Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)#[N:2].Cl.N1C=CC=CC=1.[C:34]([O:37][C:38](C)([CH3:42])[C:39](Cl)=O)(=[O:36])[CH3:35]>O1CCOCC1>[C:34]([O:37][C:38]([CH3:42])([CH3:39])[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:3]=1[C:1]#[N:2])=[O:19])(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)C(=O)NCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of tert-butyl 6-(2-cyano-3-nitrophenoxy)hexylcarbamate (333 mmol, 121 mg) (Example 225c) in dioxane (2 mL) was added con. HCl (1 mL). After 15 minutes, the solution was concentrated in vacuo and dried on high vacuum. The crude HCl salt was suspended in DCM (dry, 10 mL) and treated with pyridine (2.664 mmol, 62 μL) and 1-chloro-2-methyl-1-oxopropan-2-yl acetate (1.332 mmol, 193 μL). The reaction mixture was refluxed under a nitrogen atmosphere until clear (6 h), then cooled to room temperature and the volatiles removed in vacuo. The residue was purified on silica gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH2:8](O)[C:9](C)([CH3:11])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:9]([CH3:11])([CH3:10])[CH2:1][O:2]/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6]
Reactant: COC=CC(C)=O
Reactant: CC(C)(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)/C=C/OCC(C)(C)C
Temperature: 27.5 °C
Reaction time: 14 h

Procedure:
House vacuum was applied to a mixture of 4-methoxy-3-buten-2-one (14.0 g, 140 mmol) (Fisher Scientific), neopentyl alcohol (18.0 g. 200 mmol), pyrimidium p-toluenesulfonate (0.45 g, 1 mmol) and toluene (50 mL). This was stirred at 25-30° C. for 14 h. All solvent and volatiles were removed by vacuum and the residue was dissolved in hexane (75 mL). This was purified by chromatography (30% ethyl acetate/hexane) to give (E)-4-(2,2-dimethylpropoxy)but-3-en-2-one.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[C:23](C)[N:22]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:41](O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[C:26]([CH3:41])=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:39][CH:40]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cncc([C@H]2C[C@@](CC(C)C)(C(=O)OC(C)(C)C)N(C(=O)c3ccc(C(C)(C)C)cc3)[C@H]2c2nccs2)n1
Reactant: O=C(O)C(F)(F)F
Product: Cc1nccnc1[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)cc2)[C@H]1c1nccs1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: Cc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C

Procedure:
2-Methylbenzothiazole (22 g) in conc. sulfuric acid (80 ml) was cooled to −5° C. A mixture of conc. sulfuric acid (12 ml) in conc. nitric acid (20 ml) was added so as to maintain the temperature below 5° C. (ca. 1.5 hours). After this time the mixture was allowed to warm to room temperature and the solution poured onto ice to give a yellow precipitate. The solid was removed by filtration and recrystallised from ethanol. After filtration the solid was washed with ethanol and dried in a vacuum oven to give 18 g of the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25](OCC)=O)[CH2:20][CH2:19]2)[CH:9]=1.C[Si](C)(C)CCOC[N:46](COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC#N)CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:38][Si:2]([CH3:39])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:19][CH2:20][CH:21]([CH2:24][C:25]#[N:46])[CH2:22][CH2:23]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2ccnn12
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2c(I)cnn12

Procedure:
2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1.[Li+].[OH-]>O1CCOCC1>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(F)c(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1c(Br)nc2cc(F)c(F)cc21
Yield: 35 %

