Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Clc1ccc(Cl)nc1
Solvent: ClCCl
Product: Clc1ccc(N2CCNCC2)nc1
Temperature: 165 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
A mixture of 2,5-dichloropyridine (10.0 g, 67.6 mmol) and piperazine (58.1 g, 675 mmol) was stirred at 165° C. for 2 h. The mixture was allowed to cool, slurried with dichloromethane (200 ml) and the solid collected by filtration. The filtrate was concentrated in vacuo and the procedure repeated. The residue after concentration of the filtrate was purified by flash chromatography twice (eluting with 1% ammonia, 10% methanol in dichloromethane) to give 1-(5-chloro-2-pyridyl)piperazine (12.25 g, 92%) as a tan solid. A portion of this solid (0.484 g, 2.45 mmol) was added to a solution of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.392 g, 2.24 mmol) in toluene (10 ml) and the mixture heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and the crystallised product filtered off. Recrystallisation from toluene gave the title compound (0.229 g, 31%), m.p. 196°-198° C.; (Found: C, 63.16; H, 5.60; N, 21.18. C17H18ClN5. 0.1 PhMe requires C, 63.08; H, 5.62; N, 20.78%); δH (DMSO-d6) 2.46 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.45 (4H, t, J 5.0 Hz, 2×piperazinyl CH2), 3.67 (2H, s, CH2N), 6.82 (1H, d, J 9.1 Hz, 3'-H), 7.04 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.37 (1H, d, J 2.1 Hz, 2-H), 7.56 (1H, dd, J 9.1, 2.7 Hz, 4'-H), 8.05 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.08 (1H, d, J 2.7 Hz, 6'-H), 8.19 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.46 (1H, br s, NH); m/z (CI+, NH3) 328 [(M+H)+, 35Cl].
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:42]=[C:43]=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([NH:42][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCCCCCN=C=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, octyl isocyanate (0.44 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The slurry mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(octylamino)carboxamide (0.46 g, 56%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.85-7.68 (m, 3H), 6.43 (t, J=6.0 Hz, 1H), 6.13 (t, J=5.6 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.02-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.36-1.24 (m 12H), 0.85 (t, J=6.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.75, 169.82, 167.57, 167.03, 157.99, 141.19, 134.57, 133.33, 131.50, 126.95, 121.61, 48.82, 39.32, 38.83, 31.21, 30.93, 29.92, 28.73, 28.69, 26.37, 22.07, 21.98, 13.93; Anal. Calcd. For C23H30N4O5: C, 62.43; H, 6.83; N, 12.66. Found: C, 62.27; H, 6.94; N, 12.54.
Reaction SMILES: F/[C:2](=[CH:5]\[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)/[CH:3]=[O:4].[CH3:17][Mg]I.[Mg].CI>CCOCC>[Cl:16][C:11]1[CH:10]=[C:9]([C@@H:7]2[CH2:8][C@H:6]2/[CH:5]=[CH:2]\[CH:3]([OH:4])[CH3:17])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: C[Mg]I
Reactant: O=C/C(F)=C/[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CC(O)/C=C\[C@@H]1C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
(±)-(2Z)-2-Fluoro-3-[trans-2-(3,4-dichlorophenyl)cyclopropyl]prop-2-enal (2.59 g) (example 19) in ehter (10 ml) was treated at 0° under nitrogen with methyl magnesium iodide, prepared from magnesium turning (0.26 g) and methyl iodide (0.7 ml) in ether (20 ml). After 18 hours at 25° the mixture was worked up as usual. Purification by chromatography (silica, ether/hexane) gave (±)-(3Z)-4-[trans-2-(3,4-dichlorophenyl)cyclopropyl]but-3-en-2-ol (2.0 g). NMR 1H: 7.23(1H,d), 7.05(1H,d), 6.90(1H,dd), 4.52(1H,m), 4.23(1H,m), 3.0(1H,s), 1.80(2H,m), 1.35(3H,d), 1.18(2H,m).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH2:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]#[N:21])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C#N
Yield: 61.1 %

