Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].O.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH:12]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C=CC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.9 %

Procedure:
1-(4-Methoxyphenyl)-1-buten-3-one (35e, 0.29 g, 1.6 mmol) was dissolved in methanol (5 ml) and stirred for 5 min at room temperature. A solution of sodium hydroxide (0.14 g, 3.5 mmol) and water (5 ml) was added and the mixture stirred for 30 min at room temperature. Benzaldehyde (1b, 0.17 ml, 1.7 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to give 0.41 g (94%) of a yellow solid: mp 85-89° C. [expected mp 118-119° C.]; 1H NMR: δ 3.82 (s, 3H), 6.91 (d, 2H, J=8.5 Hz), 6.94 (d, 1H, J=15.9 Hz), 7.06 (d, 1H, J=16.1 Hz), 7.38 (m, 4H), 7.57 (m, 3H), 7.71 (dd, 2H, J=15.9, 2.0 Hz); 13C NMR: δ 55.4, 114.4, 123.3, 125.5, 127.4, 128.2, 128.8, 130.0, 130.2, 134.8, 142.6, 143.0, 161.5, 188.6.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: BrCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCCCCBr)cc2)cc1

Procedure:
To 500 ml of toluene in a 100 ml round bottom flask, fitted with a condenser and magnetic stirrer, are added 7.6 g (0.03M) of the potassium salt of 4-hydroxy-4'-nitrobiphenyl, 36.6 g (0.15M) of 1,6-dibromohexane, and 0.5 g of 18-crown-6 ether. The mixture is refluxed for about 20 hours, and then filtered hot. The solvent is evaporated, and the residual crude product is recrystallized from hexane to provide purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([C:8]2[N:9]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1OC1CC1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazole-4-carboxylate (12 g, 39 mmol) in THF (200 mL) was added 60% sodium hydride in mineral oil (1.72 g, 43 mmol) and the reaction mixture was stirred for 10 min. SEMCl (7.2 g, 43 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with ice-water and extracted with EtOAc (300 mL×2). The combined organics were dried over sodium sulfate and concentrated in vacuo afford 16 g of the title compounds.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(O[C:10](=[O:12])[CH3:11])(=O)C.O=[CH:14][C@@H:15]([C@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16]>>[C:1]([O:4][C@@H:21]1[O:22][CH2:14][C@@H:15]([O:16][C:10](=[O:12])[CH3:11])[C@H:17]([O:18][C:17](=[O:18])[CH3:19])[C@H:19]1[O:20][C:15](=[O:16])[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A 200 mL round bottom flask containing sodium acetate (3.0 g) and acetic anhydride (36 mL) was heated to 130° C. on oil bath. When bubbles started to come out, D-xylose (5.0 g, 33.3 mmol) was added gradually. When bubbles did not come out any more, the flask was put away from the oil bath and cooled to room temperature. The reaction mixture was put in a 500 mL beaker containing ice (150 g), stirred for a while and then allowed to stand for 2 hours. The resultant light-brown precipitate was filtered by suction, washed with cold water and then dried by vacuum. The crude product was recrystallized using hot ethanol. The crystals were filtered by suction, washed with cold ethanol, and dried to give the title compound. White crystals. Yield 5.55 g, 53%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][CH:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1>CS(C)=O.O>[CH3:15][CH:16]1[CH2:21][N:20]([CH2:14][CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:19][CH2:18][N:17]1[CH2:14][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[OH:13]
Reactant: CC1CNCCN1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)C(C)C2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
A mixture of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (700 mg, 3.684 mmol) and 2-methylpiperazine (184 mg, 1.842 mmol) in 2 mL DMSO was heated under microwave condition (150° C.) for 1 hr. After cooling to rt., the mixture was diluted with water (50 mL), extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried over Na2SO4, then concentrated. The residue was purified by prep-HPLC to obtain two peaks (peak 1 and peak 2). Each peak was further separated by SFC chiral chromatography to obtain three chiral isomers for each (of 8 isomers six were obtained, though two may be mixtures of 2 isomers).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[CH:10]=[O:11])=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[BH4-].[Na+].O>O1CCCC1.C(O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=2)=[N:4][C:3]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1sc(-c2cc(CO)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixed solution of the compound (1.6 g, 4.1 mmol) obtained in Example 95b in tetrahydrofuran/ethanol (v/v=1/1, 8 mL) was added sodium tetrahydroborate (230 mg, 6.1 mmol), and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from 0° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=65/35) to give the title compound (1.3 g, 84%) as a pale-orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25].N1C=CC=CC=1>C1COCC1>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([C:24]#[N:25])[CH:27]=2)=[O:34])=[C:3]([F:23])[CH:4]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(C#N)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A suspension of Example A3 (0.250 g, 0.710 mmol) in THF (10 mL) was treated with 3-cyanophenyl isocyanate (0.102 g, 0.710 mmol) followed by pyridine (0.011 g, 0.142 mmol) and stirred at RT for 2 days. The mixture was concentrated to dryness and the residue treated with MeCN. The solid was collected via filtration, treated with MeOH and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (212 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.89 (s, 1H), 8.79 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=10.6 Hz, 2H), 7.44 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 496.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:20]2)=[CH:15][CH:14]=1)C(OC(C)(C)C)=O.O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][NH:2][CH2:10][CH2:11][O:12][C:13]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([NH:23][C:24](=[O:33])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)=[N:20]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2ccc3ccc(OCCN(C)C(=O)OC(C)(C)C)nc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1ccc2ccc(NC(=O)c3ccc(OC)cc3)nc2n1
Temperature: 4 °C
Yield: 55.9 %