Procedure:
2-Bromo-5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.88 g, 1.8 mmol), 20 ml dioxane and 7 ml (7 mmol) of 1 M aqueous LiOH was used to prepare 2-bromo-5,6-difluoro-1-beta-D-ribopyranosyl-1H-benzimidazole (0.23 g, 0.63 mmol, 35% yield) according to General Procedure V; MS (ES+): m/z (rel. intensity) 388 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ7.83-7.79 (m, 1H), 7.73-7.68 (m, 1H), 5.62-5.60 (d, 1H, J=9.4 Hz), 4.10-4.08 (d, 1H, J=9.4 Hz), 3.97-3.95 (bs, 2H) 3.67-3.65 (d, 2H, J=8.2 Hz).
Reaction SMILES: [CH:1]12[CH2:18][CH:4]([CH:5]([NH:7]C(=O)OCC3C=CC=CC=3)[CH2:6]1)[CH2:3][O:2]2.[ClH:19]>CO.[Pd]>[ClH:19].[CH:1]12[CH2:18][CH:4]([CH:5]([NH2:7])[CH2:6]1)[CH2:3][O:2]2
Reactant: O=C(NC1CC2CC1CO2)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC1CC2CC1CO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (0.50 g, 2.0 mmol) and Pd/C (10%, 50 mg) in methanol (20 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After completion of the reaction, the reaction mixture was adjusted to pH around 4 by 1M HCl in methanol. The mixture was filtered through Celite® and concentrated under reduced pressure to give 2-oxa-bicyclo[2.2.1]heptan-5-amine hydrochloride (300 mg, 100% yield) as a solid. 1H NMR (500 MHz, CD3OD) δ 4.43 (s, 1H), 3.72-3.70 (m, 1H), 3.54 (d, J=7.5 Hz, 1H), 3.50-3.48 (m, 1H), 2.76 (s, 1H), 2.20-2.15 (m, 1H), 1.96 (d, J=11.0 Hz, 1H), 1.78 (d, J=11.0 Hz, 1H), 1.61 (d, J=11.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]([CH3:18])[CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:5].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:18][N:6]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:5])[C:3]1[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=1[C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1-c1ccncc1
Yield: 32.8 %

Procedure:
A solution of 2-bromo-N-methyl-N-[(1-methyl-1H-indol-2-yl)methyl]benzamide (0.30 g, 0.84 mmole), pyridine-4-boronic acid (0.20 g, 1.63 mmole), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmole), and Cs2CO3 (1.10 g, 3.38 mmole) in 10:1 DME/H2O (25 mL) was degassed, then was heated under N2 overnight. The resulting mixture was concentrated in vacuo, and the residue was taken up in 10% NaOH solution. The mixture was extracted with CH2Cl2, and the combined organic extracts were washed with brine and dried (MgSO4). Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (98 mg, 33%) as a white solid: 1H NMR (300 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: 6 8.50-8.65 (m, 2H), 7.00-7.60 (m, 10H), 6.27 (s, 1H), 4.50-5.00 (m, 2H), 3.62 (s, 3H), 2.49 (s, 3H); for the minor rotamer: δ 8.65-8.75 (m, 2H), 7.00-7.60 (m, 10H), 6.12 (s, 1H), 4.50-5.00 (m, 2H), 3.41 (s, 3H), 2.86 (s, 3H); MS (ES) m/e 356 (M+H)+. Anal. Calcd for C23H21N3O.0.10H2O: C, 77.33; H, 5.98; N, 11.76. Found: C, 77.07; H, 5.98; N, 11.56.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][CH3:16])[CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][CH3:16])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CO[C@@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1

Procedure:
With the exception that N-t-butoxycarbonyl-trans-4-methoxy-L-prolinol, instead of N-t-butoxycarbonyl-L-prolinol, was used, the same procedure as in Preparation Example 1-1 was repeated to afford the title compound. 40.8 g (97%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[S:19][CH:20]=1>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[S:19][CH:20]=1
Reactant: CCCNc1ccc2ncc(Br)n2n1
Reactant: Cc1csc(B(O)O)c1
Product: CCCNc1ccc2ncc(-c3cc(C)cs3)n2n1
Yield: 16 %

