Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][C@H:10]([OH:13])[CH2:11]Cl)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[N:7]([CH3:8])[CH2:9][C@H:10]1[CH2:11][O:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@H](O)CCl)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C[C@H]1CO1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
((S)-3-chloro-2-hydroxypropyl)-methylcarbamic acid tert-butyl ester (2.23 g, 10 mmol) was dissolved in THF (30 mL), and then an aqueous sodium hydroxide solution (0.48 g in 10 mL water) was added. The mixture was stirred for 2 h. The mixture was then concentrated under reduced pressure to remove most of the THF, and the remaining aqueous solution was extracted into ethyl acetate, washing with water. The product was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title intermediate as an oil (1.6 g). (m/z): [M+Na]+ calcd for C9H17NO3, 210.10; found 210.1. 1H-NMR (DMSO d6, 299.96 MHz): δ (ppm) 1.32-1.42 (s, 9H), 2.69-2.73 (m, 1H), 2.75-2.85 (s, 3H), 2.95-3.05 (br s, 1H), 3.10-3.15 (dm, 1H), 3.16-3.21 (d, 1H), 3.37-3.51 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:18][C:19](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:20]>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1)(=[O:20])[CH3:18]
Reactant: Nc1ccc(/C=C/C(=O)c2cccnc2)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(/C=C/C(=O)c2cccnc2)cc1

Procedure:
Ketone 30t was prepared from aniline 30r (0.045 mmol.), treated with 500 μL of a solution 40% anhydrous acetic in pyridine at room temperature for 2 hours. The solvent was removed and the product was precipitated with 1N NaOH. The solid was washed with water and obtained as a yellow solid (77% yield). mp 191-193° C. 1H NMR (CDCl3) δ 9.21 (s, 1H), 8.79 (s, 1H), 8.27 (dt, 1H, J=7.9 Hz, 1.8 Hz), 7.78 (d, 1H, J=15.7 Hz), 7.59 (s, 4H), 7.39 (m, 3H), 2.19 (s, 3H). 13C NMR (CDCl3) δ 189.42, 169.02, 153.39, 149.99, 145.83, 140.87, 136.29, 133.97, 130.08, 124.07, 120.50, 120.03, 25.11. HRMS (FAB) calcd for C16H15N2O2 ([M+H]+): 267.1128. found 267.1141.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Sn](CCCC)(CCCC)CCCC)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=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>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([C@H:8]4[CH2:7][CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1[C@H]1CC[C@@H](OC(C)=O)CC1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc([C@H]4CC[C@@H](OC(C)=O)CC4)cc3)cc3ccccc23)CC1

Procedure:
cis-4-(Tributylstannylphenyl)cyclohexyl acetate (1.37 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.11 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.16 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (1.24 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(cis-4-acetoxycyclohexyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH:1](Br)=[CH2:2].N(CC)CC.[CH2:9]([S:16]/[C:17](=[CH:20]\[CH:21]=[C:22](/[S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)\[C:23]#[C:24][C:25]#[C:26][CH3:27])/[C:18]#[CH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([S:16]/[C:17](=[CH:20]\[CH:21]=[C:22](/[S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)\[C:23]#[C:24][C:25]#[C:26][CH3:27])/[C:18]#[C:19][CH:1]=[CH2:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CBr
Reactant: C#C/C(=C/C=C(/C#CC#CC)SCc1ccccc1)SCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: c1ccccc1
Solvent: CCNCC
Product: C=CC#C/C(=C/C=C(/C#CC#CC)SCc1ccccc1)SCc1ccccc1
Reaction time: 16 h
Yield: 70 %

