Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:61][CH3:62])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:32]([NH:41]C(OC(C)(C)C)=O)=[N:33]C(OC(C)(C)C)=O)=[CH:26][C:25]=3[NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])=[O:51])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>C(Cl)Cl>[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67].[NH:31]([C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH2:9])=[NH:7])[S:11][C:12]=3[S:61][CH3:62])(=[O:16])=[O:17])[CH:19]=2)=[C:25]([NH:49][C:50]([NH:52][CH2:53][CH2:54][CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])=[O:51])[CH:26]=1)[C:32]([NH2:41])=[NH:33]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCCCS(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=N)N)cc2NC(=O)NCCCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a flask charged with [(4-{4′-(N′,N″-di-tert-butoxycarbonyl-guanidino)-2′-[3-(4-methanesulfonyl-butyl)-ureido]-6′-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (110 mg, 0.116 mmol) was added a solution of trifluoroacetic acid in DCM (3.0 mL, 50%) and stirred at ambient temperature for 1 h. The mixture was concentrated, and purified by HPLC (C18-column, 5–50% CH3CN in H2O over 15 min.) to give the title compound (63 mg, 62% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)C(C)C)(C)C.[C:32]1([C:38]2[O:42][N:41]=[C:40]([NH:43][C:44](=O)[O:45]C3C=CC=CC=3)[CH:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:44]([NH:43][C:40]2[CH:39]=[C:38]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:42][N:41]=2)=[O:45])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)on4)c3)c2cc1OC
Temperature: 50 °C
Yield: 32 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol), in tetrahydrofuran (1.5 mL) was treated with N,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from the previous step (126 mg, 0.45 mmol). The reaction mixture was heated to 50° C. for 2.5 h. After cooling to room temperature, the mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with dichloromethane and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (47.16 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 7.86 (d, 2H), 7.87-7.51 (m, 4H), 7.51-7.40 (m, 2H), 7.31-7.21 (m, 3H), 7.00 (d, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[ClH:11].[CH2:12](O)C>>[ClH:11].[CH:2]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:12][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OCCCc1ccccn1
Reactant: CCO
Agent: Cl
Product: OCCCC1CCCCC1
Reaction time: 16 h

Procedure:
To a stirred solution of compound 20 (5 g, 36.4 mmol) in ethanol (32 mL) was added concentrated HCl (3.2 mL) and the reaction mixture was degassed with N2 for 15 minutes. Platinum oxide (PtO2; 1 g) was then added and degassed for 5 minutes. Finally, the reaction mixture was hydrogenated at rt in a Parr apparatus for 16 hours under 45 psi H2 pressure. The reaction mixture was filtered through the Celite® reagent, and was washed with ethanol. The filtrate was concentrated to yield the crude product 21 which was used as such for the next step.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:13](N1C=C(C2C=CC=CC=2)C(C)=N1)[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:6]1[C:2]([CH3:1])=[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:5]1)[CH2:15][C:14]#[CH:13]
Reactant: Cc1[nH]ncc1-c1ccccc1
Reactant: C#CCCn1cc(-c2ccccc2)c(C)n1
Product: C#CCCn1ncc(-c2ccccc2)c1C
Yield: 42 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 5-methyl-4-phenyl-1H-pyrazole (515 mg, 3.25 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 255 mg (1.21 mmol, 42%) of 1-but-3-ynyl-5-methyl-4-phenyl-1H-pyrazole and 1-but-3-ynyl-3-methyl-4-phenyl-1H-pyrazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[N:11]1([C:14]2[S:15][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCC(=O)c1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 0.58 mmol 4-(5-propionyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml dioxane was added dropwise 8.76 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 90 min. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a white crystalline solid (yield 99%). MS (m/e): 226.4 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[C:31]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]2[CH:12]=1)(=[O:32])[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccncc1
Reactant: OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: O=C(OCc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1)c1ccncc1
Temperature: 25 °C

