3:16])=[CH:18]/[CH2:13][C:7]1([CH2:25][CH:23]=[CH2:24])[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC(C)(C)OO
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: c1ccccc1
Product: C=CCC1(C/C=C(\C)CO)C(=O)NC(=O)NC1=O
Reaction time: 12 h

Procedure:
To a solution of the 100 mg dienic barbituric acid prepared according to the immediately preceding Example, in 1 mL dichloromethane, was added 9 mg (84 μmol) selenium dioxide, 6 mg (42 μmol) salicyclic acid, and 0.29 mL (1.09 mmol) of a 3.8M solution of t-butylhydroperoxide in benzene. The solution was stirred well for 12 hr and concentrated. Chromatography on a 1×14 cm column, packed with 30% ethyl acetate/hexane and eluted with 25 mL each of 40%, 50%, 60%, and 70% ethyl acetate/hexane provided 21 mg of the desired
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[S:11][C:12]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[N:14]=1>O1CCCC1>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[S:11][C:12]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[N:14]=1
Reactant: c1c[nH]cn1
Reactant: BrCc1nc2c(ccc3ccccc32)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)ccc1sc(Cc3ncc[nH]3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
0.06 g of sodium hydride (60%) was added to a solution of 0.10 g of imidazole in tetrahydrofuran (30 ml). After 30 minutes of stirring at room temperature, a solution of 2-bromomethylnaphtho[1,2-d]thiazole in tetrahydrofuran (10 ml) was added to the solution. After stirring at room temperature for 1 hour and evaporation of the solvent, the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was extracted with 1N hydrochloric acid. The combined aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated to obtain 0.27 g (100%) of 2-(1-imidazolylmethyl)naphtho[1,2-d]thiazole. This free base was dissolved in methanol and mixed with 0.10 g of fumaric acid to effect crystallization to give 0.32 g of fumarate.