Procedure:
Vinyl bromide (0.5 mL, excess) was condensed into a flask under argon, followed by addition of CuI (7.2 mg, 0.015 mmol), (Ph3P)2PdCl2 (26 mg, 0.0376 mmol) and Et2NH (3 mL). Compound 10 (145 mg, 0.376 mmol) in benzene (10 mL) was added at 5° C. and the mixture was stirred in the dark for 16 h. Benzene was removed in vacuo, the residue was dissolved in CH2Cl2 (10 mL), washed with NH4Cl solution (2×15 ml) and water (15 mL), dried (MgSO4), concentrated in vacuo, and the residue purified by flash column chromatography (1:5 CH2Cl2 :hexanes) giving 11 as a yellow-green oil (109 mg, yield 70%): EI-MS, m/z 410 (M+), NH3CI-MS, m/z 428 (MNH4 +); UV (CH2Cl2) λ max 403; IR (CH2Cl2) 2226 (m), 2193 (w), 2142 (w) (all C=C), 1602 (m, C=C) cm-1 ; 1H NMR δ 7.1-7.3 (m, 10H), 6.95 (d, J=17.7, 2.1 Hz, 1 H), 5.49 (dd, J=11.1, 2.1 Hz, 1 H), 4.03 (s, 2 H), 4.02 (s, 2 H), 1.96 (s, 3 H); 13C NMR δ 116-138 (several), 94.90, 88.69, 84.46, 80.94, 72.69, 64.46, 37.52, 4.99.
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:51])[C@H:6]([O:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]4[CH:49]=[CH:48][CH:47]=[CH:46][C:36]=4[S:37][C:38]=3[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)=[CH:23][C:22]=1[Br:50])[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].CO.Cl>O.O1CCCC1>[CH2:39]([C:38]1[S:37][C:36]2[CH:46]=[CH:47][CH:48]=[CH:49][C:35]=2[C:34]=1[C:31]1[CH:32]=[CH:33][C:28]([C:24]2[CH:23]=[C:22]([Br:50])[C:21]([O:20][C@@H:6]([C:5]([OH:4])=[O:51])[CH2:7][CH2:8][NH:9][C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([OH:1])=[O:18])=[C:26]([Br:27])[CH:25]=2)=[CH:29][CH:30]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1C(=O)NCC[C@@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Sodium hydroxide (2 N, 5.0 mL) was added into a mixture of (2R)-2-[4′-(2-benzyl-benzo[b]-thiophen-3-yl)-3,5-dibromo-biphenyl-4-yloxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (1.0g, 1.26 mmol), methyl alcohol (10 ml) and tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 1 hour, poured into water, acidified with HCl (2 N), and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtAOc 2:1) gave white solid (0.82 g, 74% yield): mp 130-132° C.; MS m/e 797 (M+);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc3nncn3n2)c1
Product: CC(=O)Nc1cccc(-c2ccc3nncn3n2)c1

Procedure:
A mixture of 1.0 g. of g. of 6-(m-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 26) and 4 ml. of acetic anhydride is left at room temperature for 2 hours and then is triturated with ether and filtered. The insoluble material is recrystallized from ethyl alcohol to afford yellow crystals of 6-(m-acetamidophenyl)-1,2,4-triazolo[4,3-b]pyridazine, m.p. 248°-250° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:13]([O-])=O)[C:5]1=[O:16])[CH3:3].O>CC(O)=O.[Fe]>[NH2:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][N:4]([CH:2]([CH3:3])[CH3:1])[C:5]2=[O:16]
Reactant: CC(C)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N1Cc2c(N)cccc2C1=O
Reaction time: 2 h
Yield: 86 %

