Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[C:34]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:35][CH:36]=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 634 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][C:20]([C:26](=[O:28])[CH3:27])([CH2:24][CH3:25])[CH2:19]1.O>C1COCC1>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][CH:8]1[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][C:20]([CH:26]([OH:28])[CH3:27])([CH2:24][CH3:25])[CH2:19]1
Reactant: CCC1(C(C)=O)CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(C(C)O)CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.10 g, 2.58 mmol) in dry THF (4 ml), was added 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone (0.08 g, 0.26 mmol) in dry THF (3 ml). The reaction mixture was refluxed for 1.5 h. Water was slowly added and the reaction mixture extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the desired product, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a stirred solution of 4-bromo-1,2-difluorobenzene (3.5 g, 17.86 mmol) in dry THF was cooled to −78° C., was added a n-BuLi (10.71 mL) solution dropwise. After completion of the addition, the mixture was stirred for 15 min, and triisopropyl borate (6.71 g, 35.71 mmol) was added in one portion. The reaction flask was kept in a cooling bath for 30 min, and warmed to room temperature for 3 hours. The solvent was removed, the residue was dissolved in ether, washed with 1N HCl and water, dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by recrystallization with CH2Cl2 and hexane to give the pure 3,4-difluorophenylboronic acid (800 mg, 20%).
Reaction SMILES: ClCCl.C(O)(=O)C.[CH2:8]([O:15][C@H:16]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([CH2:30][O:31]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:23][CH:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]1[O:51][C:52](=[O:54])[CH3:53])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:15][C@H:16]1[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@@H:24]([CH2:30][OH:31])[O:23][CH:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]1[O:51][C:52](=[O:54])[CH3:53])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O

Procedure:
A solution of crude 17 in the minimum amount of dichloromethane was stirred at room temperature with aqueous 80% acetic acid (100 mL) until TLC demonstrated the disappearance of 17. Water was then added with stirring; the solid was removed and the filtrate was concentrated. The crude 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranose (18) was thus obtained; 1H NMR data: 60:40 mixture of anomers 6.32 (d, 1 H, alpha-H), 5.64 (d, 1 H, beta-H). A solution of the crude residue 18 in acetone was cooled to -5° C. and a solution of chromium trioxide in 3.5M sulfuric acid was added dropwise with stirring. The mixture was allowed to attain room temperature, and, after 5 hours at room temperature, was poured into ice-cold water and extracted with chloroform. The extract was washed with water and concentrated, and a solution of the crude methyl ester of 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranosuronic acid (19) in ether was esterified with ethereal diazomethane. The product was eluted from a column of silica gel with chloroform-ethyl acetate (20:10) to give 19 (54%). 1H NMR date: mixture of anomers alpha:beta=60:40; 7.23-7.36 (m, 5 H, arom.), 6.38 (d, 1 H, alpha-H), 5.69 (d, 1 H, beta-H), 3.72 (s, 3 H, alpha-COOMe), 3.71 (s, 3 H, beta-COOMe), 1.96-2.16 (9 H, Ac).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1.C(N(CC)CC)C.N1C=CC=CC=1.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl.C(OCC)(=O)C.O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:16]2[C:15](=[O:34])[C:14]([C:9]3[NH:8][C:7]4[CH:35]=[CH:36][C:4]([CH2:3][NH:2][S:51]([CH3:50])(=[O:53])=[O:52])=[CH:5][C:6]=4[S:11](=[O:13])(=[O:12])[N:10]=3)=[C:23]([OH:24])[C@H:22]3[C@@H:17]2[C@H:18]2[CH2:25][C@@H:21]3[CH2:20][CH2:19]2)=[CH:32][CH:31]=1
Reactant: NCc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
