Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:14][C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=O>Cl.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:6][C:5]2[N:4]([C:17]([C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[F:14])=[N:13][N:12]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(NN)nnc1Cl
Reactant: O=Cc1cc(F)ccc1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc2nnc(-c3cc(F)ccc3F)n2nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a slurry of 3-chloro-4-(1,1-dimethylethyl)-6-hydrazinylpyridazine (1.3 g, 6.5 mmol) in 0.1N hydrochloric acid (60 ml) was added 2,5-difluorobenzaldehyde (0.70 ml, 6.5 mmol) and the reaction mixture was stirred at room temperature for 30 minutes and then heated to 60° C. for 40 minutes. The reaction mixture was allowed to cool and the resultant solid was collected by filtration, dried and dissolved in ethanol (60 ml). To this solution was added iron(III) chloride hexahydrate (5.4 g, 32.5 mmol) in ethanol (15 ml) dropwise over 10 minutes at 80° C. The reaction mixture was stirred at 80° C. for 2 h, allowed to cool and the solvent removed by evaporation under vacuum. The residue was dissolved in dichloromethane (100 ml) and washed with water (3×100 ml), brine, dried (MgSO4), filtered and concentrated under vacuum to yield the title compound (0.75 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.57 (9H, s), 7.22-7.29 (2H, m), 7.65-7.71 (1H, m), 8.19 (1H, s); MS (ES+) m/e 323 [MH]+.
Reaction SMILES: [C:1]1(OC2C=CC=CC=2)C=CC=C[CH:2]=1.[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][CH:30]=[C:31]([C:35]([O-:37])=[O:36])[C:32]([O-])=[O:33])[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>CCCCCC>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[CH:25][C:26]3[C:32](=[O:33])[C:31]([C:35]([O:37][CH2:1][CH3:2])=[O:36])=[CH:30][NH:29][C:27]=3[N:28]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)N1CCN(c2nccc(NC=C(C(=O)[O-])C(=O)[O-])n2)CC1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 16 ml of diphenyl ether heated at 250° - 255°C was added with stirring 2.0 g of diethyl, N-[2-(4-acetyl-1-piperazinyl)-4-pyrimidinyl]-aminomethylenemalonate, gentle refluxing was continuted for 10 minutes, and then the mixture allowed to cool to room temperature. To the mixture was added 12 ml of n-hexane and the resulting precipitate was collected, washed with ethanol, and recrystallized from ethanol to yield 1.52 g of the product, m.p. 300° - 302°C with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].CN.CO.[CH2:31]([N:33](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:31][NH:33][C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:20][CH3:21])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=1)=[O:18]
Reactant: CCN(CC)CC
Reactant: COc1cc2nccc(Oc3ccc(Cl)c([N+](=O)[O-])c3)c2cc1C(=O)O
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1cc2c(Oc3ccc(Cl)c([N+](=O)[O-])c3)ccnc2cc1OC
Reaction time: 4 h

Procedure:
After dissolving 4-(4-chloro-3-nitrophenoxy)-7-methoxy-6-quinolinecarboxylic acid (897 mg, 2.39 mmol) in dimethylformamide (10 ml) under a nitrogen atmosphere, a 40% methylamine-methanol solution (2.0 ml), triethylamine (1.0 ml) and (1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino)) phosphonium hexafluorophosphate (1.27 g, 2.87 mmol) were added in that order at room temperature and the mixture was stirred for 4 hours. The reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (928 mg, quantitative) as white crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][CH3:13])[CH:4]=1)=O.C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH:33][C:34]([O:36][CH3:37])=[O:35])=[CH:4][C:5]=1[O:12][CH3:13])([OH:9])=[O:8]
Reactant: COc1cc(C=O)ccc1C(=O)O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reaction time: 1 h

