Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[C:3]#[N:4].C(OCCCC)(=O)CCC>CCCCCC.C(O)CCC>[OH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[C:3]#[N:4]
Reactant: N#C[C@H](O)c1cccc(Oc2ccccc2)c1
Agent: CCCCOC(=O)CCC
Solvent: CCCCCC
Solvent: CCCCO
Product: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C

Procedure:
The racemic ester, (R,S)-Cyano(3-phenoxyphenyl)methyl butyrate, (750 g) prepared by the method described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu, G.; DeshpandeA Tetrahedron Asymmetry 2000, 11, 3303–3309) is dissolved in a mixture of hexane (11 lit) and n-butanol (700 ml). The enzyme lipase from Candida rugosa (EC 3.1.1.3, Type VII, Sigma, USA) was immobilized in gelatin matrix according to the procedure described in literature by Fadnavis and Koteshwar (Fadnavis, N. W. and Koteshwar, K. Biotechnology Progress, 1999, 15, 98–104). The enzyme powder of average particle size 1 mm (1.5 Kg powder, 250 g enzyme) was placed in the reactor and the reaction mixture of the racemic ester in hexane was circulated at a flow rate of 85 ml/min through the enzyme reactor. The reaction temperature was maintained at 25° C. by means of a constant temperature circulating water bath. The progress of the reaction was monitored by chiral HPLC as described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu. G.; Deshpande. A. J. Chromatography A 2000, 189–193). The reaction was continued till almost all of the (R)-ester had reacted (8 h, 49% conversion) and the reaction came to a standstill. The reaction mixture was then drained from the bioreactor and the cycle was repeated The recovered reaction mixture consisting of unreacted (S)-ester, (R)-α-hydroxy-3-phenoxy-benzeneacetonitrile and butyl butyrate was then treated further to obtain (S)-α-hydroxy-3-phenoxy-benzeneacetonitrile as described in literature by Fadnavis and co-workers (Fadnavis, N. W.; Luke Babu, R.; Sheelu, G.; Deshpande, A. Tetrahedron Asymmetry 2001, 12, 1695–1699). The enzyme placed in the bioreactor was used over 50 cycles over a period of one month without loss of activity (<5%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6](COCC[Si](C)(C)C)[N:7]=2)[CH:3]=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (40 mg, 0.075 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 1.25 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. 1H-NMR (CDCl3, 500 MHz) δ 10.05 (bs, 1H), 7.90 (s, 1H), 7.73 (d, J=1.5, 1H), 7.25 (m, 2H), 7.10 (d, J=1.5, 1H), 7.05 (m, 2H), 4.48 (q, J=6.4, 1H), 3.39 (d, J=8.9, 1H), 3.25 (d, J=8.9, 1H), 2.91 (m, 1H), 2.84 (m, 1H), 2.75 (m, 1H), 2.68 (m, 1H), 1.60-2.30 (bs, 1H), 2.20 (m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.80 (m, 1H), 1.42 (d, J=6.7, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 162.5, 160.6, 139.5, 135.9, 133.7, 128.7 (d, J=7.7), 128.0, 126.5, 125.5, 122.3, 115.6, 115.4, 113.5, 79.0, 78.2, 50.7, 42.6, 42.5, 41.4, 33.9, 33.6, 22.2.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH2:37][C:38]#[N:39].C(=O)([O-])[O-].[Na+].[Na+].O>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:37][C:38]#[N:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: N#CCN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Yield: 53.2 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013 mol) in methylisobutyl keton (100 ml) was stirred and refluxed. The mixture was cooled and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5 and 99/1). The pure fractions were collected and the solvent was evaporated, yielding 3.64 g (53%) of (±)-cis-1-[3,5-bis (trifluoromethyl)benzoyl]-4-[4-(cyanomethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (intermediate 6).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12](=O)[NH2:13])[CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[N:17]=[C:18]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[S:19][C:20]=1[C:21](=[O:30])[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]>>[NH2:15][C:16]1[N:17]=[C:18]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:13][CH2:12][CH:10]3[CH2:9][N:8]([CH3:6])[CH2:11]3)=[O:37])=[CH:34][CH:33]=2)[S:19][C:20]=1[C:21](=[O:30])[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Product: CN1CC(CNC(=O)c2ccc(Nc3nc(N)c(C(=O)c4c(F)cccc4F)s3)cc2)C1