(1R,2S,7R,8S)-5-(7-Aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one hydrochloride (crude from previous step, ˜0.77 mmol) was dissolved in methylene chloride (10 mL). Triethylamine (2 mL) and pyridine (2 mL) were added. Methane sulfonyl chloride (2 mL) was added and the mixture stirred at 25° C. for 20 min. Water (50 mL) was added and the mixture stirred for 5 min. The solution was diluted with ethyl acetate (200 mL) and washed with 1.0 M aqueous hydrochloric acid solution (3×300 mL), saturated aqueous ammonium chloride solution (2×200 mL) and saturated aqueous brine solution (200 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.139 g, 0.238 mmol, 31%) as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.19-1.25 (1H, m), 1.40-1.64 (5H, m), 2.50-2.54 (1H, m), 2.64 (1H, d, J=2.5 Hz), 2.92 (3H, s), 3.04 (1H, d, J=8.8 Hz), 3.53 (1H, d, J=9.5 Hz), 4.25 (2H, d, J=6.2 Hz), 4.42 (1H, d, J=15.8 Hz), 4.97 (1H, d, J=14.7 Hz), 7.12-7.17 (2H, m), 7.33 (2H, dd, J=7.7 Hz, J2=5.4 Hz), 7.52 (1H, d, J=8.7 Hz), 7.63-7.70 (2H, m), 7.81 (1H, s). LC-MS (ESI) calculated for C26H27FN4O6S2 574.14. found 575.3 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[O-]S(C(F)(F)[F:36])(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([F:36])=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:24]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Solvent: O
Product: Fc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (380 mg, 0.926 mmol) was dissolved in dichloromethane (5 ml), and N-fluoro-2,4,6-trimethylpyridinium triflate (402 mg, 1.39 mmol) was added. After agitation for 30 minutes at room temperature, water was added and extraction was done with dichloromethane. After washing the organic layer with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. Purification was done by silica gel chromatography (hexane:ethyl acetate=4:1), and 122 mg of 4,6-dimorpholino-5-fluoro-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained (yield 31%). The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 82 are shown below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.O>C(=O)([O-])[O-].[Na+].[Na+].C(O)C.C1(C)C=CC=CC=1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[S:8][CH2:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]3)=[CH:20][CH:21]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2SC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2SC1
Yield: 98.4 %

Procedure:
A solution of ethyl 6-bromo-2H-thiochromene-3-carboxylate (1.00 g, 3.34 mmol), 4-methylphenyl borate (0.55 g, 4.01 mmol) and tetrakistriphenylphosphine palladium (0.19 g, 0.167 mmol) in 2M sodium carbonate (3.5 ml), ethanol (3 ml) and toluene (25 ml) was stirred at 80° C. for 24 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid and saturated brine, and dried with magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography [hexane:ethyl acetate (5:1)] to give ethyl 6-(4-methylphenyl)-2H-thiochromene-3-carboxylate (1.02 g, 99%) as yellow powder.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]12[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:13][CH2:12][CH2:11][NH:10]2.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:19][CH:20]([Cl:24])[C:21]([N:10]1[C:9]2([CH3:8])[N:14]([C:15](=[O:18])[CH2:16][CH2:17]2)[CH2:13][CH2:12][CH2:11]1)=[O:22]
Reactant: CC12CCC(=O)N1CCCN2
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC12CCC(=O)N1CCCN2C(=O)C(Cl)Cl
Temperature: -10 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
10.5 g (0.105 mole) of triethylamine are added to a solution of 15.4 g (0.1 mole) of 6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane in 100 ml of toluene. The mixture is cooled to -10° C. and 14.8 g (0.1 mole) of dichloroacetyl chloride are added dropwise at from -10° to -5° C. The batch is stirred for a further 4 hours and the triethylamine hydrochloride which has precipitated is filtered off. After evaporating the toluene from the filtrate, crystals separate out, and these can be recrystallized from a 1:3 toluene/acetone mixture. 17.7 g of 5-dichloroacetyl-6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane, a melting point 144°-147° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O.C([O-])(=[S:19])C.[K+]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][S:19][C:12]1=[O:13]
Reactant: CCc1cccc(C)c1NC1CCOC1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: COCCOCCOC
Product: CCc1cccc(C)c1NC1CCSC1=O
Temperature: 150 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
11 g (0.05 mol) of N-(2-methyl-6-ethylphenyl)amino-tetrahydrofuran-2-one and 6.6 g (0.05 mol) of potassium thioacetate are dissolved in 200 ml of diethylene glycol dimethyl ether and the solution is stirred for 20 hours at 150° C. After cooling, the mixture is poured into ice-water and extracted with methylene chloride. The combined extracts are washed repeatedly with water, dried over sodium sulfate and filtered and the filtrate is concentrated. After distillation under a high vacuum, the residue yields 5.2 g (44.2% of theory) of N-(2-methyl-6-ethylphenyl)-amino-tetrahydrothiophen-2-one. Boiling point 160°-165° C. under 0.45 mm Hg.