Procedure:
Prepared from the product of step A and 4-methylthiophene-2-boronic acid according to general procedure 2 providing the title compound (30 mg, 16%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (s, 1H), 7.45 (m, 2H), 6.90 (t, J=1.1 Hz, 1H), 6.55 (d, J=9.6 Hz, 1H), 3.31 (t, J=7.1 Hz, 2H), 2.20 (s, 3H), 1.66 (sext, J=7.2 Hz, 2H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.5, 138.5, 137.6, 130.9, 127.7, 126.8, 125.7, 125.4, 121.4, 113.6, 44.8, 22.9, 15.6, 12.0; HPLC tR=13.5 min (Luna), 98.7%; ES-MS: (M+H)=273 m/z.
Reaction SMILES: [OH:1][CH:2]([C:16]1[N:20]([CH3:21])[CH:19]=[N:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1>O1CCOCC1.O=[Mn]=O>[CH3:21][N:20]1[C:16]([C:2]([CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:1])=[CH:17][N:18]=[CH:19]1
Reactant: Cn1cncc1C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
A homogeneous solution of tert-butyl 4-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)piperidine-1-carboxylate (32.2 g, 109 mmol, Intermediate 1: step a) in 1,4-dioxane (436 mL) was treated with MnO2 (47.6 g, 547 mmol) and stirred at 100° C. open to the air overnight (17 hours). Since the reaction was only ˜50% complete by NMR, the reaction was cooled to room temperature and additional MnO2 was added (48.0 g, 552 mmol) and the reaction stirred open to the air at 100° C. for 6.5 hours, then at room temperature for 18 days, then filtered through a pad of Celite® and the black filter cake washed with EtOAc. The crude filtrate was treated with a third portion of MnO2 (28.5 g, 327 mmol) and stirred at room temperature overnight. The reaction was then filtered as above and concentrated to provide the crude title compound as a clear dark yellow oil. This oil was purified by FCC with an EtOAc to 50% acetone/EtOAc gradient to provide the title compound as a clear dark yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1.[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([NH:17][C:18]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[O:19])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccnc(C2(C)CC2)c1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C2(C)CC2)c1
Reaction time: 14 h
Yield: 94.2 %

Procedure:
A mixture of 4-methyl-5-[2-(1-methyl-cyclopropyl)-pyridin-4-yl]-thiazol-2-ylamine (Step 40.2) (211 mg, 0.86 mmol) and 1,1′-carbonyldiimidazole (210 mg, 1.3 mmol, 1.5 eq) in DCM (10 mL) is stirred for 14 h at reflux and allowed to cool. The resulting precipitate is collected by filtration to provide 275 mg of the title compound as white solid: ESI-MS: 338.2 [M−H]−.
Reaction SMILES: [CH:1](C1C=CC(CN(C)C(=O)OCC2C=CC=CC=2)=CC=1)=O.C(=NC1C=CC=C2C=1COC2=O)C1C=CC=CC=1.C[O-].[Na+].CO.[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH3:78])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OCC)(=O)CC>[CH2:45]([O:52][C:53]([N:55]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([CH:64]2[C:73](=[O:74])[C:72]3[C:71]([C:75]([O:77][CH2:78][CH3:1])=[O:76])=[CH:70][CH:69]=[CH:68][C:67]=3[NH:66][CH:65]2[C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)=[CH:60][CH:59]=1)[CH3:56])=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Reactant: CN(Cc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Agent: C[O-]
Agent: O=C1OCc2c(N=Cc3ccccc3)cccc21
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of benzyl 4-formylbenzyl(methyl)carbamate (566 mg, 2 mmol) and 4-(benzylideneamino) isobenzofuran-1-one (474 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. A solution of sodium methoxide in methanol [sodium (184 mg, 8 mmol) in methanol (15 mL)] was then added dropwise. After the addition, the mixture was stirred at 25° C. for 18 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 10:1) to give a mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)-phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, yield 20%) as a light yellow solid. LC-MS (ESI) m/z: 535 (M+1)+ and 549(M+1)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:13]([CH:16]=[N:17]O)([CH2:14][OH:15])[O:12][C@@H:11]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][C:29]([O-])=[O:30].[Na+].C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[Si:1]([O:8][C@@H:9]1[C@@:13]([C:16]#[N:17])([CH2:14][O:15][C:29](=[O:30])[CH3:28])[O:12][C@@H:11]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=NO)(CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@@]1(C#N)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 4703.9 %