Procedure:
To a suspension of 4-formyl-2-methoxybenzoic acid obtained above in tetrahydrofuran was added methyl (triphenylphosphoranylidene)acetate (3.3 g) at ambient temperature, and the mixture was stirred for 1 hour at the same temperature. The mixture was concentrated in vacuo, and ethyl acetate and saturated sodium bicarbonate solution were added thereto. The separated aqueous layer was adjusted to pH 4 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with hot diisopropyl ether to give methyl 4-carboxy-3-methoxycinnamate (1.2 g).
Reaction SMILES: I[CH2:2][CH:3]1[S:7][CH2:6][CH:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.[N-:12]=[N+:13]=[N-:14].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:12]([CH2:2][CH:3]1[S:7][CH2:6][CH:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)SC1CSC(CI)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)SC1CSC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution, under argon, of 0.183 g of product from Example 140 in 1.0 ml of dry methylene chloride is treated with 0.689 g of tetra-n-butylammonium azide. The reaction mixture is stirred vigorously overnight at room temperature. The reaction is concentrated in vacuo and the residue purified by chromatography (silica gel: 0-10% diethyl ether/hexane) to give 0.061 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:25][CH2:24][CH:23]([NH:26]C(=O)C)[CH2:22][CH2:21]1.[OH-].[Na+].[ClH:32]>>[ClH:32].[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:20]1[CH2:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH2:25]1
Reactant: CC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1CCc2c(N3CCC(N)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A mixture of 2 g of 9-fluoro-8-(4-acetylamino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 50 ml of a 10% aqueous sodium hydroxide solution was heated for 10 hours. After completion of reaction, the reaction mixture was cooled and adjusted to pH 4 with dilute hydrochloric acid (10%) to form precipitations, which then were recrystallized from ethanol-water to give 0.7 g of 9-fluoro-8-(4-amino-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride. m.p. not lower than 300° C., white rhombic crystals.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[NH:15][CH2:16][CH2:17][NH2:18])=O.C[O-].[Na+].Cl>CO>[NH:15]1[C:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:6]=2[C:4](=[O:3])[NH:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1sc2ccccc2c1NCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NCCNc2c1sc1ccccc21
Temperature: 0 °C
Yield: 64 %

Procedure:
A solution of 3-(2-aminoethylamino)benzo[b]-thiophene-2-carboxylic acid methyl ester hydrochloride (339 mg, 1.18 mmol) and freshly prepared sodium methoxide (from 134 mg, 2.48 mmol of sodium) in 5 mL of methanol is heated at reflux for 18 hours. Upon cooling, the reaction is neutralized with 25 mL of 1N HCl and cooled to 0° C. for 1 hour. The resulting yellow crystalline material is filtered and dried under vacuum at 60° C. for several hours to provide 2,3-dihydro-1H-benzothieno-[3,2-e]-1,4-diazepin-5-one in 64% yield. Chromatography, eluting with a gradient of 2% methanol in ethyl acetate in 5% methanol in ethyl acetate, gives analytically pure, 2,3-dihydro-1H-benzothieno-[3,2-e]-1,4-diazepin-5-one, mp 210°-212° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH2:19]([O:26][C:27]1[C:49]([O:50][CH3:51])=[CH:48][C:30]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][C@H:34]2[CH2:39][O:40][Si](C(C)(C)C)(C)C)=[O:32])=[C:29]([N+:52]([O-:54])=[O:53])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O.[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:19]([O:26][C:27]1[C:49]([O:50][CH3:51])=[CH:48][C:30]([C:31]([N:33]2[CH2:37][C:36](=[CH2:38])[CH2:35][C@H:34]2[CH2:39][OH:40])=[O:32])=[C:29]([N+:52]([O-:54])=[O:53])[CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of TBAF (2.10 mL of a 1M solution in THF, 2.10 mmol) was added to the silyl-ether 16 (0.86 g, 1.68 mmol) in THF (20 mL) at 0° C. (ice/acetone). The reaction mixture was allowed to warm to room temperature following a colour change (yellow→dark red). After a further 40 minutes TLC (50% EtOAc/Pet-Ether 40°-60°) revealed the complete disappearance of starting material. Saturated NH4Cl (100 mL) was added and the reaction mixture extracted with EtOAc (3×40 mL), washed with brine (30 mL), dried (MgSO4), filtered and evaporated in vacuo to give a dark orange oil which was purified by flash chromatography (60% EtOAc/Petroleum Ether) to provide the pure alcohol 17 as a white solid (0.64 g, 96%): [α]19D=−22.9° (c=0.20, MeOH); 1H NMR (270 MHz, CDCl3) (Rotamers) δ 7.78 and 7.76 (s×2, 1Harom), 7.49-7.33 (m, 5Harom), 6.91 and 6.82 (s×2, 1Harom), 5.22 (s, 2H, PhCH2O), 5.10 (m,1H, OH), 5.03-5.01 (m, 1H, NCH2C═CH2), 4.90-4.85 (m,1H, NCH2C═CH2), 4.65-4.55 (m, 1H, NCHCH2OH), 3.99 and 3.95 (s×2, 3H, OCH3), 3.90-3.72 (m, 4H, NCHCH2OH and NCH2C═CH2), 2.90-2.87 (m,1H, NCH2C═CH2CH2), 2.53-2.47 (m, 1H, NCH2C═CH2CH2); 13C NMR (67.8 MHz, CDCl3) (Rotamers) δ 177.4 (NC═O), 155.1 (Cquat), 148.3 (Cquat), 142.6 (Cquat), 137.0 (Cquat), 135.2 (Cquat), 128.9,128.6 and 127.6 (BnC—Harom), 109.1 (C—Harom), 108.5 (C—Harom), 108.3 (NCH2C═CH2), 71.4 (PhCH2O), 65.2 and 63.7 (NCHCH2OH), 60.4 (NCHCH2OH), 56.8 and 56.7 (OCH3), 53.0 and 50.1 (NCH2C═CH2), 35.1 and 34.4 (NCH2C═CH2CH2); MS (EI), m/z (relative intensity) 398 (M+, 2), 380 (3), 368 (4), 354 (1), 286 (M-NCH2C═CH2CH2CHCH2OH, 54), 270 (2), 256 (1), 164 (2), 136 (4), 135 (3), 121 (4), 112 (NCH2C═CH2CH2CHCH2OH, 3), 91 (PhCH2, 100), 82 (3), 69 (4), 65 (6); IR (NUJOL7) 3600-3200 (br, OH), 2923, 2853, 1718, 1663, 1611 (NC═O), 1577, 1517, 1460, 1376, 1332, 1275, 1224, 1176, 1052, 990, 925, 886, 862, 796, 759, 723, 702 615 cm−1; exact mass calcd for C21H22N2O6 m/e 398.1478, obsd m/e 398.1490.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2.[C:23]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([Br:36])=[CH:33][CH:34]=2)[N:29]([C:37](OC2CC(F)(F)C2)=[O:38])[CH2:28][C@@H:27]1[CH3:46])(=[O:25])[CH3:24]>>[C:23]([N:26]1[C:35]2[C:30](=[CH:31][C:32]([Br:36])=[CH:33][CH:34]=2)[N:29]([C:37]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:38])[CH2:28][C@@H:27]1[CH3:46])(=[O:25])[CH3:24]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CC(F)(F)C2)C[C@@H]1C
Reactant: OC1CCOCC1
Agent: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCOCC2)C[C@@H]1C