Reaction SMILES: [CH3:1][NH:2][N+:3]([O-:5])=[O:4].S(=O)(=O)(O)O.[N+:11]([N:14]([CH3:17])[CH2:15]O)([O-:13])=[O:12]>>[N+:3]([N:2]([CH2:15][N:14]([N+:11]([O-:13])=[O:12])[CH3:17])[CH3:1])([O-:5])=[O:4]
Reactant: CN[N+](=O)[O-]
Reactant: CN(CO)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CN(CN(C)[N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The solution of 2-nitro-2-aza-1-propanol in methylene chloride produced in Example 2 was combined with an additional 56 grams of methylnitramine. This mixture was slowly added to 300 ml of stirred concentrated sulfuric acid which had previously been cooled to -5° C. to -10° C. The temperature of the reaction mixture was kept at from 0° C. to -5° C. throughout the controlled addition. After the addition was completed, the mixture was poured into a large excess of ice water. Following the separation of the methylene chloride phase, the water phase was repeatedly extracted with methylene chloride. All the methylene chloride fractions were then combined, twice washed with water, and then dried with magnesium sulfate. The magnesium sulfate was filtered out and then the methylene chloride was removed by evaporation under vacuum, leaving an oily liquid. The oily liquid was converted into solid white crystals of 2,4-dinitro-2,4-diazapentane (m.p. 56° C., 65 grams pure) by precipitation from a chloroform/hexane solvent misture.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[C:3]([NH:18][C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2C)CN(C(=O)C(F)(F)F)CC3)cc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc3c(c2C)CNCC3)cc1C(F)(F)F
Yield: 67.4 %

Procedure:
N-(8-Methyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.15 g) in methanol: 2N sodium hydroxide (15 ml 2:1) was stirred at room temperature for 1 h. 2M hydrochloric acid (4.5 ml) was added and solvent (10 ml) removed at reduced pressure. The residual solvent was extracted with dichloromethane, the organic phase washed with brine, dried MgSO4) and solvent removed at reduced pressure to give N-(8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.08 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([N:22]4[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=3)[O:12][N:11]=2)[CH:14]=1
Reactant: Brc1cccc(-c2nc(-c3cccnc3)no2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc(-c4cccnc4)no3)c2)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A solution of the product of Example 63 (200 mg, 0.66 mmol) and tert-butyl piperazine-1-carboxylate (Aldrich, 123 mg, 0.66 mmol) in toluene (anhydrous, 10 mL) was degassed and purged with nitrogen three times, sodium t-butoxide (Aldrich, 64 mg, 0.66 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Aldrich, 12.1 mg, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Aldrich, 23.0 mg, 0.040 mmol, xantphos) were added, degassed and purged with nitrogen three times. The mixture was then heated to 100° C. and stirred under nitrogen for 15 hours. It was then cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with brine (2×5 mL), concentrated, purified with chromatography (v. ethyl acetate/hexane=1/1, Rf=0.6) to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.49 (s, 9H), 3.25-3.30 (m, 4H), 3.56-3.71 (m, 4H), 7.31 (ddd, J=8.4, 2.6, 0.8 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.64 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.70 (dt, J=8.0, 1.1 Hz, 1H), 7.79 (dd, J=2.4, 1.7 Hz, 1H), 8.56 (dt, J=7.9, 2.0 Hz, 1H), 8.74 (dd, J=4.9, 1.5 Hz, 1H), 9.29 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 408 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[C:20]([O:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC(CC1OCCO1)OCCO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCOC(C)CC1OCCO1

Procedure:
Following the above procedure, the monomer was prepared using 22 g triethylamine, 35.2 g 2-[2-(2-hydroxyethoxy)-propyl]-1,3-dioxolane, 23.22 g methacryloyl chloride, and 180 ml methylene chloride. The product was purified by vacuum distillation at 93.2° C. under 0.2 mm Hg pressure.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:17]([C:10]3[CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH3:16])=[O:18])=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