Procedure:
2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 30 mg, 0.094 mmol) and 4-pyridinecarboxylic acid (0.12 mmol) are dissolved in dimethylformamide (0.5 mL) and diethyl cyanophosphonate (35 mg, 0.2 mmol, 93% grade), followed by triethylamine (35 mg, 0.35 mmol) are added dropwise. The resulting solution is stirred at room temperature until the reaction is complete as determined by TLC and then diluted with hexane/ethyl acetate (30 mL of a 1:1 mixture) and washed with water (3×). The organic phase is then shaken with dilute hydrochloric acid. In cases were the hydrochloride salt of the product deposits at this stage it is filtered off, washed with water and then hexane and dried. If no deposit is observed, the acidic phase is separated, washed once with hexane/ethyl acetate (15 mL of a 1:1 mixture) and basified with saturated sodium bicarbonate solution. This is then extracted with dichloromethane (15 mL) five times and the dichloromethane solution dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (d6-DMSO) δ 5.43 (s, 2H), 7.15 (d, J=6.9 Hz, 1H), 7.25 (t, J=8.8 Hz, 2H), 7.30 (d, J=5.9 Hz, 2H), 7.50–7.53 (m, 2H), 7.84–7.87 (m, 3H), 8.55 (d, J=5.7 Hz, 2H), 8.79 (d, J=5.9 Hz, 2H), 8.82 (d, J=7.1 Hz, 1H); APESI-MS m/z 425 (M+1)+.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([NH2:37])=[N:27][CH:28]=[N:29][C:30]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:4]1([CH2:3][CH:2]([N:34]2[CH2:35][CH2:36][N:31]([C:30]3[N:29]=[CH:28][N:27]=[C:26]([NH2:37])[C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[CH2:32][CH2:33]2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Nc1ncnc(N2CCNCC2)c1-c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C(Cl)CN2CCC2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc(N2CCN(C(CN3CCC3)c3ccc(C(F)(F)F)cc3)CC2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
In a microwave vial containing 1-[2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-azetidine (32.26 mg; 0.12 mmol; 1.00 eq.) from last step in acetonitrile (2.00 ml) was added 5-(4-fluoro-phenyl)-6-piperazin-1-yl-pyrimidin-4-ylamine (33.43 mg; 0.12 mmol; 1.00 eq.), followed by DIPEA (0.06 ml; 0.37 mmol; 3.00 eq.). The clear solution was stirred at 60° C. overnight and then 75° C. for 3 h before the mixture was concentrated and purified with waters pre-HPLC. LC-MS: (M+1=501, obsd.=501)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:21]([OH:25])(=[O:24])[CH:22]=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]([C:6]1[CH:9]=[C:10]([CH:11]=[CH:12][C:5]=1[O:4][C:1](=[O:3])[CH3:2])[CH:23]=[CH:22][C:21]([OH:25])=[O:24])=[O:8]
Reactant: CC(=O)Oc1ccc(I)cc1C=O
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C
Yield: 58.8 %

Procedure:
2-Acetyloxy-5-iodobenzaldehyde (0.2 g, 0.69 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (0.673 ml, 4.82 mmol) and acrylic acid (0.095 ml, 1.38 mmol) are added dropwise with stirring, followed by 0.016 g of tri-o-tolylphosphine (0.069 mmol) and 0.008 of palladium(II) acetate (0.047 mmol). The mixture is heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is purified by column chromatography on silica gel, eluting with mixtures of ethyl acetate-hexane of increasing polarity. 3-Formyl-4-acetyloxycinnamic acid (0.095 g) is obtained as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1.I[CH3:35].[H-].[Na+]>CN(C=O)C>[CH3:35][O:1][CH:2]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:6]=[N:5]1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(Cn1ncc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1=O)c1ccccc1
Yield: 34.8 %

Procedure:
A mixture of the product from Example 441, 2-(2-hydroxy-2-phenylethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (210 mg, 0.45 mmol), iodomethane (56 μL, 0.90 mmol), and an 80% oil dispersion of sodium hydride (18 mg, 0.59 mmol) in anhydrous DMF (16 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and 2 N aqueous hydrochloric acid. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a yellow oil which was purified by column lo chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were combined and concentrated in vacuo , and the residue was triturated with hexanes to provide the title compound (yield: 75 mg, 34.7%). mp 135-137° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 3.26 (s, 3H), 4.33-4.52 (m, 2H), 4.91 (dd, J=9 Hz, 3 Hz, 1H), 6.99 (t, J=9 Hz, 2H), 7.20 (dd, J=9 Hz, 3 Hz, 2H), 7.31-7.50 (m, 7H), 7.87 (s, 1H), 7.89 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 479 (M+H)+. Anal. calc. for C26H23FN2O4S: C, 65.25; H, 4.84; N, 5.85. Found: C, 64.98; H, 4.83; N, 5.81.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O.C(OCC)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][CH3:17]
Reactant: CCI
Reactant: Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(C)cc1Br
Yield: 81.7 %

