Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.CCN(C(C)C)C(C)C.[CH3:53][CH:54]([CH3:66])[C@H:55]([NH:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)[C:56](O)=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:56](=[O:57])[C@H:55]([CH:54]([CH3:53])[CH3:66])[NH:59][C:60]5[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=5)=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:37]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: CC(C)[C@H](Nc1cccnc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](Nc5cccnc5)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr2NEt (0.18 mL, 1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88) (0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then it was directly purified by prep HPLC (Luna 5u C18/MeCN—H2O—NH4OAc). The resulting solid was repurified by flash chromatography (SiO2/0-10% MeOH—CH2Cl2) and the obtained product was lyophilized from CH3CN—H2O to give the title compound (0.044 g, 56%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 11.76 (s, 1H), 8.07 (d, J=2.6 Hz, 1H), 7.62-7.85 (m, 8H), 7.49-7.51 (m, 2H), 7.24-7.29 (m, 1H), 6.99-7.06 (m, 2H), 6.46-6.49 (m, 0.5H), 5.97-5.99 (m, 0.5H), 5.71 (d, J=9.0 Hz, 1H), 5.55 (d, J=10.6 Hz, 1H), 5.22-5.44 (m, 1H), 5.03-5.09 (m, 2H), 4.04-4.13 (m, 2H), 3.78-3.90 (m, 3H), 3.66-3.71 (m, 1H), 3.53 (s, 3H), 2.03-2.19 (m, 2H), 1.84-2.01 (m, 4H), 0.81-1.01 (m, 12H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]3[NH:15][CH2:16][CH2:17][CH:11]23)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[CH:20](O)=O.Cl>O1CCOCC1>[CH3:20][N:15]1[CH2:16][CH2:17][CH:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:14][CH2:13][CH:12]12
Reactant: O=[N+]([O-])c1ccc(N2CCC3NCCC32)cc1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC2C1CCN2c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 1-(4-nitrophenyl)octahydropyrrolo[3,2-b]pyrrole (0.7 g), formaldehyde (37%; 0.27 ml), formic acid (0.28 ml) and dioxane (1 ml) was heated to reflux for two hours. The cooled reaction mixture was mixed with hydrochloric acid (2M; 1.7 ml) and concentrated. The residue was taken up in water, and potassium hydroxide was added until the reaction was strongly alkaline. The resulting precipitate was filtered off with suction. The product with the molecular weight of 247.30 (C13H17N3O2); MS (ESI): 248 (M+H+) was obtained in this way.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=[C:26]([C:28](=[O:30])[CH3:29])[CH:27]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])C>[OH-].[Na+]>[C:28]([C:26]1[CH:27]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])[CH:23]=[C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:30])[CH3:29]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccccc2)c1
Yield: 65.4 %

Procedure:
A similar procedure as described in Example 4, step 5 was used, starting from 4-[3-[6-(5-acetyl-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (282 mg, 0.47 mmol) and 1.0 N aqueous sodium hydroxide (10 mL) to afford 4-[3-[6-(5-acetyl-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (168 mg, 66%) as a white solid: ES(+)-HRMS m/e calcd for C33H38O7 (M+Na)+ 569.2510. found 569.2508.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>COCCOC.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>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Brc1cnc(I)nc1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
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: COCCOC
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol), tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ 0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint. OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:29][C:30]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:30]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4F)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 2,3-difluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 539.3(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH:11](O)=O>C=O.O>[CH3:11][N:7]1[CH2:8][CH2:9][CH:4]([C:3]([O:2][CH3:1])=[O:10])[CH2:5][CH2:6]1
Reactant: COC(=O)C1CCNCC1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: COC(=O)C1CCN(C)CC1

Procedure:
Dissolve isonipecotic acid methyl ester in formaldehyde (19.4 mL of a 37.5% solution in water, 262 mmol) and treat with formic acid (10.2 mL of a 90% solution, 240 mmol). Heat on a steam bath for 2 hours and evaporate the solvent in vacuo. Dissolve the residue in ethyl ether, dry (MgSO4), filter and evaporate the filtrate in vacuo. Purify by distillation under an argon atmosphere to give 1-methyl-4-piperidinecarboxylic acid, methyl ester as a clear colorless oil (bp 195°-205° C., 760 mm).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:8]=[C:9]([N:11]2[C:15]([CH:16]([O:18][CH3:19])[CH3:17])=[N:14][CH:13]=[N:12]2)[CH:10]=1)=[O:4].[Li+].[OH-]>>[CH3:19][O:18][CH:16]([C:15]1[N:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[CH:8]=2)[N:12]=[CH:13][N:14]=1)[CH3:17]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2ncnc2C(C)OC)c1
Agent: [Li+]
Agent: [OH-]
Product: COC(C)c1ncnn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1