Procedure:
A solution of N-{7-[2-(N-Methyl-N-tert-butoxycarbonylamino)ethoxy]-1,8-naphthyridin-2-yl}-4-methoxybenzamide (20 g) in trifluoroacetic acid (60 cc) is stirred for 1 hour at a temperature in the region of 20° C. The reaction mixture is poured into water (100 cc) and neutralized with 4N sodium hydroxide (180 cc). The insoluble product obtained is separated by filtration, washed with water and dried in the air, and is then dissolved in boiling acetonitrile (250 cc). After 2 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×20 cc) and dried at 50° C. under reduced pressure (0.07 kPa). N-[7-(2-Methylaminoethoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (8.7 g), m.p. 146° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: Nc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1ccc(F)cc1
Yield: 68.5 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 105-107° C., was obtained in 68.5% yield.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:20](=[O:21])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Reaction time: 4 h

Procedure:
To the solution of 2-(benzylthio)-5-nitroaniline (2.61 g, 10 mmol) in DMF (10 ml), added ethyl chloroformate (1.05 ml, 1 lmmol), followed by DIPEA (2.1 ml, 12 mmol). Stirred for 4 hours. Diluted with EtOAc, washed with water and brine, dried over Na2SO4. Concentrated to give ethyl 2-(benzylthio)-5-nitrophenylcarbamate as product.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[N:41](C3CCCCO3)[N:40]=2)[CH:36]=[CH:37][CH:38]=1.OC1C=C(C2C3[C:66](=CC=C(C#N)C=3)[N:65]([CH:74]3CCCCO3)N=2)C=CC=1.Cl>O1CCCC1>[CH3:66][N:65]([CH3:74])[CH2:2][CH2:1][CH2:6][O:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[NH:41][N:40]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc(-c2n[nH]c3ccc(C#N)cc23)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 56.2 %