Procedure:
The title compound was prepared from 3-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester after 1) reduction in a manner similar to similar to Step 2 in Example A39 and 2) subsequent coupling with 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) in a manner similar to Step 3 in Method A.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:9][NH:8][C:6](=[O:7])[C:5]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:11][C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1cnc(Cl)cc1-c1ccccc1C
Reactant: CN1CCNCC1
Product: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A solution of 3.2 g (12.2 mmol) 6-chloro-N-methyl-4-o-tolyl-nicotinamide in 6.7 ml (60.3 mmol) 1-methylpiperazine was stirred at 100° C. for 2.5 h. The reaction mixture was cooled to r.t., treated with 10 ml 0. 1N NaOH and extracted. The aqueous phase was separated and extracted twice with THF and the organic phases were washed twice with brine. The combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2: MeOH=99:1) to yield 3.3 g (83.7%) product as beige foam.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1.O1CCCCC1OCCN1C([Sn](CCCC)(CCCC)CCCC)=CN=C1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[N:36]=[CH:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cncn1CCOC1CCCCO1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cn(CCO)cn4)ccc2-3)n(C(C)C)n1

Procedure:
Similar to described in General Procedure G: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole to give 440 after THP-removal with aqueous HCl purification by reverse phase HPLC (55 mg). LCMS: 437.1.
Reaction SMILES: C(S[C:6](=[O:19])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:20][C:21]2[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=2[Cl:27])=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)Nc1cc(O)ccc1Cl

Procedure:
The title compound was prepared by the method of Preparation 11b using 2-(4-bromobenzyl)-3-oxothiobutyric acid S-tert-butyl ester and 3-amino-4-chlorophenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH3:10][S:11]SC.Cl.CCOCC>CN(C=O)C.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: CSSC
Reactant: Fc1cc(I)ccc1Br
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc(Br)c(F)c1
Yield: 490.5 %

Procedure:
A stirred suspension of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332 mmol), NiBr2 (7.26 g, 33.2 mmol), 2,2-dipyridyl (5.19 g, 33.2 mmol) and zinc dust (27.2 g, 415 mmol) in DMF (600 mL) was treated with MeS—SMe (15.65 g, 166 mmol), and the mixture was heated in a sand bath set for 80° C. After 10 min (color changes to black and reaction was complete according to HPLC analysis), the mixture was poured onto water. 1N HCl (100 mL) was added along with Et2O (300 mL), and the suspension was filtered through a glass fritted funnel. The zinc plug was further washed with Et2O and the Et2O layer was separated and the aqueous layer was extracted with Et2O (3×). The organic extracts were then dried over Na2SO4 and the solvent evaporated (note that the product is very volatile) to afford 1-bromo-2-fluoro-4-(methylthio)benzene (180 g), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 1H), 6.97 (dd, 1H, Ja=9.1 Hz, Jb=2.0 Hz), 6.90-6.86 (m, 1H), 2.46 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(OCC)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(CO)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CCOCC
Product: Cc1cc(CO)nc(Nc2ccc(F)cc2)n1

Procedure:
50 mg (0.32 mmol) of the compound from example 5A and 350 mg (3.15 mmol) of 4-fluoroaniline are stirred together at 160° C. for 2 h. The reaction mixture is then poured into 10 ml of diethyl ether. The precipitate is filtered off and discarded and the filtrate is then purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane→dichloromethane/ethanol 50:1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13](Cl)=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1c(Br)cccc12
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1c(Br)cccc12
Yield: 88.6 %

Procedure:
0.8 g (2.4 mmol) 6-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 0.8 g (9.3 mmol) piperazine were refluxed in 10 ml mesitylene for 2.5 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 0.8 g (85%) 6-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([CH3:11])[CH:3]=1.O.O.O.[O-:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(C)c(C#N)c(Cl)n1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(C#N)c(Oc2ccccc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
4,6-dimethyl-2-chloro-nicotinonitrile (600 mg, 3.60 mmol) was dissolved in 30 mL of anhydrous THF and then added with sodium phenoxide trihydrate (3.06 g, 18.00 mmol) and stirred at 80° C. overnight. The mixture was extracted with methylene chloride, dried with anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. A silica gel column chromatography (10% EtOAc/Hexane) was performed on the resulting residue and 730 mg (90%) of 4,6-dimethyl-2-phenoxy-nicotinonitrile was obtained in white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[F:16][C:17]([F:38])([F:37])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([C:18]([OH:23])([C:19]([F:20])([F:21])[F:22])[C:17]([F:38])([F:16])[F:37])=[CH:25][CH:26]=3)[CH2:32][CH2:33]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Amino-3-(trifluoromethoxy)benzoic acid (2.045 mmol, 0.452 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0,621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.26 g). MS (ESI) m/z 546.5 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:23])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.[Cu].CN(C)C=O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([CH:16]=[C:15]([O:14][CH3:13])[CH:20]=1)[O:23][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(O)Cc1c(F)cccc1Cl
Agent: I[Cu]I
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(Oc2cccc(F)c2CC(=O)O)c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
N,N-Dimethylformamide (20 ml) was added to 2-chloro-6-fluorophenyl acetic acid (3.77 g), 3,5-dimethoxyphenol (3.08 g), potassium carbonate (5.52 g), copper iodide (950 mg) and copper (250 mg), for stirring at 120° C. for 20 hours. The resulting solution was partitioned between ethyl acetate and dilute hydrochloric acid, and the organic phase was washed in water and in an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, to distill off the solvents under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=7:3), to recover 2-(3,5-dimethoxyphenoxy)-6-fluorophenyl acetic acid (5.27 g; yield of 86%). By 2H-NMR (90 MHz, CDCl3), the compound has the peaks shown below.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:10]2)=[C:4]([F:25])[CH:3]=1.[Cu][C:27]#[N:28].CN(C)C=O.[OH-].[NH4+]>O>[O:23]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:24])[N:14]1[CH:11]1[CH2:12][CH2:13][CH:9]([C:5]2[C:4]([F:25])=[CH:3][C:2]([C:27]#[N:28])=[C:7]([F:8])[CH:6]=2)[CH2:10]1
Reactant: N#C[Cu]
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(C2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1F

