Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=1[OH:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:33])([F:34])[F:35])[C:26]=3[Cl:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C(F)(F)F)c2Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 74.1 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-chloro-3-trifluoromethyl-phenol (53 mg, 0.26 mmol) to give the title compound (52 mg, 74%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.Cl.CN(C)CC(O)=O>[Cu]I>[O:7]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Product: N#Cc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
To phenol (1.23 g, 13.10 mmol), copper(I) iodide (333 mg, 1.75 mmol), cesium carbonate (5.69 g, 17.47 mmol), 4-iodobenzonitrile (2.00 g, 8.73 mmol) and N,N-dimethylglycine hydrochloride (366 mg, 2.62 mmol) under nitrogen was added degassed 1,4-dioxane (10.0 mL). The whole mixture was heated at 90° C. for 88 hours. The cooled mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed with brine (100 mL) and dried with Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography EtOAc/Hex (1:12→1:8) to give the pure product as a white solid (quantitative yield). 1H NMR (300 MHz, CDCL3) δ(ppm): 7.00 (2H, d, J=9.1 Hz), 7.06 (2H, d, J=7.6 Hz), 7.23 (1H, t, J=7.2Hz), 7.41 (2H, t, J=8.1 Hz), 7.59 (2H, d, J=9.1 Hz). 13C NMR (75 MHz, CDCL3) δ(ppm): 105.9, 118.0 (CH), 119.0, 120.5 (CH), 125.3 (CH), 130.4 (CH), 134.2 (CH), 154.9, 161.8. MS (FAB+): 196 (MH+). HRMS for C13H9NO (MH+): calculated: 196.0762; found 196.0780.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15]1([CH2:19][C:20]#[N:21])[CH2:18][O:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[NH2:21][CH2:20][CH2:19][C:15]1([NH:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:18][O:17][CH2:16]1
Reactant: N#CCC1(NCc2ccccc2)COC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCC1(NCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a cooled slurry of lithium aluminium hydride (327 mg, 8.6 mmol) in anhydrous diethyl ether (40 mL), was added a solution of 3-(benzylamino)oxetan-3-acetonitrile (1.0 g, 4.3 mmol) in anhydrous diethyl ether (10 mL) dropwise at 0° C. After being stirred at 0° C. for 2 hours, the reaction was quenched by introducing disodium sulfate decahydrate slowly. After being stirred for 30 minutes, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column to afford 800 mg of 3-(aminoethyl)-N-benzyloxetan-3-amine as a light yellow oil (yield was 79%).
Reaction SMILES: Br[CH2:2][Mg].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:6].N>C(OCC)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:2])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: [Mg]CBr
Reactant: COc1cccc(C(C)=O)c1
Agent: N
Solvent: CCOCC
Product: COc1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Bromomethylmagnesium (3 M diethyl ether solution) (24 ml, 72 mmols) was dropwise added to a diethyl ether (200 ml) solution of 3-methoxyacetophenone (10 g, 67 mmols) at room temperature. After the addition, the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonia was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of 2-(3-methoxyphenyl)propan-2-ol (11 g, 98%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][N:10](C(OCCCC)=O)[CH2:9]2)[C:5](=[CH:20][C:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[O:22])[NH:4][C:3]1([CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[C:5](=[CH:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[O:22])[NH:4][C:3]1([CH2:31][C:32]1[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=1)[CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1
Reactant: CCCCOC(=O)N1CCC(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNC2)cc1

Procedure:
Using the same procedure as described in Example 3, the title compound of 46A (6.73 mmol) was treated with TFA (10 ml) in CH2Cl2 to give the title compound of 46B (2.232 g, 4.53 mmol, 78% yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[O:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)[C:17]=3[CH:16]=[C:15]([F:33])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[F:33][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:21]2[O:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:17]=2[CH:16]=1
Reactant: CC(=O)c1oc2c(C3CCN(C(=O)OC(C)(C)C)C3)cc(F)cc2c1Cc1cccc(F)c1
Agent: Cl
Product: CC(=O)c1oc2c(C3CCNC3)cc(F)cc2c1Cc1cccc(F)c1