Procedure:
Triphenylphosphine (1.31 g, 5.00 mmol), tetrahydrofuran (4.00 mL), 3-N,N-dimethylaminopropanol (0.592 mL, 5.00 mmol) and diethylazodicarboxylate (0.788 mL, 5.00 mmol) were added to 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 15.5 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel pretreated with 2% triethylamine/hexanes followed by 0-20% ethyl acetate/hexanes elution, sonication of the product in ethyl acetate (3 mL), addition of hexanes (20 mL) and filtration gave the title compound (0.225 g, 56% yield). ES-MS (m/z) 321 [M+1]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH:14]=O)[CH2:4][CH3:5])[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[K+]>CO.O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH:14]=[N:17][OH:18])[CH2:4][CH3:5])[CH3:2]
Reactant: NO
Reactant: CCN(CC)Cc1ccnc(F)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)Cc1ccnc(F)c1C=NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a solution of compound 88 (150 mg, 0.71 mmol) in methanol (2 mL) was added a solution of hydroxylamine hydrochloride (74 mg, 1.07 mmol) and potassium acetate (105 mg, 1.07 mmol) in water (7 mL). The mixture was stirred at room temperature for 4 h and the methanol was then evaporated under reduce pressure. A saturated aqueous sodium chloride solution (10 mL) was added and the mixture was extracted with dichloromethane (4×20 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, AcOEt→AcOEt/EtOH, 85/15, vi/v) to give compound 89 (131 mg, 0.58 mmol) as a white solid. Yield 81%; Rf (Al2O3, AcOEt/EtOH, 85/15, v/v) 0.89; mp 97-99° C.; IR (KBr) ν 1264, 1331, 1392, 1605, 2750-2980, 3100, 3191 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.05 (t, 6H, J=7.1 Hz), 2.57 (q, 4H, J=7.1 Hz), 3.83 (s, 2H), 7.56 (d, 1H, J=5.1 Hz), 8.13 (d, 1H, J=5.1 Hz), 8.43 (s, 1H); ESI-MS m/z 225.8 [M+H]+.
Reaction SMILES: O[C:2]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=[CH:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:23][NH:24][NH2:25]>C(O)C>[CH3:23][N:24]1[C:2]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[CH:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:25]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)C=C(O)c1cc(OC)c(OC)c(OC)c1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(C)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Ethyl 4-hydroxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-butenoate (3.0 g) was dissolved in ethanol (30 mL), and to the solution methylhydrazine (468 mg) was added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the title compound.
Reaction SMILES: C([Li])CCC.Br[CH:7](Br)[CH2:8][C:9]1[C:10]([CH:28]([CH3:30])[CH3:29])=[N:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[C:32](=[O:34])=[O:33].Cl>CCCCCC.C1COCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:11]=[C:10]([CH:28]([CH3:29])[CH3:30])[C:9]=2[C:8]#[C:7][C:32]([OH:34])=[O:33])=[CH:16][CH:17]=1
Reactant: O=C=O
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CC(Br)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C#CC(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
30.3 ml (48.4 mmol) of a 1.6M solution of n-butyllithium in hexane were added dropwise at -70° C. to a solution of 11.5 g (24.2 mmol) of 1,1-dibromo-2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethane (Example 1a) in 70 ml of THF. The resulting solution was stirred at -70° C. for 1 h and then at room temperature for 1 h and subsequently cooled to -60° C. 10.7 g (242 mmol) of crushed dry ice were added and then the reaction mixture was slowly brought to room temperature, hydrolyzed on ice-water, acidified with dilute hydrochloric acid and extracted several times with ether. The combined organic phases were washed with saturated NaCl solution, dried over MgSO4 and evaporated. The residue was 11.0 g of the title compound which was reacted further without purification. For analytical purposes, a small amount of the crude product was purified on silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])C.[OH-].[Na+]>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:7]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
1-(3-Methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (1.44 g,) was dissolved in 50 ml of methanol and 25 ml of 20% aqueous NaOH was added. The reaction mixture was stirred at 50° C. for 1.5 h until there was no starting material checked by TLC. The reaction mixture was concentrated to about 20 ml, 200 ml of water was added. The resulting solution was neutralized with 5 M hydrochloric acid to pH 2 and the precipitates formed were collected by filtration, washed with water and dried to give 1-(3-methyl-butyl)-4-nitro-1H-pyrrole-2-carboxylic acid (1.29 g, 99%). 1H NMR (DMSO-d6) δ13.12 (br. s, 1H), 8.27 (d, 1H), 7.26 (d, 1H), 4.36 (t, 2H), 1.59 (dd, 2H), 1.50 (dt, 1H), 0.88 (d, 6H).
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[Cl:44][C:45]1[C:46]([CH2:54][NH:55][CH:56]2[CH2:58][CH2:57]2)=[CH:47][C:48]2[O:52][CH2:51][O:50][C:49]=2[CH:53]=1>>[CH:7]([OH:8])=[O:6].[Cl:44][C:45]1[C:46]([CH2:54][N:55]([CH:56]2[CH2:57][CH2:58]2)[C:36]([C:15]2[C@@H:14]3[NH:9][C@H:10]([CH2:17][C:16]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=2)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]3)=[O:37])=[CH:47][C:48]2[O:52][CH2:51][O:50][C:49]=2[CH:53]=1
Reactant: Clc1cc2c(cc1CNC1CC1)OCO2
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)N(Cc3cc4c(cc3Cl)OCO4)C3CC3)[C@@H](C1)N2
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and (6-chlorobenzo[1,3]dioxol-5-ylmethyl)cyclopropylamine. LC-MS: Rt=0.90; ES+: 684.19.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:27])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[C:28](Cl)(=O)[C:29](Cl)=O.C(N(CC)CC)C>ClCCl.C(O)C>[Cl:1][C:2]1[C:3]([OH:27])=[C:4]([CH:8]=[C:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:20][CH:21]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:28][CH3:29])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To a solution of 3-chloro-2-hydroxy-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)benzoic acid (0.60 g) in dichloromethane (20.0 mL) was added oxalyl chloride (0.29 g) under ice-cooling, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was added to a solution of triethylamine (2.00 mL) in ethanol (40.0 mL), and the mixture was stirred for 1 hr. The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate solution, and the organic layer was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.20 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 20 mg, 19%; LC/MS tr 1.59 min; MS(ES+) m/z 350 (M+H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1>C(N)C.CS(C)=O.CO>[CH3:6][N:7]([CH3:2])[C:5]1[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])=[N:7][C:2]([NH:10][CH2:11][CH3:12])=[CH:3][CH:4]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Agent: CCN
Solvent: CO
Solvent: CS(C)=O
Product: CCNc1ccc(N(C)C)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 19 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (50 mg, 0.12 mmol) was placed in a microwave vial and dissolved in ethylamine (70% weight in water, 1 ml). The mixture was heated at 160° C. for 3 h under microwave irradiation. The solvent was removed under a stream of nitrogen to give a crude residue that was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method C). The product was loaded onto a 1 g aminopropyl column, eluted with MeOH and the solvent removed under a stream of nitrogen to give the title compound (5 mg) as an orange solid.