Procedure:
5-[5-(1-Methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid methyl ester was hydrolysed with LiOH following the procedure of step 2, Example 8, to give 5-[5-(1-methoxy-ethyl)-[1,2,4]triazol-1-yl]-4′-methyl-biphenyl-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:29]3[C:30]([CH3:39])=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][CH2:32]4)=[C:14]([C:20](C)(C)[O:21][SiH2]C(C)(C)C)[O:15][C:16]2=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][NH2:41].CCO>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:29]3[C:30]([CH3:39])=[C:31]4[C:36](=[CH:37][CH:38]=3)[O:35][CH2:34][CH2:33][CH2:32]4)=[C:14]([CH2:20][OH:21])[N:41]([CH3:40])[C:16]2=[O:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2c(C(C)(C)O[SiH2]C(C)(C)C)oc(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Reactant: CN
Solvent: CCO
Product: Cc1c(-c2c(CO)n(C)c(=O)c3cc(OCc4ccccc4)ccc23)ccc2c1CCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
The mixture of 7-Benzyloxy-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(5-methyl-chroman-6-yl)-isochromen-1-one (5.0 g, 9.21 mmol) and CH3NH2/EtOH (10 mL) was stirred at 80° C. for 1 hour. The solvent was removed in vacuo and the resulting mixture was acidified by HCl-EA solution to pH 1-2. The mixture was diluted with water and extracted with EA (3*100 mL) and dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography column on silica gel to afford title product (3.5 g, 86%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[CH:44]=[CH:43][NH:42][C:39]3=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>Cl.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>[NH:42]1[C:39]2=[N:40][CH:41]=[C:36]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]6[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=6)[C:5]=5[C:4]=4[N:3]=3)[CH:37]=[C:38]2[CH:44]=[CH:43]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(-c3cnc4[nH]ccc4c3)nc12
Temperature: 25 °C
Yield: 46.5 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (300 mg, 0.77 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (188 mg, 0.77 mmol), potassium carbonate (317 mg, 2.3 mmol) and tetrakis(triphenylphosphine)palladium (45 mg, 0.04 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, and concentrated. 40 mL water was added. The resulting mixture was filtered to obtain a crude product, which was dissolved in 10 mL 6N hydrochloric acid, and washed with DCM (4×50 mL). The aqueous phase was added dropwise to an aqueous sodium carbonate solution, filtered, and washed with water. The resulting crude product was washed with methanol to produce 9-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H, 3H)-dione (170 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]Br>ClCCl>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Br:13])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)c(Cl)c1F

Procedure:
19.2 g of 2,4-difluoro-3-chloronitrobenzene and 3 g of anhydrous FeCl3 are heated to +140° C., 5.1 ml of bromine are added dropwise with stirring, and the mixture is stirred for a further 48 hours at that temperature. The reaction mixture is cooled and is then taken up in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated. The residue is purified on a silica gel column using hexane/dichloromethane (10:1) as eluant. The title compound of formula ##STR10## is obtained in the form of a brown oil; refractive index nD25 : 1.5720.
Reaction SMILES: OC1C=C(C=CC=1[NH2:11])C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH2:11]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: NC(=O)Nc1ccccc1Br

Procedure:
The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-bromo phenyl isocyanate (24 mmol) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane (4.0 g, 48%). EI-MS m/z 351 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20]I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].[Li]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][CH:24]([C:23](=[O:28])[CH3:22])[C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ICCC=CCCc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)CC(C)=O
Agent: [Li]
Product: CC(=O)C(CCC=CCCc1ccc(OCc2ccccc2)cc1)C(C)=O