The product of step 2 (146 mg, 0.512 mmol, 1.00 equiv), 1H-indazol-5-amine (68 mg, 0.512 mmol, 1.00 equiv) and EDC (118 mg, 0.615 mmol, 1.20 equiv) were suspended in 8.0 mL DMF. Et3N (0.086 mL, 0.615 mmol, 1.20 equiv) was added and the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (100% EtOAc) to provide 0.070 g (33%) of the title compound as a white solid. MS (ES+) m/e 415 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([N+:21]([O-])=O)[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([NH2:21])[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(-c2cnn(Cc3ccccc3)c2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ncc(-c2cnn(Cc3ccccc3)c2)cc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
A suspension of 5-(1-benzyl-1H-pyrazol-4-yl)-2-methoxy-3-nitropyridine (Preparation 8a, 3.5 g, 11.28 mmol) in acetic acid (50 mL) was added to a cooled (10° C.) suspension of zinc (3.67 g, 56.25 g) in acetic acid (50 mL) and the resulting mixture was stirred at ambient temperature for 1.5 hours. The mixture was filtered and the solid washed with methylene chloride (50 mL). The combined filtrate and washings were evaporated and the residue was purified by flash chromatography (20-40% ethyl acetate in hexanes) to give a brown oil which was treated with a 1:1 mixture of hexanes/diethyl ether (40 mL). The resulting solid was filtered, washed with hexane and dried to yield the title compound (2.33 g, 74%) as a beige solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[C:5]([F:10])=[C:4](Cl)[C:3]=1[F:12].C1C=CN=C(C2C=CC=CN=2)C=1>[Zn].Cl[Ni]Cl>[F:8][C:7]1[CH:2]=[C:3]([F:12])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: Fc1c(Cl)c(F)c(Cl)c(F)c1Cl
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Product: Fc1cc(F)cc(F)c1

Procedure:
In Russ. J. of Org. Chem., vol. 36, 1, pp. 132-33 (2000) describes the dehalogenation of 1,3,5-trichlorotrifluorobenzene by means of zinc in the presence of NiCl2 and bipyridine to give 1,3,5-trifluorobenzene.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:33]=[C:32]([C:34]5([CH:37]=O)[CH2:36][CH2:35]5)[O:31][N:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[CH3:40][NH:41][CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(C(F)(F)F)=O>ClCCCl.[Cl-].[Na+].O.C(Cl)Cl>[CH3:40][N:41]([CH2:37][C:34]1([C:32]2[O:31][N:30]=[C:29]([NH:28][C:27]([N:23]3[C:24]4[C:20](=[CH:19][C:18]([O:17][C:14]5[C:15]6[CH2:16][NH:8][CH2:9][C:10]=6[N:11]=[CH:12][N:13]=5)=[CH:26][CH:25]=4)[CH:21]=[CH:22]3)=[O:39])[CH:33]=2)[CH2:35][CH2:36]1)[CH3:42]
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cc(C5(C=O)CC5)on4)c3)c2C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC1(c2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)no2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-{1-[5-(1-formyl-cyclopropyl)-isoxazol-3-ylcarbamoyl]-1H-indol-5-yloxy}-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (120 mg, 0.226 mmol) in DCE (2 ml), dimethylamine (0.34 mL, 0.679 mmol) and sodium triacetoxyborohydride (192 mg, 0.905 mmol) are added. After 2 h the reaction is complete, brine is added and the product is extracted with EtOAc. The organics are dried and evaporated to give the crude product. The mixture is diluted with DCM (10 mL) and then TFA (10 ml, 130 mmol) is added. After 10 minutes the volatiles are removed in vacuo. The product is dissolved in EtOAc and then NH4OH is added. The organics are removed and the crude product separated via FCC eluting with DCM:MeOH:NH4OH (100:0:0 to 92:7:1) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid [5-(1-dimethylaminomethyl-cyclopropyl)-isoxazol-3-yl]-amide. MS (ESI) m/z 460.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (s, 1H) 8.29 (d, J=8.84 Hz, 1H) 8.16 (d, J=3.79 Hz, 1H) 7.47 (d, J=2.27 Hz, 1H) 7.16 (s, 1H) 6.82 (s, 1H) 6.75 (d, J=4.04 Hz, 1H) 4.06-4.15 (m, 1H) 2.57 (s, 2H) 2.20 (s, 6H) 1.17 (d, J=2.27 Hz, 2H) 0.93 (d, J=2.27 Hz, 2H).