Procedure:
A suspension of 91.35 g (0.225 mol) of 2-[3-(4-bromo-2,5-difluorophenyl)cyclopentyl-1H-isoindole-1,3-(2H)-dione, 22.4 g (0.25 mol) of copper (I) cyanide and 250 ml of N,N-dimethylformamide was stirred and heated in a nitrogen atmosphere at 170° for 18 hours. The cooled mixture was poured into a solution of 100 ml of concentrated ammonium hydroxide in 1 L of water. The aqueous mixture was extracted with ether (4×350 ml) and the combined ether layers were washed with water (3×300 ml), dried (MgSO4), and evaporated in vacuo to give 71.2 g of the title compound which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[C:3]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.C1(=[O:28])CCCCC1.C1([N:35]=[C:36]=[O:37])C=CC=CC=1>C(N(CC)CC)C>[CH3:1][C:2]([CH3:21])=[C:3]1[CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[CH:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:36](=[O:37])([O-:28])[NH2:35]
Reactant: O=C=Nc1ccccc1
Reactant: O=C1CCCCC1
Agent: CC(C)=C1C=CC=CC1c1ccc(OCC(O)CO)cc1
Solvent: CCN(CC)CC
Product: NC(=O)[O-]

Procedure:
100 g of phenoxy resin (YP-50, hydroxyl group equivalent=284, Toto Kasei Inc., trade name) and 330 g of cyclohexanone were introduced into a 1 L separable flask fitted with a reflux condenser, thermometer and stirrer, and the mixture heated with stirring to dissolve the resin. Subsequently, 41.9 g phenyl isocyanate and 0.3 g triethylamine were added, and reacted at 130° C. for 3 hours. Next, the product was reprecipitated in ethanol, and dried to give a phenoxy resin to which carbamate had been added. This resin was then dissolved in dimethylformamide (DMF) to give a concentration of 30 mass %, and the resin primer of Example 4 was thus obtained.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][NH2:30])=[CH:25][CH:24]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:30][CH2:29][CH2:28][O:27][C:26]2[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: COc1ccc(OCCN)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: COc1ccc(OCCNC(=O)COc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 2-(4-methoxy-phenoxy)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C21H25NO7 [M+H]+: 404.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](I)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[CH:22](=[O:24])[CH3:23].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH:22]([OH:24])[CH3:23])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCc2ccccc2)c(I)n1
Reactant: CC=O
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cl)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution (100 mL) of 3-(benzyloxy)-6-chloro-2-iodopyridine (17.4 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (60.2 mL) of isopropylmagnesium bromide in tetrahydrofuran at −45° C., and the mixture was stirred at the same temperature for 1 hr. Acetaldehyde (10.2 mL) was added to the reaction mixture, and the mixture was stirred at −45° C. for 30 min then at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (6.82 g, 52%) as a pale-yellow oil.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
50 g of carbobenzoxy-DL-alanine are dissolved in 400 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 30 g of thionyl chloride and stirred for 40 minutes, a suspension of 50 g of 2-amino-5-nitro-2'-fluorobenzophenone in 200 ml of absolute tetrahydrofuran then being rapidly added dropwise. Subsequently, the mixture is stirred at room temperature for 18 hours, the solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution. The mixture is extracted with methylene chloride, the organic solution is dried with sodium sulphate, filtered and concentrated. The residue is crystallised from ethanol and yields rac-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate which is further processed directly as the crude product.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH3:33][O:34][CH2:35][C:36]([CH3:44])([CH3:43])[C:37](N(OC)C)=[O:38]>>[CH3:33][O:34][CH2:35][C:36]([CH3:44])([CH3:43])[C:37]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:38]
Reactant: COCC(C)(C)C(=O)N(C)OC
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Product: COCC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12

Procedure:
3-Methoxy-2,2-dimethyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 3,N-dimethoxy-2,2,N-trimethyl-propionamide following general procedures as described in these Examples, to afford a pale yellow solid. M+H=400.