Procedure:
A stirred mixture of 5.0 grams (0.022 mole) of 2-(1-methylethyl)-4-nitroisoindolin-1-one and 10 mL of water in 100 mL of HOAc was warmed to 50 C., and 5.0 grams of iron dust was slowly added. Upon completion of addition, the reaction mixture was stirred at 25 C. for about two hours, then it was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc. The organic layer was separated and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and methylene chloride as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 3.6 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[S:9])=[CH:3][CH:2]=1.[CH3:11][C:12]([CH3:19])([CH:17]=[CH2:18])[CH2:13][CH2:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[S:9])[CH2:18][CH2:17][C:12]([CH3:19])([CH3:11])[CH:13]=[CH2:14])=[CH:3][CH:2]=1
Reactant: C=CC(C)(C)CC[Mg]Br
Reactant: Cc1ccc(N=C=S)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(C)CCC(=S)Nc1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dehydrated tetrahydrofuran (30 ml) solution of p-tolyl isothiocyanate (1.8 g), a tetrahydrofuran solution of the above (3,3-dimethyl-4-pentenyl)magnesium bromide was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes. After raising the temperature to room temperature and further stirring for 30 minutes, an aqueous saturated ammonium chloride solution was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.2 g of the target compound.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: CN(c1ccc(O)cc1)c1cnc2cc(Cl)ccc2n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-methyl-N-(6-chloro-2-quinoxalinyl)amino]phenol (4 mmole), ethyl 2-bromopropionate (1 ml), potassium carbonate (1.0 g) and butanone (100 ml) was heated under reflux for a period of 12 hr. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography over silica gel (eluant dichloromethane/ethanol 98:2) to give ethyl 2-{4-[N-methyl-N-(6-chloro-2-quinoxalinyl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O.C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: Nc1ccccc1O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)cc(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g (37.9 mmol) of 3,5-dibromobenzaldehyde and 5 g (45.5 mmol) of 2-aminophenol were dissolved in 200 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 20.2 g (45.5 mmol) of lead(IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was added to the obtained reactant. The mixture was extracted with ethyl acetate and treated under a reduced pressure to remove the solvent, obtaining 5.7 g (Y=42%) of a white solid.
Reaction SMILES: OC[CH2:3][CH2:4][C:5]1[NH:6]C=CN=1.N1C=CC=C(N=C=O)C=1.[C:19]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][C:29]1[N:30]=[C:31]([F:53])[N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1)=[O:24])(=O)[CH3:20]>>[F:53][C:31]1[N:32]([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:33]=[C:29]([CH2:28][CH2:27][CH2:26][O:25][C:23](=[O:24])[NH:22][C:19]2[CH:20]=[N:6][CH:5]=[CH:4][CH:3]=2)[N:30]=1
Reactant: CC(=O)NC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: OCCCc1ncc[nH]1
Agent: O=C=Nc1cccnc1
Product: O=C(Nc1cccnc1)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
A solution of the hydroxypropylimidazole was treated with 3-pyridylisocyanate as for the starting material of Example 12, to give 2-fluoro-4-[3-(pyrid-3-yl)carbamoyloxypropyl]-1-triphenylmethylimidazole having the following n.m.r. spectrum in CDCl3 : 1.97 (m, 2H); 2.5 (t, 2H); 4.16 (t, 2H); 6.25 (s, 1H); 6.9 (br s, 1H); 7.0-7.5 (m, 15H); 7.7-8.6 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1[CH2:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]2[CH:10]([CH:27]3[CH2:26][CH:25]2[CH:24]=[CH:23]3)[CH:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1=CCC=C1
Reactant: CC(C)(C)OC(=O)N1C(=O)C=CC1C(C)(C)O[SiH2]C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1C(C)(C)O[SiH2]C(C)(C)C
Yield: 67 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxymethyl)-5-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (27) (4 g; 12.2 mmol) and freshly distilled cyclopentadiene (8 mL; 12 eq.) were heated in a sealed tube in toluene for 6 h at 110° C. Concentration and purification by flash chromatography (10% EtOAc/90% hexanes) afforded 3.23 g (67%) of the desired product 28. 1H NMR (CDCl3) □ 6.1 (bs, 1H), 6.0 (bs, 1H), 3.8 (dd, 1H), 3.6 (d, 1H), 3.5 (s, 1H), 3.3 (s, 1H), 3.1 (dd, 1H), 2.9 (s, 1H), 2.6 (bs, 1H), 1.6 (d, 2H), 1.5 (s, 9H), 1.3 (d, 1H), 0.9 (s, 9H), 0.15 (s, 3H), 0.1 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([CH3:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: N#Cc1cnccn1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24](Cl)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC2N([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)C3C(SC=2C=1)=CC=CC=3.O1CCOCC1.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.CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:44]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(Cl)ccc32)CC1
Reactant: Brc1ccc2c(c1)Sc1ccccc1N2C1CCNCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4cccnc4)ccc32)CC1

Procedure:
Using an adaptation of the method described in Procedure 16, substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 2i, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, Cp2Fe(PtBu2)2PdCl2 for Pd(PPh3)4 and a 5:1 mixture of dioxane:water for NMP, the title compound 4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 3i was obtained. MS m/z (MH+) 444.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:12][CH:13]=O)=[CH:3]1.[Cl-].[C:16]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH+:24]=[C:23]([CH3:28])[C:22]2([CH3:30])[CH3:29])([OH:18])=[O:17].CCOCC>CN(C=O)C>[CH3:29][C:22]1([CH3:30])[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:16]([O-:18])=[O:17])[CH:20]=2)[N+:24]2[CH:23]=[CH:28][C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:12][C:13]1=2
Reactant: Cn1cc(C=CC=O)c2ccccc21
Reactant: CC1=[NH+]c2ccc(C(=O)O)cc2C1(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc[n+]3c(c2)C(C)(C)c2cc(C(=O)[O-])ccc2-3)c2ccccc21
Temperature: 120 °C
Yield: 17.6 %

