Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][NH:28][CH:29]3[CH3:34])=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[CH:33][C:24]=4[C:19]4[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=4)[CH:29]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncc(-c2cccc3c2CCNC3C)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ncc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].Br[CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:16]>>[F:1][C:2]([F:4])([F:3])[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:14]([C:15]([OH:17])=[O:16])[CH:32]([CH3:34])[CH3:33])=[CH:8][CH:7]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Product: CC(C)[C@H](Nc1ccc(SC(F)(F)F)cc1)C(=O)O

Procedure:
Following the procedure of Example 43, p-aminophenyl trifluoromethyl sulfide is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)valine, MS m/e 475 (M+).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[CH3:24][O:25][CH2:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:31][C:28]3([CH2:27][CH2:26][O:25][CH3:24])[CH2:30][CH2:29]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COCCC1(N)CC1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccnc(OC)c4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57-0.73 (m, 4 H) 1.79 (t, J=7.1 Hz, 2 H) 3.14 (s, 3 H) 3.39 (t, J=7.1 Hz, 2 H) 3.79 (s, 3 H) 7.37 (br. s., 1 H) 7.44 (br. s., 1 H) 7.99 (d, J=5.6 Hz, 1 H) 8.31 (d, J=7.8 Hz, 2 H) 8.57 (br. s., 1 H) 8.77 (s, 1H) 8.79-8.84 (m, 1 H) 13.52 (br. s., 1 H). MS m/z 410 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>ClCCl>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)CC1
Reaction time: 2 h

Procedure:
A solution containing 4-piperidinol (5 g) and triethylamine (7 ml) in dichloromethane (50 ml) was treated with benzyl chloroformate (7.5 ml), added dropwise, and the resulting mixture was allowed to stand for 2 hours. The mixture was diluted with dichloromethane (50 ml) and washed with water (2×50 ml) and with saturated brine (50 ml). The organic solution was dried (MgSO4) and concentrated. The residue was purified by column chromatography, eluting with ether/hexane (50%, then 75%) followed by ether, to give 1-(benzyloxycarbonyl)piperidin-4-ol (7.5 g) as a colourless oil; NMR Spectrum 1.2-1.4 (2H, m); 1.6-1.8 (2H, m); 3.0-3.2 (2H, m); 3.6-3.8 (3H, m); 4.7 (1H, d); 5.05 (2H, s); 7.3-7.4 (5H, m).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[O:13]=[C:14]([OH:25])[C@@H:15]([C@H:17]([C@@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])[OH:16]>>[CH2:23]([OH:24])[C@@H:21]([OH:22])[C@@H:19]([OH:20])[C@H:17]([OH:18])[C:15]([C:14]([OH:25])=[O:13])=[O:16]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
It is shown in Examples 7 to 9 that starting from D-glucose it is preferable to start at higher pH to prepare the intermediate, D-gluconic acid, and after equimolar consumption of alkali (sodium hydroxide, potassium hydroxide, sodium carbonate, etc.) a pH drop to 5.0 or below 5.0 is allowed, to obtain high yields of 2-keto-D-gluconic acid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][CH2:4][CH:5]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C[N+](=O)[O-])c1cccc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1