Procedure:
To a solution of 2-bromo-4-methyl-phenol (1 g, 5.346 mmol) in acetone (10 mL) were added potassium carbonate (740 mg, 5.346 mmol) and ethyl iodide (868 μL, 10.69 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (5 mL) and water (2 mL). The product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine (1×5 mL) and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 2-bromo-1-ethoxy-4-methyl-benzene (940 mg, 82%).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C([Li])CCC.[CH3:33][C:34]([CH3:45])([CH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1)[CH:35]=O>CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1.CCCCCC.[Cl-].[Na+].O>[CH3:33][C:34]([CH3:45])([CH2:37][O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][O:40]1)/[CH:35]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(C)(C=O)COC1CCCCO1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(/C=C\CCCC(=O)O)COC1CCCCO1
Reaction time: 1 h
Yield: 151.5 %

Procedure:
To a suspension of 4.43 g (10 mmols) of (4-carboxybutyl)triphenylphosphonium bromide in 20 ml of hexamethylphosphorictriamide and 28 ml of tetrahydrofuran was added dropwise at 0°-5° C., and under argon, 12 ml of 1.6 M butyllithium in hexane. The reaction mixture turned deep red in color. After stirring for 1 hr. at room temperature, 1.08 g (5.86 mmoles) of 2,2-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]propanal (H. Marschall, et al., Chem. Ber. 107, 887 (1974)) in 3 ml of tetrahydrofuran was added. The resulting mixture was stirred for 17 hrs. at room temperature and then diluted with brine and extracted with hexane. The aqueous phase was acidified with a saturated solution of oxalic acid and extracted four times with ether. The ether extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo to yield 2.4 g of crude (Z)-7,7-dimethyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-5-octenoic acid which was subsequently converted into the methyl ester derivative by treatment with a freshly prepared ethereal solution of diazomethane. The crude ester (2.35 g), obtained after removal of the solvent, was chromatographed on a silica gel column. A mixture of hexane-ether (7:3) eluted 1.24 g (75.2%) of (Z)-7,7-dimethyl-8-[(tetrahydro-2H-pyran-2-yl)oxy]-5-octenoic acid methyl ester. This material was dissolved in 15 ml of methanol and treated with 0.5 ml of 2 N hydrochloric acid. The mixture was stirred for 3 hrs. at room temperature. Ca. 10 ml of methanol was evaporated in vacuo. The remaining solution was diluted with ether and poured into a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried (MgSO4), and concentrated under reduced pressure to yield 0.940 g of crude material. Chromatographic purification of the product on a silica gel column yielded 0.610 g (69.8%) of pure (Z)-8-Hydroxy-7,7-dimethyl-5-octenoic acid methyl ester (98.9% pure, by GC).
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:19][C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Product: C#CC(Nc1ccc(F)cc1)c1ccccc1
Reaction time: 12 h
Yield: 97 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and p-fluoroaniline (0.130 g, 1.17 mmol). The reaction was conducted at room temperature for 12 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 95/5. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.214 g, 96%). HPLC analysis indicated the enantiomeric excess of the product was 94% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=22.5 (major), 29.4 (minor) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.48-7.41 (m, 4H), 7.39-7.34 (m, 1H), 6.96-6.89 (m, 2H), 6.63-6.56 (m, 2H), 6.11 (ddd, J=16.8, 10.4, 6.0 Hz, 1H), 5.36 (dt, J=17.2, 1.2 Hz, 1H), 5.31 (dt, J=10.0, 1.2 Hz, 1H), 4.95 (d, J=5.6 Hz, 1H), 4.02 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 155.76 (d. J=234 Hz), 143.44 (d, J=2.3 Hz), 141.61, 128.71, 127.45, 127.03, 116.03, 115.44 (d, J=22.1 Hz), 114.30 (d, J=8.4 Hz), 61.36. Anal. Calcd for C15H14NF: C, 79.27; H, 6.21; N, 6.16; F, 8.36. Found: C, 79.16; H, 6.24; N, 6.24; F, 8.46.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.[N:30]1([O:39][C:40](N(C)C)=[N+](C)C)[C:34]2C=CC=CC=2N=N1.Cl.CNOC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:30]([O:39][CH3:40])[CH3:34])=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(Cl)nc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
To a solution of 2-Amino-6-chloro-nicotinic acid (4.99g, 28.965 mmol, Example 2) in anhydrous N,N-dimethylformamide (50 mL) were added 1-hydroxybenzotriazole hydrate (6.21g, 40.57 mmol, Advanced ChemTech) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (15.38 g, 40.5648 mmol, Aldrich) at 0° C. A solution of N,O-dimethylhydroxylamine hydrochloride (306 mg, 3.15 mmol, Aldrich) in anhydrous N,N-dimethylformamide (15 mL) was treated with N,N-diisopropylethylamine (8.28 g, 64.1 mmol) and immediately added to the reaction which was stirred at 0° C. for ˜10 minutes then at room temperature for 4-5 hrs. The reaction was diluted with ethyl acetate (150 mL) and water (100 mL) and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with water (3×) and saturated sodium chloride, dried and concentrated. The crude product was purified on silica gel with 90/10→70/30 of hexanes/ethyl acetate to give 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (4.72 g, 21.92 mmol, 75.7 % yield). HRMS, observed: 215.0463, Calcd for M+: 215.0462.
Reaction SMILES: CN(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)C(=O)[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:9]([C:18]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(C2OC(=O)c3ccccc32)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
5 g of 3-(p-dimethylaminophenyl)-phthalide was dispersed into 20 cc of 10% aqueous solution of sodium hydroxide and the resultant mixture was heated at 90° C. for one hour with stirring to obtain a homogeneous solution. After cooling the solution to room temperature, 50 cc of 6% aqueous solution of potassium permanganate was dropped into the solution for about one hour. Then the solution was heated at 60° C. for one hour with stirring and cooled to precipitate manganese dioxide. The manganese dioxide was filtered off. Hydrochloric acid was added into the filtrate until the pH of the filtrate became 6.0 to precipitate pale yellow solid. The solid was filtered and then dried. The yield was 1.4 g. Recrystallization from a diluted aqueous solution of acetic acid gave benzophenone derivative represented by the following formula in the form of pale yellow crystals whose m.p. was 203° C. ##STR59##
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7]([CH2:9][CH3:10])=[CH:6]O[CH:4]1OC)[CH3:2].[N+:13]([O-])([O-])=O.[NH4+]>O.C(O)(=O)C.[N+]([O-])(O)=O>[CH2:1]([C:3]1[CH:4]=[N:13][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2]
Reactant: CCC1=COC(OC)C(CC)C1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCc1cncc(CC)c1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
170 parts of 3,5-diethyl-2,3-dihydro-2-methoxy-4H-pyran are dissolved in 25 parts of water, 300 parts of acetic acid and 2 parts of 60 percent strength nitric acid at 22° C. After 15 minutes, a solution of 88 parts of ammonium nitrate in 80 parts of water is added. The resulting solution is run into 800 parts of acetic acid at 110° C. in the course of 20 minutes, whilst stirring. The reaction mixture is left to cool, the acetic acid, water and methanol are distilled off, 200 parts of water are added to the residue and the solution is rendered alkaline with 25 percent strength ammonia solution. The 3,5-diethylpyridine is extracted with ether. Distillation gives 87 parts (64% of theory) of 3,5-diethylpyridine of boiling point 92° C./15 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-])=O.CC1C=CC=C([N+]([O-])=O)C=1N>>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Agent: Cc1cccc([N+](=O)[O-])c1N
Product: Nc1cccc2cn[nH]c12