Procedure:
1-[5-Fluoro-3-(3-fluoro-benzyl)-7-pyrrolidin-3-yl-benzofuran-2-yl]-ethanone was prepared by treating 3-[2-acetyl-5-fluoro-3-(3-fluoro-benzyl)-benzofuran-7-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester with ethanolic HCl using the procedure described for step 4 of Example 2, (M+H)+ 356.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].[CH3:34][O:35][CH2:36][CH2:37]O.Cl.O1CCOCC1>>[CH3:34][O:35][CH2:36][CH2:37][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: COCCO
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (10.0 mg, 21 μmol) was combined with 2-methoxyethanol (0.1 mL, 1.3 mmol). A solution of 4 M HCl in dioxane (53 μL, 0.2 mmol) was added, and the resulting mixture was stirred for 1 hour at room temperature. LC/MS showed the mass of the desired product. The mixture was concentrated by rotary evaporation and purified (reverse phase column) to yield the title compound (2.7 mg, purity 95%) as a white solid TFA salt. MS m/z [M+H]+ calc'd for C25H26ClFN4O6, 533.15. found 533.1.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O)[O:6][CH2:5][CH2:4][O:3]1.[Cl:14][C:15]1[CH:33]=[CH:32][C:18]2[O:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH2:22][N:23]([C:24]([NH:26][NH2:27])=[O:25])[C:17]=2[CH:16]=1>>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([NH:27][NH:26][C:24]([N:23]2[CH2:22][C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[O:19][C:18]3[CH:32]=[CH:33][C:15]([Cl:14])=[CH:16][C:17]2=3)=[O:25])=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: COC(=O)CCCC1(C)OCCO1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC1(CCCC(=O)NNC(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)OCCO1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[4-(2-methyl-1,3-dioxolan-2-yl)-1-oxobutyl]hydrazide (26) was prepared in the manner described above in Example 18 from methyl 2-methyl-1,3-dioxolane-2-butanoate (25), prepared as described above in Example 25, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared in the manner described above in Example 1, on a 2 mmol scale to yield 0.47 g (53%) of product. Analysis calculated for C22H24N3O5Cl 0.2 H2O (M.W. 449.51): C, 58.79; H, 5.74; N, 9.35; Cl, 9.15. Found: C, 58.47; H, 5.58; N, 9.30; Cl, 9.15.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([CH2:31][C:32](O)=[O:33])#[N:30]>>[C:29]([CH2:31][C:32]([N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]3[N:16]([N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]=3[C:26]([NH2:28])=[O:27])[C:20]=2[CH2:21]1)=[O:33])#[N:30]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Reactant: N#CCC(=O)O
Product: N#CCC(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1

Procedure:
The desired compound was prepared from 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide and 2-cyanoacetic acid according to the procedure similar to that for compound 54. 1H NMR (400 MHz, DMSO-d6 at 80° C.) δ 11.55 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.11-6.93 (m, 4H), 6.22 (br s, 2H), 4.68 (s, 2H), 4.14 (s, 2H), 3.86-3.79 (m, 2H), 2.84-2.73 (m, 2H). MS (ESI) m/e [M+1]+ 440.9.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][C:14]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:24][C:21]([O:20][C:18]([N:16]1[CH2:15][C:14]2([CH2:25][CH:26]([C:27]([OH:29])=[O:28])[N:12]([C:10](=[O:11])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:13]2)[CH2:17]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C1CC2(CN(C(=O)OC(C)(C)C)C2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)O)CN(C(=O)OC(C)(C)C)C2)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
To a solution of 2-(1,1-dimethylethyl) 7-ethyl 6-{N-[(methyloxy)carbonyl]-L-valyl}-2,6-diazaspiro[3.4]octane-2,7-dicarboxylate (146) (344 mg, 0.78 mmol) in THF/water/methanol (3 mL/1.5 mL/1.5 mL) was added lithium hydroxide monohydrate (65 mg, 1.56 mmol) and the reaction stirred at room temperature for 1.5 h whereupon it was treated with 1N HCl (1.5 mL). The reaction was partitioned between EtOAc and water (30 mL each), the aqueous layer was extracted with EtOAc (30 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (245 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s., 1H) 7.06-7.66 (m, 1H) 4.13-4.32 (m, 1H) 3.88-4.12 (m, 2H) 3.56-3.89 (m, 5H) 3.39-3.57 (m, 3H) 2.24-2.45 (m, 1H) 1.99-2.19 (m, 1H) 1.80-1.95 (m, 1H) 1.26-1.44 (m, 9H) 0.56-1.00 (m, 6H). LC-MS ESI (M−H)−=412.41.
Reaction SMILES: [CH:1](=[N:5][OH:6])[CH:2]([CH3:4])[CH3:3].[CH2:7]([Cl:10])[C:8]#[CH:9].CCN(CC)CC.Cl([O-])=O.[Na+]>C(Cl)Cl>[Cl:10][CH2:7][C:8]1[O:6][N:5]=[C:1]([CH:2]([CH3:4])[CH3:3])[CH:9]=1
Reactant: C#CCCl
Reactant: CC(C)C=NO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.1 %