Procedure:
A solution of 3'-O-t-butyldimethylsilyl-4'-hydroxyiminomethylthymidine (1.98 g, 4.95 mM) the compounds of Formula 13, prepared, e.g., as described in Preparation 9) with NaOAc (7 mg, 0.09 mM) in Ac2O (7 ml) was stirred at 80° C. for 72 hours, allow to cool and treated with 10 g of ice followed by sat. NaHCO3. The solution was extracted CH2Cl2 (3×100 ml), and the organic phases were combined and dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by flash column chromatography silica gel eluting with (20% acetone/CH2Cl2) affording 3'-O-t-butyldimethylsilyl-4'-cyano-5'-O-acetylthymidine (1.7 g, 4.0 mM). MP 67°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:27]Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:27])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 400 mg, 75% of 4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide, 1H nmr (CDCl3 /300 MHz) 8.06 (s, 1H), 7.81(d, J=8.4 Hz, 2H), 7.53(d, j=8.4 Hz, 2H), 7.43(brs, 2H), 7.42(d, J=8.4 Hz, 2H), 7.32(d, J=8.4 Hz, 2H).
Reaction SMILES: CO.[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]>[C].[Pd].O1CCOCC1>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc([N+](=O)[O-])c(C)n2)c1C
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(N)c(C)n2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methanol (50 ml), 1,4-dioxane (200 ml) and 10% palladium-carbon (containing ca. 50% water; 5 g) were added to 5-methyl-1-(6-methyl-5-nitropyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (15 g) and the mixture was stirred under hydrogen atmosphere at room temperature for four hours. The reaction solution was filtered through Celite, the filtrate was concentrated in vacuo and the resulting solid was washed with n-hexane to give 1-(5-amino-6-methyl-pyridin-2-yl)-5-methyl-1H-pyrazol-4-carboxylic acid ethyl ester as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=2)[N:9]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[F:28])[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(C(F)(F)F)cc3c2=O)cc1C
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3F)c3ccc(C(F)(F)F)cc3c2=O)cc1C
Yield: 79.9 %

Procedure:
Compound 4f was prepared following the procedure described in Step 3 of Example 1. Briefly described here, 55 mg (0.16 mmol) of 3-(3,4-dimethyl-benzoyl)-6-trifluoromethyl-1H-quinolin-4-one 3b, 8 mg (0.21 mmol) of 60% sodium hydride and 40 mg (0.21 mmol) of 2-fluorobenzyl bromide were combined in 0.5 mL N,N-dimethylformamide at rt for 16 h. Flash chromatography of the crude product using 10-80% ethyl acetate in hexane yielded 58 mg of the product 4f as white solid: LC-MSD, m/z for C26H19F4NO2 [M+H]+=454.5, HPLC retention time: 2.9 min: 1H NMR (400 MHz, CDCl3): δ 2.3 (s, 3H), 2.35 (s, 3H), 5.5 (s, 2H), 7.05-7.2 (m, 4H), 7.3-7.4 (m, 1H), 7.5-7.6 (m, 2H), 7.65 (s, 1H), 7.8-7.85 (m, 1H), 8.3 (s, 1H), 8.75-8.8 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13](=[O:29])[N:14]2[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13](=[O:29])[N:14]2[C:21]1[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COc1cc(-c2cc(F)ccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=C1CCc2c(-c3cc(F)ccc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl

Procedure:
5-(2-Chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone was prepared from 5-(2-chloro-5-fluorophenyl)-1-(2,6-dichlorophenyl)-3,4dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 10) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 438.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J=7.5 Hz, 2H); 7.36 (t, J=8 Hz, 1H); 7.27 (m, 2H); 7.07 (m, 1H); 6.38 (s, 1H); 5.83 (s, 1H); 2.73 (m, 4H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]2[CH2:35][CH2:34]2)=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N-:36]=[N+:37]=[N-:38].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:31]([CH:33]3[CH2:35][CH2:34]3)=[N:38][N:37]=[N:36]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(COc2ccc(-n3nnnc3C3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
Trifluoromethane sulfonic anhydride (9.42 ml) was added dropwise over 10 min to a solution of cyclopropanecarboxylic acid(4-benzyloxy-phenyl)-amide (15 g) and sodium azide (3.64 g) in acetonitrile (250 ml) at 0°. The reaction mixture was stirred at room temperature under nitrogen for 16 h. 10% Aqueous sodium hydrogen carbonate (80 ml) was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2×100 ml). The combined organic parts were dried over anhydrous sodium sulphate and concentrated in vacuo to give a brown oil. Purification by chromatography with ethyl acetate:isohexane (1:1) as eluant afforded the title compound (2.4 g) as a yellow solid, m.p. 118°.