Procedure:
Tetrahydro-2H-pyran-4-yl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was prepared from tetrahydro-2H-pyran-4-ol and (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one according to the procedure outlined above for 3,3-difluorocyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 397, 399 [M+1]+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)=[CH:4][N:3]=[CH:2]1.Cl.[F:16][C:17]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:18]=1[CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:16][C:17]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:18]=1[CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[O:10])[CH2:22][CH2:21]1
Reactant: O=C(O)c1ccccc1-c1cnco1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1-c1cnco1)N1CCC(O)(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
A suspension of 2-(1,3-oxazol-5-yl)benzoic acid (0.15 g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.16 g), HATU (0.36 g) and triethylamine (1.1 mL) in DMF (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: c1cn[nH]c1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)cnc1-n1cccn1
Temperature: 120 °C
Reaction time: 26.5 h

Procedure:
To a mixture of 5-bromo-2-chloro-3-nitropyridine (10 g, 42 mmol) in 1,4-dioxane (100 ml) was added pyrazole (5.8 g, 85 mmol). The resulting mixture was stirred at 120° C. for 26.5 h., and then evaporated after cooling to r.t. The crude material was purified by flash chromatography (0 to 5% EtOAc/Hexanes) to give the desired product 5-Bromo-3-nitro-2-pyrazol-1-yl-pyridine. 1H NMR: (CD3OD) δ 8.77 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 7.73 (s, 1H), 6.57 (s, 1H); LC/MS: (ES+) m/z (M+H)+=269, 271, HPLC Rt=1.223.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1cc2cc(Br)ccc2cn1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc2cnc(OCc3ccccc3)cc2c1
Temperature: 80 °C
Yield: 18.8 %