Procedure:
Of the compound from Example 100A, 3.87 g (11.2 mmol) were hydrogenated in 230 ml of methanol with 5 ml of Raney nickel suspension (50% in water) at a hydrogen pressure of 3 bar for 3 h. The reaction mixture was filtered over celite and washed with methanol, and the filtrate was freed from the solvent on a rotary evaporator. The residue was dried in an HV. This gave 3.50 g (99% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][C:37]=1F)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH:35]=[CH:36][C:37]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6]
Reactant: CN(C)C(=O)c1ccc(F)c(Cl)c1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 31 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (206 mg, 0.6 mmol), 3-chloro-4-fluoro-N,N-dimethyl-benzamide (CAS no. 871657-07-7) (192 mg, 0.9 mmol) and potassium carbonate (166 mg, 1.2 mmol) in N,N-dimethylacetamide (5 mL) was stirred at 160° C. for 6 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL), washed with water (2×20 mL) and brine (10 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-4% methanol in DCM to afford the product (98 mg, 31%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.27 (m, 1H), 2.54-2.67 (m, 1H), 2.55 (s, 3H), 2.93 (s, 3H), 2.98-3.19 (m, 6H), 3.34-3.57 (m, 2H), 4.92 (t, 1H), 6.86 (s, 1H), 7.06 (d, 1H), 7.16 (s, 1H), 7.33 (d, 1H), 7.40 (s, 1H), 7.57 (s, 1H), 8.13 (s, 1H), 8.53 (s, 1H), 9.51 (s, 1H); m/z 524 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[N:8]1.[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[CH2:42][C@@H:41]([N:43]([CH2:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[C:54]([C:62]([F:65])([F:64])[F:63])[CH:53]=4)[C:44]4[N:49]=[CH:48][C:47](Br)=[CH:46][N:45]=4)[CH2:40][C@H:39]3[CH2:66][CH3:67])[C:35]([Cl:68])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22].N#N.C([O-])([O-])=O.[Na+].[Na+]>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.ClCCl.O.COCCOC>[CH2:21]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[CH2:42][C@@H:41]([N:43]([CH2:51][C:52]4[CH:57]=[C:56]([C:58]([F:61])([F:60])[F:59])[CH:55]=[C:54]([C:62]([F:65])([F:63])[F:64])[CH:53]=4)[C:44]4[N:49]=[CH:48][C:47]([C:10]5[CH:9]=[N:8][N:7]([CH:2]6[CH2:3][CH2:4][CH2:5][CH2:6][O:1]6)[CH:11]=5)=[CH:46][N:45]=4)[CH2:40][C@H:39]3[CH2:66][CH3:67])[C:35]([Cl:68])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(Br)cn4)C[C@H]3CC)n2)CC1
Reactant: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(-c5cnn(C6CCCCO6)c5)cn4)C[C@H]3CC)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25 ml round-bottom flask is charged with 1-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (83 mg, 0.3 mmol), 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidine-4-carboxylic acid ethyl ester (178 mg, 0.23 mmol) under N2. Pd(PPh3)4 (57 mg, 0.05 mmol) is added promptly and the flask is recharged with N2. Then DME (1 ml), Na2CO3 (1 M in H2O, 0.45 ml, 0.45 mmol) are added. The mixture is then heated to 95 degree for 2 hrs. After cooling down to rt, NaIO4 (140 mg, 0.72 mmol) is added into reaction mixture. Stirring is continued for 1 h to give white suspension. H2O and dichloromethane are added, and then organic layer is collected. Removal of solvent give 1-{4-[(2R,4S)-4-((3,5-bis-trifluoromethyl-benzyl)-{5-[1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}-amino)-2-ethyl-pyrrolidin-1-yl]-5-chloro-pyrimidin-2-yl}-piperidine-4-carboxylic acid ethyl ester which is used without further purification.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([NH:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc(C)[nH]n1
Yield: 59.6 %

Procedure:
50.4 g (0.6 mol) of sodium bicarbonate were added in small amounts at room temperature to a solution of 19.4 g (0.2 mol) of 3-amino-5-methyl-1H-pyrazole in 200 cm3 of water. 37.8 cm3 (0.4 mol) of acetic anhydride were added dropwise to this solution and then the mixture was heated at reflux for 2 hours. The solution was subsequently brought back to room temperature, a white solid crystallized and was pulled dry on sintered glass and then washed with 100 cm3 of water. After drying under vacuum at 40° C., 16.6 g of the expected product were obtained in the form of pearlescent-white crystals, the melting point of which was between 210° C. and 212° C.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:36]=4[F:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Reactant: Fc1ccc(CBr)c(F)c1
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: [Na+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(F)cc3F)c2)c(=O)c2[nH]c(Cl)nc21
Yield: 38.4 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (81 mg, 0.2 mmol) and sodium carbonate (85 mg, 0.8 mmol) were stirred in dry DMF (2 ml) with 2,4-difluorobenzyl bromide (166 mg, 0.8 mmol) at 45° C. for 18 h. The mixture was degassed and stirred with tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) and morpholine (176 mg, 2 mmol) at rt for 6 h. The reaction was worked up and purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH, eluting with DCM-MeOH (1:1) with 5% added AcOH) to yield the title compound (37.7 mg) as a solid.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]=1[CH3:15].[BrH:16]>>[BrH:16].[OH:3][C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]=1[CH3:15]
Reactant: COc1ccc2c(c1C)CCNCC2
Agent: Br
Agent: Cl
Product: Cc1c(O)ccc2c1CCNCC2