Procedure:
A mixture of 3-(1-methyl-1H-indol-3-yl)prop-2-enal (2.37 g, 12.8 mmol) and 5-carboxy-2,3,3-trimethyl-3H-indolium chloride (3.06 g, 12.8 mmol) in 20 ml of DMF was heated at 120° C. for 17 h. After cooling, ether was added and the solids precipitated. The resulting solids was collected and further purified by silica gel chromatography (eluent: dichloromethane/methanol=10/1 to 2/1) to afford 0.83 g of a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:21]1[C:22]2[N:23]([CH:28]=[CH:29][N:30]=2)[C:24](Br)=[CH:25][N:26]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:37]([Sn:41](Cl)([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH3:40]>C1COCC1>[NH3:7].[C:1]([O:5][C:6](=[O:31])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:21]1[C:22]2[N:23]([CH:28]=[CH:29][N:30]=2)[C:24]([Sn:41]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:25][N:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CN1CCN(c2ccc(N(C(=O)OC(C)(C)C)c3ncc(Br)n4ccnc34)cc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C)CC3)cc2)c2nccn12
Product: N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 148 %

Procedure:
In the same way as described for Compound 212, step 2, using a solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-carbamic acid tert-butyl ester (0.3 g, 0.62 mmol) in THF (5 mL), and isopropylmagnesium chloride (0.46 mL of a 2M solution in THF, 0.67 mmol). After stirring for 5 min, tributyltin chloride (0.28 mL, 1.04 mmol) is added and the reaction is stirred at −78° C. for 10 min before being allowed to warm to room temperature. After stirring at room temperature for 30 min, the mixture is concentrated. The crude mixture is purified by silica gel flash column chromatography using 95:5 DCM:NH3 (7M in MeOH), to give [4-(4-methyl-piperazin-1-yl)-phenyl]-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (0.32 g, 70%) as a yellow oil. LCMS: Rt 7.03 min (92.3%), m/z (ES+) 695, 697, 699.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][CH2:18][C:19]([N:21]=[C:22]=[O:23])=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:22]([NH:21][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[O:23])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NC(=O)CCCl
Solvent: Cc1ccccc1
Product: O=C(CCCl)NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
11.45 g (0.05 mol) of 3,5-bis-trifluoromethylaniline were dissolved in 80 ml of dry toluene, and 6.7 g (0.05 mol) of β-chloropropionyl isocyanate in 20 ml of dry toluene were added. The mixture was stirred at 60° C. for 1 hour, the solvent was distilled off in vacuo and the residue was taken up in petroleum ether. The crystalline product was filtered off and dried. 14.5 g (80.5% of theory) of N-(3,5-bis-trifluoromethyl-phenyl)-N'-(β-chloropropionyl)-urea, which melts at 175° C., were obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([NH:1][C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)(=[O:22])[CH3:21]
Reactant: Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Yield: 78 %

Procedure:
A suspension of 2-amino-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (2.0 g) in acetic anhydride (180 ml) and acetic acid (20 ml) was refluxed for 16 hours. The hot suspension was filtered and the filtrate was concentrated under reduced pressure until crystallization started. The precipitate was filtered off to give the pure title compound in 78% yield. The compound was characterized by its mass spectrum as follows: MS (m/z): 299 ([M+H]+, 100).
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:19])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH2:20].N1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:22]([O:20][C:24]1[CH:23]=[CH:22][C:2]([C:1]([O:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:19])=[CH:17][CH:16]=2)=[O:6])=[CH:26][CH:25]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:3][CH2:4][CH3:5]
Reactant: c1ccncc1
Reactant: O
Reactant: CCCCCOC(C)CCCOc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCC(C)OCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Then, the acid chloride dissolved in toluene was dropped into a solution of 2.6 g of 4-(4'-pentyloxypentyloxy)phenol in 12 ml of pyridine at below 10° C. in 15 min. After the addition, the mixture was stirred at room temperature for 15 hours. After the reaction, the mixture was poured into cold water and extracted with ether. The ether layer was washed successively with 5%-hydrochloric acid, water, 5%-NaOH aqueous solution and water and dried with anhydrous Na2SO4. After distilling off the solvent, the product was recrystallized from ethanol to obtain 4.4 g of 4-(4'-pentyloxypentyloxy)phenyl 4-octyloxybenzoate.