Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][N:36]=1)CCC>C1(C)C=CC=CC=1.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>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCN(c2ccc(-c3nccs3)nn2)CC1)N1CCN(C2CCC2)CC1
Temperature: 120 °C

Procedure:
In a sealed tube, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-piperazin-1-yl}pyridazine (100 mg, 0.264 mmol), and 2-tributylstannylthiazole (197 mg, 0.528 mmol), Pd(PPh3)4 (30 mg, 0.262 mmol) in toluene (5 mL). Degas with N2 and seal the tube. Heat the mixture at 120° C. overnight. Cool and filter the solution through Celite. Wash the Celite bed with EtOAc (25 mL). Evaporate the solvent and dissolve the residue in 3N HCl (50 mL). Extract with CH2Cl2 (2×25 mL). Discard these organic extracts. Basify the aqueous phase with 10 N NaOH and extract with CH2Cl2 (2×40 mL). Combine these organic extracts and wash once with saturated aqueous KF solution (50 mL). Dry the organic extract and evaporate to yield the title compound. 1H NMR (CDCl3) δ 8.07 (d, 1H) 7.88 (d, 1H), 7.37 (d, 1H) 6.99 (d, 1H), 3.78 (t, 4H), 3.66-3.62 (m, 4H), 3.26 (s, 2H), 2.75-2.66 (m, 5H), 2.35-2.29 (m, 4H), 2.07-2.00 (m, 2H), 1.90-1.84 (m, 2H), 1.74-1.71 (m, 2H); LC-MS (M+1) 428.17.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 6 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (375 mg, 2.43 mmol) in dry N,N-dimethylformamide (DMF) under room temperature (rt) was added 4-fluoroaniline (0.23 mL, 2.44 mmol), and the reaction mixture was stirred for 6 hours. To the mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 465 mg, 2.43 mmol) and 4-dimethylaminopyridine (DMAP, 75 mg, 0.61 mmol), and was stirred for additional 12 hours. Reaction mixture was dumped to water followed by ethyl acetate partition. Organic layers were combined, washed by 3N hydrochloric acid and water, and concentrated in vacuo to give crude methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. Crude methyl ester was saponificated by 10% sodium hydroxide solution (10 mL) in methanol (20 mL). Reaction mixture was heated at 65° C. for 3 hrs. Solid precipitated during acidic workup by 3N hydrochloric acid was collected by filter, washed by methanol (small amount), water and diethyl ether, dried to give an intermediate compound, 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:10]([C:22](O)=[O:23])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:21])[N:16]([OH:20])[N+:17]([O-:19])=[O:18]>>[NH:9]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:10]([C:22]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:21])[N:16]([OH:20])[N+:17]([O-:19])=[O:18]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N(O)[N+](=O)[O-])C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N(O)[N+](=O)[O-])C(=O)NCc1ccccc1
Yield: 81 %

Procedure:
Boc-Arg(NO2)(OH)CONHBn was prepared according to Example 42 by coupling benzylamine to Boc-Arg(NO2)(OH)COOH in a 81% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].[H-].[Na+].[CH:21]([O:24][C:25](Cl)=[O:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH:21]([O:24][C:25]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:2])=[CH:11][CH:10]=2)[C:6]([CH3:18])=[C:7]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:26])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(C(=O)OC(C)C)c2ccc(F)cc12
Reaction time: 8 h

Procedure:
5-Fluoro-3-methyl-2-pyridin-3-yl-indole (Example 3, 0.246 g, 1.044 mmol) is dissolved in DMF (9 mL). NaH (60%, 0.054 g, 1.357 mmol) is added and the mixture is stirred for 1 h, whereupon isopropylchloroformate (1.0M in toluene 2.1 mL, 2.1 mmol) is added. The mixture is stirred overnight, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase is dried over MgSO4 and concentrated in vacuo to give a residue, which is purified by silica gel flash chromatography (ethyl acetate-heptane, 1:4 to 2:3) to give 5-fluoro-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid isopropyl ester as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.07 (d, J=6.3 Hz, 6H), 2.12 (s, 3H), 4.93-5.04 (m, 1H), 7.09-7.17 (m, 1H), 7.30 (dd, J=8.8, 2.3 Hz, 1H), 7.54-7.59 (m, 1H), 7.84-7.89 (m, 1H), 8.23 (dd, J=9.1, 4.5 Hz, 1H), 8.53-8.56 (m, 1H), 8.61 (dd, J=4.5, 1.6 Hz, 1H). HRMS (ESI) m/z 313.1353 [(M+H)+ Calcd for C18H18FN2O2: 313.1352].
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 20 parts of 1-(2-bromoethyl)-4-nitrobenzene, 21.8 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 14.4 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylacetamide is stirred and heated for 4.50 hours at 70° C. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The first fraction is collected and the eluent is evaporated, yielding a first fraction of 14 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C The second fraction is collected and the eluent is evaporated. The residue is purified once more by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The pure fraction is collected and the eluent is evaporated, yielding a second fraction of 2.8 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][OH:10]>[O-2].[O-2].[Mn+4].CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1ccc(Br)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: Nc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 71.1 %