Procedure:
Hydrogenation of 7-nitroindazole (prepared from 2-methyl-6-nitroaniline according to the literature procedures. Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D Org. Synth. Collect. Vol I, 20, 73-74.) gave 7-aminoindazole. This was reacted as above with 2-iodo-3-nitrobenzoic acid to give 2-(1H-indazol-7-ylamino)-3-nitrobenzoic acid (19%, crude). This was purified by treating with an ethereal solution of CH2N2 followed by chromatography on silica gel to give methyl 2-(1H-indazol-7-ylamino)-3-nitrobenzoate (72%); mp (EtOAc/n-hexane) 137-138° C.; 1H NMR [(CD3)2SO] δ 3.49 (s, 3 H, OCH3), 6.72 (br d, J=7.2 Hz, 1 H, ArH), 6.91 (t, J=7.7 Hz, 1 H, ArH), 7.17 (t, J=8.0 Hz, 1 H, ArH), 7.45 (d, J=8.0 Hz, 1 H, ArH), 8.07-8.12 (m, 2 H, 2xArH), 8.18 (dd, J=8.2, 1.5 Hz, 1 H, ArH), 9.45 (br s, 1 H, diphenylamine NH), 13.36 (br s, 1 H, indazole NH). Also isolated was methyl 2-8 (1-methyl-1H-indazol-7-yl)amino]-3-nitrobenzoate (3%); mp (EtOAc/n-hexane) 137-138° C.; 1H NMR [(CD3)2SO] δ 3.72 (s, 3 H, OCH3), 4.19 (s, 3 H, NCH3), 6.46 (d, J=7.2 Hz, 1 H, ArH), 6.83 (dd, J=8.2, 7.4 Hz, 1 H, ArH), 7.18 (t, J=8.0 Hz, 1 H, ArH), 7.30 (d, J=8.3 Hz, 1 H, ArH), 8.18-8.22 (m, 2 H, 2xArH), 8.34 (s, 1 H, ArH), 9.97 (s, 1 H, NH).