Procedure:
[I; Ar is 3-C6H5CH2OC6H4, R0 is H, R' and R" are CH3CO, Y is CH=CHCH2CH2 ] was prepared by reacting 6-(4-benzyloxyphenyl)-3-hexenyl iodide (Preparation D16) with lithium pentane-2,4-dione. The product was chromatographed on activated magnesium silicate and eluted with benzene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]#[C:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1>C1COCC1>[OH:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:18]#[C:17][Se:16][C:3]3[C:2]([CH3:1])=[CH:11][C:10]4[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=4[CH:4]=3)=[N:20][CH:21]=2)=[CH:55][CH:56]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cc2c(cc1[Se]C#Cc1ccc(C(=O)Nc3ccc(O)cc3)cn1)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to that of Example 10, by reaction of 300 mg (0.72 mmol) of the 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-napthylselanylethynyl)nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide and 95 mg (0.87 mmol) of 4-aminophenol in 20 ml of THF, and after purification on a column of silica (ethyl acetate 20/heptane 80), 20 mg (6%) of a yellow solid are obtained. m.p.=172° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Oc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
4-Chlorophenyl chloroformate (317 μL, 2.24 mmol) in dichloromethane (2 mL) was added to a mixture of 3-acetyl-α, α-dimethylbenzylamine 24 and diisopropylethylamine (390 μL, 2.24 mmol). The reaction mixture was stirred for 2 h. It was then diluted with dichloromethane, washed with 1 N HCl, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 25 (594 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.73 (s, 6H), 2.60 (s, 3H), 5.65 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.25 (d, J=6 Hz, 2H), 7.44 (t, J=8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.07 (1H, s); 13C NMR (DMSO-d, 100 MHz) δ 27.45, 29.79, 55.50, 124.23, 124.55, 127.31, 129.28, 129.55, 129.79, 130.39, 137.30, 148.70, 150.32, 152.97, 198.64; ESI-HRMS for C18H19NO3Cl (M+H)+ calcd. 332.1053. found 332.1059.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[C:12]1([NH:11][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CCCCC1
Reaction time: 18 h
Yield: 91.5 %

Procedure:
Cyclohexanecarbonyl chloride (14.66 g, 0.1 mol) was added dropwise to a stirred solution of aniline hydrochloride (12.96 g 0.1 mol) and N, N-diisopropylethylamine (15.20 g, 0.2 mol) in dichloromethane (100 ml). The solution was stirred under an atmosphere of argon for 18 h, washed with 0.1 N-HC1 (3×50 ml) and dilute sodium hydrogen carbonate solution (50 ml), dried (MgSO4), and evaporated in vacuo to give the product (18.6 g) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC1C=C(F)C=CC=1N>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[OH:9])[CH:7]=1
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Nc1ccc(F)cc1F
Solvent: C1COCCO1
Product: COc1ccc(Br)cc1C(O)c1ccc(Br)cc1
Temperature: 135 °C
Yield: 64.5 %

Procedure:
(5-Bromo-2-methoxy-phenyl)-(4-bromo-phenyl)-methanone (16.5 g; 44.6 mmol), R-(+)-BINAP (1.38 g; 2.23 mmol), Pd(OAc)2 (1.499 g; 6.69 mmol), PPh3 (3.03 g; 11.6 mmol), Cs2CO3 (29.1 g; 89.2 mmol) and 2,4-Difluoroaniline (6.8 ml; 66.9 mmol) are dissolved in dioxane (600 ml) and heated to 135° C. for 1.5 hours. The reaction mixture is cooled, filtered, evaporated and purified via chromatography (SiO2; acetone/hexanes 5:95>10:90) to yield the title product as yellow crystals (10.7 g; 57%).
Reaction SMILES: [C:1]([O:4][CH:5](Br)[CH3:6])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:14][C:15]1[C:25]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[CH:31]=[CH:30][C:29]=2[F:41])=[C:24]([F:42])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20]>CC(N(C)C)=O>[F:14][C:15]1[C:25]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[CH:31]=[CH:30][C:29]=2[F:41])=[C:24]([F:42])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([O:21][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:20]
Reactant: CC(=O)OC(C)Br
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
1-bromoethyl acetate (700 mg, 1.7 mmol, 1.0 eq) was dissolved in DMA (10 mL) at room temperature. K2CO3 (120 mg, 0.9 mmol, 0.5 mmol) was added and the mixture stirred for 90 min at 30° C. under a nitrogen atmosphere. The reaction was cooled to −5° C. and 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (350 mg, 2.1 mmol, 1.2 eq) was added. The reaction was warmed to 30° C. over 30 min and stirred for a further 30 min. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo and the residue obtained purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a colourless oil (200 mg, 23%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14](F)[N:15]=[C:16]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>FC(F)(F)CO.C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([NH:28][C:29]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=3)[N:15]=[C:16]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 90 °C
Yield: 61.8 %

Procedure:
To a suspension of (7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-(2,4,6-trimethyl-phenyl)-amine (42 mg, 0.12 mmol) and 4-aminobenzonitrile (55 mg, 0.47 mmol) in 2,2,2-trifluoroethanol (4 mL) was added trifluoroacetic acid (0.072 mL, 0.94 mmol). The resulting solution was heated at 90° C. for 16 h, then cooled to room temperature. The reaction was concentrated to produce a brown oil and diluted with CH2Cl2 (30 mL). The organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 34 mg (64%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.