Procedure:
To acetone (300 ml) were added (2-amino-5-bromophenyl)methanol (23.32 g) and active manganese dioxide (58.5 g), and the mixture was stirred at room temperature for 17.5 hours and filtered. The solvent was evaporated under reduced pressure to give 2-amino-5-bromobenzaldehyde (16.41 g, 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (177 mg), 76 mg of triethylamine and 61 mg of 4-N,N-dimethylaminopyridine were dissolved in 2 ml of dry dichloromethane. Ethyl chloroformate (81 mg) was added thereto under ice-cooling in a nitrogen stream. The mixture was stirred under ice-cooling for 3.5 hours, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-ethoxycarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11]([OH:13])=O)[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:25][P:26]([NH2:31])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24].[H-].[Na+]>C1COCC1.CN(C=O)C.O>[CH2:23]([O:25][P:26]([NH:31][C:11]([CH:10]1[C:5]2[CH:4]=[C:3]([CH3:16])[C:2]([CH3:1])=[CH:15][C:6]=2[C:7](=[O:14])[CH2:8][S:9]1)=[O:13])([O:28][CH2:29][CH3:30])=[O:27])[CH3:24]
Reactant: CCOP(N)(=O)OCC
Reactant: Cc1cc2c(cc1C)C(C(=O)O)SCC2=O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOP(=O)(NC(=O)C1SCC(=O)c2cc(C)c(C)cc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.945 g) in THF (10 ml) were added oxalyl chloride (0.609 g) and DMF (2 drops), and the mixture was stirred at room temperature for 1 hour. On the other hand, a mixture of diethoxyphosphorylamine (4.9 g), sodium hydride in oil (60%, 0.32 g) and THF (30 ml) was stirred with ice-cooling for 30 minutes and, then, the above solution was added. The mixture was stirred with ice-cooling for 30 minutes, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give N-diethoxyphosphoryl-6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.29 g, 19%). Recrystallization from ethyl acetate gave colorless prisms melting at 192°-1931/2° C.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O>C(OCC1C=CC=CC=1)(=O)C=C>[CH:8]([C:7]1[O:11][C@H:2]2[N:3]([C:4](=[O:5])[CH2:1]2)[CH:6]=1)=[CH2:9]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: C=CC(=O)OCc1ccccc1
Product: C=CC1=CN2C(=O)C[C@H]2O1
Yield: 83.3 %

Procedure:
(5R)-3-Vinyl-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (345 mg., 2.5 mmole) was prepared from clavulanic acid (3.0 mmole) as described in Example 1. This diene was dissolved in benzyl acrylate (7 ml) and the resulting solution was heated at 80° (bath temperature) for 1.5 hours. The bulk of the benzyl acrylate was then removed by distillation at 100° (bath temperature)/0.5 mm Hg pressure; and the resulting residue was chromatography on silica gel (25 g) using 1:9→1:4 ethyl acetate/petroleum ether (b,p. 60°-80°) to give, in order of elution, the following compounds: (5R)-11-benzyloxycarbonyl-3-oxo-6-oxa-2-azatricyclo[5.4.0.02,5 ]-undec-7,8-ene as colourless prisms (20 mg), isomer I of the title compound as a colourless gum (80 mg), and isomer II of the title compounds as a colourless gum (55 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH2:20]F)=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([CH3:20])=[CH:15][N:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1F
Reactant: Nc1nc(Cl)ncc1CF
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc(-c2cc(Cl)ccc2F)nc1N