Procedure:
A mixture of 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxamide (0.45 g, 1.35 mmol), pyridine (0.21 g, 2.71 mmol) and trifluoroacetic anhydride (0.57 g, 2.71 mmol) in dioxane (12.0 mL) was heated at reflux for 16 h and concentrated in vacuo to dryness. The residue was purified by column chromatography eluted with ethyl acetate in hexane (20%) to afford the title compound as a colourless solid (0.26 g, 63%): mp 190-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.38-7.33 (m, 2H), 7.18-7.12 (m, 2H), 4.97 (s, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2 (d), 161.3, 156.0, 150.3, 132.5, 132.4, 130.5 (d), 115.9 (d), 113.3, 97.5, 48.3, 17.2; MS (ES+) m/z 316.9 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Na].[CH3:16][CH:17]([C:19]1[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30](O)=[O:31])[C:22]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[C:21]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:20]=1[C:48]([NH:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:49])[CH3:18].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[F:41][C:38]1[CH:37]=[CH:36][C:35]([C:22]2[N:23]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:31])[C:19]([CH:17]([CH3:18])[CH3:16])=[C:20]([C:48](=[O:49])[NH:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:21]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)NCCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 2-(2-aminoethoxyl)ethylcarbamate (150 mg, 0.735 mmol) is then taken up in CH3CN (10 mL) along with the sodium salt of atorvastatin (0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture is stirred at room temperature for 18 h. It is then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-((3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanamido)ethoxy)ethylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[OH:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:31][C:22]3[CH:23]=[CH:24][C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: Oc1ccc2ccccc2c1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(Oc3ccc4ccccc4c3)n2)cc(OC)c1OC
Yield: 38 %

Procedure:
Using Method X, with 200 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine (all amounts scaled accordingly) and 2-naphthol, 78 mg of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.ClCCl.CO>C(COC)OC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N+:6]([O-:19])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnc2[nH]ccc2c1
Solvent: COCCOC
Solvent: CO
Solvent: ClCCl
Product: [O-][n+]1cc(F)cc2cc[nH]c21
Yield: 56.3 %

Procedure:
5-Fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide can be obtained as in example 4 stage 4(a) but starting from 2.7 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine, and 6.22 g of 3-chloro-perbenzoic acid in 70 cm3 of dimethoxyethane. In this way, after flash chromatography on a silica column [eluent: dichloromethane/methanol (95/5 by volume)], 1.70 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide is obtained as a powder with the following characteristics:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27].CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:31][CH2:30][CH2:29][C@H:25]5[C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@H]3C(N)=O)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and L-prolinamide, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 338 as a white solid (115 mg, 44%). LCMS: RT=2.48 min, [M+H]+ 409. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1H, s), 7.88 (1H, s), 7.83 (1H, s), 7.33 (1H, br), 6.92 (1H, br), 5.97-5.96 (1H, m), 5.94 (1H, s), 4.53-4.45 (4H, m), 4.30 (1H, d, J=8.51 Hz), 3.59 (1H, s), 3.37 (1H, d, J=9.93 Hz), 2.18 (1H, m), 1.95 (3H, m), 1.47 (6H, dd, J=6.59, 3.43 Hz)
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[CH2:26][CH2:27][CH3:28].C[N:31](C)C(=O)C>>[CH:25](=[N:31][C:23]1[S:22][C:4]2[C:5]([OH:21])=[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)[C:7](=[O:8])[NH:2][C:3]=2[CH:24]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CCCC=O
Reactant: CC(=O)N(C)C
Product: CCCC=Nc1cc2[nH]c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c2s1
Temperature: 25 °C
Yield: 65 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with butyraldehyde (0.5 g, 6.9 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.075 g, 65%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:23]
Reactant: O=C=NCCCl
Reactant: CC(C)CN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 73.4 %

Procedure:
3.6 g of D-glucose, 2.5 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 5.0 g of 1-(2-chloroethyl)-3-isobutyl-3-D-glucopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:53])([CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)[CH3:31])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]3[N:49]=[CH:50][N:51]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH3:52])[CH2:15][O:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)[CH3:31])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]3[N:49]=[CH:50][N:51]=[C:24]23)[CH2:21][CH2:22]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(C(C)c2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogen carbonate (1.20 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-(1-{4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}ethyl)biphenyl-2-carbonitrile (0.39 g) was added, and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.16 g, 37%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:32]2[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: COc1ncc(-c2ccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cn2)cn1

Procedure:
By carrying out the operation analogously to example 213, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methoxy-5-pyrimidineboronic acid, the desired product is obtained and is used directly in the deacetylation stage.
Reaction SMILES: [Br:1][CH2:2][O:3][CH3:4].[CH2:5]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:6]>CCCCCC>[Br-:1].[CH2:5]([N+:7]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:2][O:3][CH3:4])[CH3:6]
Reactant: CCN(CC)CC
Reactant: COCBr
Solvent: CCCCCC
Product: CC[N+](CC)(CC)COC
Product: [Br-]
Yield: 85 %