Procedure:
7-Methoxy-6-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (8.6 g) was treated with 48% HBr (100 ml) at 110° C. for 4 hours; volatiles were evaporated under reduced pressure obtaining crude 7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine hydrobromide (10.2 g).
Reaction SMILES: [OH-:1].[Na+:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5].O.[OH-].[Na+]>O>[OH2:6].[OH-:1].[Na+:2].[OH2:6].[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Na+:2]
Reactant: C=CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(=O)[O-]

Procedure:
On the other hand, a sodium hydroxide water solution is prepared in another reactor by dissolving 65.8 g of 98 wt % sodium hydroxide in 200 g of ion exchange water. Then, 150 g of acrylic acid is poured into a flask, and the above sodium hydroxide water solution is poured into the flask while the flask is cooled to neturalize the acrylic acid. As a result, a sodium acrylate water solution is produced. The density of sodium acrylate in the resulting water solution is 45 percent by weight.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:11]OS(C)(=O)=O)([CH2:9][OH:10])[CH2:7][N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]1[C:8]([CH2:11][N:24]=[N+:25]=[N-:26])([CH2:9][OH:10])[CH2:7][N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5]1
Reactant: CON=C1CN(Cc2ccccc2)CC1(CO)COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=C1CN(Cc2ccccc2)CC1(CO)CN=[N+]=[N-]
Temperature: 110 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
1-benzyl-4-methanesulfonyloxymethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime was dissolved in 400 ml of dimethylformamide and thereto 21 g of sodium azide was added and the resulting solution was stirred for 6 hours at 110° C. The reaction mixture was concentrated under the reduce pressure, diluted with 300 ml of ethylether, washed twice with each 200 ml of water and twice with each 200 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure to give 31 g of 1-benzyl-4-azidomethyl-4-hydroxymethyl-pyrrolidine-3-one-O-methyloxime (yield: 87.3%). The obtained compound and 18 ml of triethylamine were added into 300 ml of dichloromethane and cooled to 0-5° C., and thereto 9.0 ml of methanesulfonylchloride was slowly added by dropping. The reaction temperature was increased up to room temperature and the mixture was stirred for 1 hour. The reaction mixture was washed with 200 ml of water and 200 ml of saline solution, dried with magnesium sulfate, filtered and concentrated under the reduced pressure and the concentrated residue was purified by silicagel column chromatography(ethylacetate:normal hexane=1:3) to give 38.8 g of the titled compound (yield: 98.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][O:12][C:11]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>O1CCCC1.C(OC(C)C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[O:12][CH2:13][C:14]([NH:18][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CNC(=O)COC(=O)NCCc1ccc(Br)cc1
Yield: 90.2 %