Procedure:
trans-Dichlorobis(triphenylphosphine)palladium (II) (1.179 g, 1.680 mmol), 5-chloro-2-fluorophenylboronic acid (6.1 g, 35.3 mmol), 2-chloro-5-fluoromethylpyrimidin-4-amine (2.411 g, 16.80 mmol), 2M Na2CO3 (8.40 mL, 16.80 mmol) were combined in dioxane (79 mL) and refluxed for 1 hour. The reaction was cooled, concentrated and the solids were suspended in brine (50 mL) and then extracted with EtOAc (20 mL). The layers were separated, the organics were dried over Na2SO4, filtered and concentrated to give a residue which was passed through a silica plug (12 g) to give 2-(5-chloro-2-fluorophenyl)-5-methylpyrimidin-4-amine which was without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (3H, d, J=0.76 Hz) 6.85 (2H, br. s.) 7.31 (1H, dd, J=10.61, 8.84 Hz) 7.46-7.55 (1H, m) 7.88 (1H, dd, J=6.57, 3.03 Hz) 8.06 (1H, d, J=0.76 Hz). ESI-MS: m/z 238.1 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:50])[F:49])[CH:45]=4)[NH:40][N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([NH:26][C:27]([C:29]1[C:37]2[C:32](=[N:33][CH:34]=[C:35]([C:38]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH:48]([F:49])[F:50])[CH:45]=4)[N:40]([CH2:2][C:3](=[O:4])[N:5]4[CH2:10][CH2:9][N:8]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]4)[N:39]=3)[N:36]=2)[N:31]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: O=C(CCl)N1CCN(CC(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)N4CCN(CC(F)(F)F)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 99044.6 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (115 mg, 471 μmol) in DMF (16 mL) under Ar, potassium carbonate (200 mg, 1.45 mmol) was added in a single portion at 25° C. After 1 h, a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol) in DMF (4.00 mL) was added in a single portion and the reaction was stirred at 60° C. After 18 h, the reaction was cooled to 25° C. and quenched with water (400 mL). The product was extracted with ethyl acetate (3×150 mL) and the organics were washed with brine (200 mL). The organics were dried over sodium sulfate and concentrated to give a yellow oil. The oil was dried in vacuo (300 mTorr, 25° C.) and purified by chromatography (silica, 12 g Analogix column, 5-80% ethyl acetate in hexanes, gradient over 1 h) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-oxo-2-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (69.0 mg, 93.3 mmol, 99%) as a yellow solid. MS (M)'=739; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.60 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=9.3 Hz, 1H), 7.40 (dd, J=2.0, 8.8 Hz, 1H), 7.21 (t, J=74.3 Hz, 1H), 5.74 (s, 2H), 5.67 (s, 2H), 3.64 (br. s, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.46 (d, J=4.5 Hz, 2H), 2.77 (br. s, 2H), 2.61 (d, J=18.8 Hz, 4H), 1.52 (s, 9H), 0.86 (t, J=8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:7][CH2:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:7]=[CH:6]2
Reactant: COc1cc2c(c(OC)c1OC)C=C(/C=C/C(=O)O)CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COc1cc2ccc(/C=C/C(=O)O)cc2c(OC)c1OC
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Added to a solution of 100 mg (0.34 mmol) of 3-(3,4-dihydro-6,7,8-trimethoxy-2-naphthyl)prop-(2E)-enoic acid synthesized by the process described in Referential Example 6 in toluene (2 ml) was 102 mg (0.41 mmol) of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and the mixture was stirred for 1 hour and 30 minutes at 100° C. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 88 mg (yield: 88%) of crude crystals of the title compound. The crude crystals were recrystallized from chloroform-hexane, thereby obtaining a pale red crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc([N+](=O)[O-])c(N)n1
Temperature: -30 °C
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
2-Amino-6-picoline (5.1 g, 47.1 mmol) was weighed into a 500 mL round bottom flask, and the flask was cooled to -30° C. Concentrated H2SO4 (20 mL) was added, which caused some fuiming to occur. Concentrated HNO3 (10 mL, 160 mmol) was then added dropwise slowly. The reaction was allowed to warm to RT over 30 min, then was heated in an oil bath set at 80° C. After 90 min, the reaction was removed from the heating bath, and ice was added. 6.25 N NaOH (150 mL, 937.5 mmol) was added slowly, and the resulting yellow precipitate was collected on a sintered glass funnel. Drying in a vacuum desiccator gave the title compound (1.7 g, 24%): TLC Rf (5% MeOH/CHCl3) 0.77; 1H NMR (250 MHz, CDCl3) δ 8.31 (d, 1H), 6.32 (d, 1H), 2.46 (s, 3H); MS (ES) m/e 154.0 (M+H)+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][S:28]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:30])=[O:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][S:28]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:34][CH:33]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-methylsulphonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[Br:12][CH2:13][CH2:14]Br.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:12][CH2:13][CH2:14][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: CCCOc1cccc(O)c1
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCOc1cccc(OCCBr)c1
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 3-(n-propoxy)phenol (15.2 g; 0.1 mol; from Example A above) in 1,2-dibromoethane (100 ml; 1.16 mol) was added to a solution of tetrabutylammonium hydrogen sulphate (34 g; 0.1 mol) and sodium hydroxide (8.0 g; 0.2 mol) in water (100 ml). The mixture was stirred vigorously whilst a 50% solution of sodium hydroxide in water (33 ml) was added dropwise over half an hour. Stirring was subsequently continued for one hour. The organic phase was separated, washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue treated with diethyl ether (150 ml). The precipitated salt was removed by filtration and the diethyl ether evaporated. The residue was distilled to yield (14.0 g; 54%) of the title compound as an oil (97% purity). bp 112-115° C. (0.05 mm Hg) MW=259 (GC-MS)
Reaction SMILES: [NH+]1C=CC=CC=1.C([N:10]1[C:14]([NH2:15])=[N:13][C:12]([S:16]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])(=[O:18])=[O:17])=[N:11]1)(=O)C.Cl>[OH-].[Na+]>[Cl:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:27])[C:20]=1[NH:19][S:16]([C:12]1[N:13]=[C:14]([NH2:15])[NH:10][N:11]=1)(=[O:18])=[O:17]
Reactant: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
The product of stage (d) (53.6 g) was dissolved in 2N sodium hydroxide (200 ml), and was stirred at room temperature for 10 minutes. The solution was then taken to pH=5 with 2N hydrochloric acid, and the product was filtered off, washed with a little water and ether, and then dried in vacuo to give 35.4 g of the desired product, mp 265°-267° C.