Procedure:
To a 25 mL round-bottomed flask containing 6-bromoisoquinolin-3-ol (500 mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide (0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. The reaction was heated to 80° C. overnight. After cooling to RT, the reaction mixture was concentrated in vacuo, and taken up in DCM and water. The water was extracted with DCM (2×), and the combined organic fractions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purify by flash column chromatography (10-30-50% EtOAc/Heptanes), providing the title compound (132 mg, 0.420 mmol, 19% yield). M+1=316.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.92 (s, 1H), 7.85 (d, J=1.25 Hz, 1H), 7.74 (d, J=8.78 Hz, 1H), 7.31-7.52 (m, 6H), 6.99 (s, 1H), 5.48 (s, 2H).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[C:4]=1[F:13].Br[C:16]1[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:12])[C:4]=2[F:13])=[CH:17][N:18]=1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1F
Reactant: Nc1ncc(Br)cn1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ncc(-c2ccc(C(=O)O)c(F)c2F)cn1
Temperature: 110 °C

Procedure:
A mixture of 4-(dihydroxyboryl)-2,3-difluorobenzoic acid (0.47 g, 2.3 mmol), 5-bromopyrimidin-2-amine (0.44 g, 2.6 mmol), tetrakis(triphenylphosphine)palladium (0.1 g, 0.1 mmol), and potassium carbonate (0.96 g, 7.0 mmol) in toluene (4.0 mL), ethanol (2.0 mL) and water (2.0 mL) was heated at 110° C. for 3 h. After cooling to RT, the mixture was washed with ether to remove impurity. The aqueous layer was adjusted to pH 6 with 1N HCl. The solid was filtered, washed with water and ether to give the desired product. LCMS: (M+H)=252.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][OH:4].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:4][CH2:3][CH:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCC(F)CO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
17 g of 2-fluorodecanol and 60 ml of pyridine were charged into a 300 ml three-necked round bottom flask and cooled to 0° C. to which 24 g of p-toluenesulfonyl chloride was added in 15 min. The system was held at 0° C. for 1 hour and then subjected to reaction for 7 hours while being held below 20° C. Then, the mixture was charged into water and acidified with hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with water, dried with magnesium sulfate and then purified by silica gel chromatography with the use of dichloromethane as the eluent to obtain 23 g of 2-fluorodecyl p-toluenesulfonate.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@@H:53](C)[C:54]([NH:56][CH:57]2[CH2:60]N[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C.O1CCCC1>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:60])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (585 mg) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (223 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.57 ml) and a solution of the compound (1.26 g), which had been obtained in (2), in anhydrous tetrahydrofuran (10 ml) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (1.047 g) was obtained as an amorphous substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[CH2:11]([N:13]([CH2:24][CH3:25])[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)=[O:15])[CH3:12].[Cl-].[NH4+]>O1CCCC1>[CH2:24]([N:13]([CH2:11][CH3:12])[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[CH:18][CH:17]=1)=[O:15])[CH3:25]
Reactant: COc1ccccc1Br
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OC)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-bromoanisole (12.1 ml) dissolved in tetrahydrofuran (200 ml) was added with magnesium (2.368 g) and stirred at 60° C. for 1 hour to prepare a Grignard reagent. This Grignard reagent was added with a solution of 4-diethylcarbamoylbenzaldehyde (10.0 g) dissolved in tetrahydrofuran (200 ml) with ice cooling and stirred at room temperature for 1 hour. The reaction mixture was added with saturated aqueous ammonium chloride (400 ml) with ice cooling to quench the reaction and then extracted twice with dichloromethane (400 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:1) to obtain 14.14 g of the title compound. Yield: 93%.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:14]=1[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:8]([O:7][P:5]([O:11][CH2:12][C:13]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:14]=1[C:15]([OH:17])=[O:16])([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:9]=[CH2:10]
Reactant: C=CCOP(=O)(OCC=C)OCc1cc(C#N)ccc1C(=O)OCc1ccc(OC)cc1
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOP(=O)(OCC=C)OCc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-methoxybenzyl 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoate (949.1 mg, 2.07 mmol) obtained from Example 4-(5) and anisole (1.0 g, 9.2 mmol) was cooled to 0° C., and trifluoroacetic acid (5 ml) was added thereto. The resulting mixture was warmed to room temperature and allowed to stand for 15 minutes, diluted with toluene, and concentrated under reduced pressure to eliminate the volatile components (repeated three times). Hexane was added to the residue, and then the supernatant solution was removed to give crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoic acid. This crude product was dissolved in dichloromethane (20 ml), and oxalyl chloride (1.27 g, 10 mmol) and N,N-dimethylformamide (15 μl) were added thereto at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes, and the solvent was distilled off under reduced pressure. The residue was diluted with toluene, and the solution was concentrated under reduced pressure to eliminate the volatile components (repeated three times), and crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-4-cyanobenzoyl chloride was obtained.