Procedure:
77 g (0.6 moles) of bromomethylmethyl ether (a reagent available from Tokyo Chemical Industry Co., Ltd.) was added dropwise in 51 g (0.5 moles) of triethylamine (a reagent available from Tokyo Chemical Industry Co., Ltd.), and the mixture was allowed to react at 60 to 70° C. for 6 hours. After completion of the reaction, hexane was added for crystallization, thereby obtaining 96 g (percent yield: 85%) of a crystal of triethyl(methoxymethyl)ammonium bromide. 52 g (0.18 moles) of lithium bis(trifluoromethylsulfonyl)imide (a reagent available from Kanto Chemical Co., Inc.) was added to 34 g (0.15 moles) of this triethyl(methoxymethyl)ammonium bromide, and the mixture was allowed to react in an aqueous system. Subsequently, the reaction mixture was stirred for aging at room temperature for 3 hours. After completion of stirring, a lower layer (product) was separated. The separated product was washed with pure water four times and then washed with hexane four times. After completion of washing, the product was dried in vacuo at 100° C. and at a degree of vacuum of 0.5 kPa for 5 hours. Confirmation of the thus obtained product was carried out by means of 1H-NMR, 13C-NMR and 19F-NMR. A yield of the product (colorless transparent liquid) was 59 g (percent yield: 93%)
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][CH2:12][C:13]2[C:14]([OH:21])=[N:15][C:16]([CH3:20])=[CH:17][C:18]=2[CH3:19])=[O:10])=[CH:7][C:6]=1[Cl:24].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[Cl:24][C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][C:5]=1[O:4][C:3]1[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=1[C:32]1[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=1)[C:9]([NH:11][CH2:12][C:13]1[C:14]([OH:21])=[N:15][C:16]([CH3:20])=[CH:17][C:18]=1[CH3:19])=[O:10]
Reactant: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3Br)c(Cl)c2)c(O)n1
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3-c3ccncc3)c(Cl)c2)c(O)n1
Temperature: 90 °C
Reaction time: 12 h
Yield: 32.6 %

Procedure:
4-(2-Bromophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (90 mg, 0.2 mmol), pyridin-4-ylboronic acid (48 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol), sodium carbonate (62 mg, 0.6 mmol), dioxane (8 mL) and water (2 mL) were added to a flask. The mixture was stirred at 90° C. for 12 hours under nitrogen atmosphere. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-(pyridin-4-yl)phenoxy)benzamide as a light yellow solid (30 mg, 32%). LRMS (M+H+) m/z: calcd 459.13. found 459. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.57 (d, J=6.3 Hz, 2H), 8.40 (t, J=4.5 Hz, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.7 Hz, J=2.1 Hz, 1H), 7.62-7.46 (m, 4H), 7.36 (t, J=6.3 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.78 (d, J=6.3 Hz, 1H), 5.84 (s, 1H), 4.24 (d, J=4.5 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:2]([C:10]([N:12]1[CH2:26][CH2:25][CH2:24][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h
Yield: 78.5 %

Procedure:
To a solution of Boc-D-Phe-Pro-OBn (145 g, 320 mmol) in p-dioxane (660 mL) was added a solution of lithium hydroxide monohydrate (54 g, 1,280 mmol) in water (330 mL) with vigorous stirring. After 4 hours, the solution was concentrated in vacuo to about one-fourth the original volume and diluted with water (350 mL) and 0.1N sodium hydroxide (100 mL). The aqueous phase was washed three times with diethyl ether (250 mL) and then acidified to pH 3 with solid citric acid which caused a precipitate to form. The solid was filtered, washed twice with water, and then dried under high vacuum, to yield 91 g (78%) of a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:47](/[CH:50]=[CH:51]\[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:46][C:40]=1[O:41][CH2:42][C:43](O)=[O:44]>ClCCl.O>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:43](=[O:44])[CH2:42][O:41][C:40]3[CH:46]=[C:47](/[CH:50]=[CH:51]\[C:52]4[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=4)[CH:48]=[CH:49][C:39]=3[O:38][CH3:37])[S:10][C:6]=2[CH:5]=1
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(OC(F)(F)F)cc2s1
Yield: 795.8 %

Procedure:
To a solution of 6-(trifluoromethoxy)-2-aminobenzothiazole (234 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8j) (470 mg, 80% yield)
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]([C:8]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1)=[O:7].[ClH:34]>C(OCC)(=O)C.C(O)(C)C>[ClH:34].[CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]([C:8]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC(=O)C(C)(C)C)(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of piperidine-1,3,3-tricarboxylic acid 1-tert-butyl 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester (250 mg 0.54 mmol) in ethyl acetate (3 mL) is added a solution of hydrogen chloride in isopropanol (3 mL 5-6N). The mixture is stirred at room temperature for 3 h, then concentrated under reduced pressure. The solid is triturated in diisopropyl oxide to give piperidine-3,3-dicarboxylic acid 3-benzyl 3-(3,3-dimethyl-2-oxobutyl)ester, hydrochloride melting at 1500.