Procedure:
The procedure described in Example 2 (step 2.2.) is repeated. Starting from 2.6 g (9.15 mmol) of 3-[2-(4-bromophenyl)ethyl]-1,3-oxazolidine-2,4-dione, prepared in Example 3 (step 3.1.), and 18.3 ml (36.6 mmol) of methylamine (2M) in tetrahydrofuran, and after the product has been taken up in diisopropyl ether, 2.6 g of pure product are obtained in the form of a white solid.
Reaction SMILES: [C:1]([C:3]([CH2:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]=1[N+:25]([O-:27])=[O:26])([CH2:7][CH2:8][CH:9]=[CH2:10])C(O)=O)#[N:2].CCCCCCC.C(OCC)(=O)C>CC(N(C)C)=O>[N+:25]([C:13]1[CH:14]=[CH:15][C:16]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][C:12]=1[CH2:11][CH:3]([CH2:7][CH2:8][CH:9]=[CH2:10])[C:1]#[N:2])([O-:27])=[O:26]
Reactant: C=CCCC(C#N)(Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C=CCCC(C#N)Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
To a round bottom flask equipped with a stir bar, condenser, and a nitrogen inlet 2-cyano-2-(2-nitro-5-phenoxy-benzyl)-hex-5-enoic acid (4.0 g, 10.92 mmol) was added and dissolved in dimethylacetamide (10 mL). The solution was heated to 150° C. for 3 hours. The reaction mixture was allowed to room temperature, then the solvent was removed under reduced pressure. The resulting crude product was dissolved in ethyl acetate and washed 3 times with 1N HCl followed by one wash with saturated brine solution. The organic layer was separated and dried with anhydrous sodium sulfate and the solvent was removed to yield crude material. The crude material was subjected to flash chromatography (mobile phase 9:1 heptane:ethyl acetate) to yield a yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:12]=[CH:11][CH:10]=[CH:9][C:4]=1/[C:5](=[N:7]/[NH2:8])/[NH2:6].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:28](=O)[CH:29]=O)[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:28]2[N:6]=[C:5]([C:4]3[C:3]([C:2]([F:13])([F:1])[F:14])=[N:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[N:8][CH:29]=2)[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]
Reactant: N/N=C(\N)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)C=O)cc([N+](=O)[O-])c1OC
Solvent: CCO
Product: COc1cc(-c2cnnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of (Z)-2-(trifluoromethyl)nicotinohydrazonamide (1.02 g, 5 mmol) in ethanol (30 mL) was added 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetaldehyde (1.19 g, 5 mmol). The reaction mixture was heated to reflux for 5 hours. It was then cooled to room temperature and the solvent was removed by evaporation. The residue was dissolved in dichloromethane (30 mL) and the organic phase was washed with water and dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from isopropanol to give 5-(3,4-dimethoxy-5-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-triazine, 1.628 g (80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[SH:8].[Cl:15][C:16]1[N:21]=[C:20](S(C)(=O)=O)[N:19]=[C:18]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[CH:17]=1>C(O)(C)(C)C.CCOC(C)=O>[CH3:32][C:29]1[CH:28]=[C:27]([NH:26][C:18]2[CH:17]=[C:16]([Cl:15])[N:21]=[C:20]([S:8][C:7]3[CH:6]=[CH:5][C:4]([NH:9][C:10]([CH:12]4[CH2:13][CH2:14]4)=[O:11])=[CH:3][C:2]=3[F:1])[N:19]=2)[NH:31][N:30]=1
Reactant: O=C(Nc1ccc(S)c(F)c1)C1CC1
Reactant: Cc1cc(Nc2cc(Cl)nc(S(C)(=O)=O)n2)[nH]n1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CC4)cc3F)n2)[nH]n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of N-(3-fluoro-4-mercaptophenyl)cyclopropane-carboxamide (1.0 g, 4.8 mmol) and 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (1.4 g, 4.8 mmol) in t-butanol (10 ml) was heated 70° C. for 18 h. Reaction mixture cooled to room temperature then diluted with EtOAc (60 ml), washed with sat. NaHCO3 solution (30 ml), brine (30 ml), dried (MgSO4), filtered and concentrated in vacuo. Crude product was purified by flash chromatography on silica (EtOAc/Petrol 20 to 60%) to give the title compound as white solid (800 mg, 40%). ES+ 419.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH2:21][CH3:22])[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:21]([C:4]1[CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]=1[N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCc1cc(Br)cc(CC)c1-n1ccnc1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(-c2ccccc2)cc(CC)c1-n1ccnc1-c1ccccc1
Yield: 82.1 %

Procedure:
A 2-necked 250 mL round-bottom flask was charged with 1-(4-bromo-2,6-diethylphenyl)-2-phenyl-1H-imidazole (6.75 g, 19 mmol), phenylboronic acid (4.63 g, 38 mmol), dicyclohexyl (2′,6′-dimethoxy-biphenyl-2-yl)phosphine (0.312 g, 0.76 mmol), and tripotassium phosphate monohydrate (12.1 g, 51 mmol) in 100 mL of toluene and 10 mL of water. The mixture was degassed by bubbling nitrogen directly into solution for 20 min. Pd2(dba)3 was added and the reaction heated to reflux overnight under nitrogen. The organic layer was separated and solvent was evaporated. The material was column purified by silica gel chromatography eluting with 20% ethyl acetate/hexanes. 5.5 g (82% yield) of product was obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[N:13]1[O:14][CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][C:17]=12.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[Br:12][C:10]1[CH:11]=[C:7]([C@@:17]23[CH2:18][O:19][CH2:20][CH2:21][C@H:16]2[CH2:15][O:14][NH:13]3)[S:8][CH:9]=1
Reactant: Brc1csc(Br)c1
Reactant: C1CC2CON=C2CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Brc1csc([C@@]23COCC[C@H]2CON3)c1
Reaction time: 1 h

Procedure:
n-Butyllithium (2.63 M, 2.99 ml) was added dropwise to a solution of 2,4-dibromothiophene (2.00 g) in toluene-THF (10:1) (22 ml) at −78° C. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (500 mg) in toluene-THF (10:1) (10 ml) and a boron trifluoride-diethyl ether complex (990 μl) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (700 mg).