Procedure:
To a stirring solution of 1.0 g (11.5 mmol) of isobutyraldehyde oxime, 0.9 g (12.1 mmol) of propargyl chloride, and 0.7 mL (5.02 mmol) of Et3N in 30 mL of CH2Cl2 at 0° C. was added 125 mL of sodium chlorite solution (>4% chlorine). The ice bath was removed and stirring was continued with warming to r.t. After 1.5 h, CH2Cl2 was added, and the organic layer was washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 1.14 g of 5-(chloromethyl)-3-isopropylisoxazole as a pale yellow liquid in about 62% yield. (60%)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([O:17][C:18](=[O:34])[C:19]([CH2:31][CH2:32]O)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>CN(C)C1C=CN=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:31][CH2:32][O:13][C:12](=[O:14])[CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:34])[CH3:24]
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(CCO)(C(=O)OCC)c1ccccc1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)C(CCOC(=O)Cc1cccc([N+](=O)[O-])c1C)(C(=O)OCC)c1ccccc1
Yield: 89.7 %

Procedure:
The 2-methyl-3-nitrophenylacetic acid (307 mg) obtained in Example 5c), 4-dimethylaminopyridine (217 mg) and the 2-(2-hydroxyethyl)-2-phenylmalonic acid diethyl ester (250 mg) obtained in Example 5e) were subjected to reactions similar to those in Example 1-3c) to give the title compound (366 mg).
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CC(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)C>>[CH3:28][N:29]([CH3:31])[CH:30]=[C:3]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[C:2](=[O:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccccc2)CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To the compound tert-butyl 4-(2-oxo-2-phenylethyl)piperazine-1-carboxylate (18 g) taken in round bottom flask, Bredereck's reagent (11.33 g) was added very slowly under nitrogen atmosphere. The reaction mixture was stirred at 55° C. for over-night. The progress of reaction was monitored by TLC. After consumption of starting material, diethyl ether was added to the reaction mixture. The resulting solid was filtered and dried under reduced pressure to afford tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate as pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[BrH:30].BrBr>C(O)(=O)C>[BrH:30].[BrH:30].[BrH:30].[Br:30][CH2:28][C:27](=[O:29])[CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 85 parts of 4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-2-butanone and 600 parts of acetic acid was acidified with glacial acetic acid saturated with hydrogen bromide. A solution of 32.6 parts of bromine in acetic acid was added dropwise. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated. The residue was stirred in 4-methyl-2-pentanone. The product was filtered off and dried, yielding 111 parts (80%) of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-2-butanone trihydrobromide (458).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: Sc1cccc(Br)c1
Product: OCCSc1cccc(Br)c1

Procedure:
Alkylation of 3-bromobenzenethiol with 2-bromoethanol according to the method used in Example 18, gave 2-(3-bromophenylthio)ethanol (125) as a yellow oil without purification. Yield (3.6 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J=2.0 Hz, 1H), 7.31 (ddd, J=0.8, 1.6, 8.0 Hz, 1H), 7.27 (ddd, J=0.8, 1.6, 8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 3.75 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H), 2.18 (brs, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:35])[C:14]2[CH:19]=[N:18][C:17](S(C)(=O)=O)=[N:16][C:15]=2[N:24]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)[CH:25]=1)=[O:11])[CH3:8]>>[CH2:7]([O:9][C:10]([C:12]1[C:13](=[O:35])[C:14]2[CH:19]=[N:18][C:17]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:16][C:15]=2[N:24]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)[CH:25]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COCCCN
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 Step F, the title compound was prepared from 3-methoxy-propylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 20 mg, 0.040 mmol). 11 mg of 8-Indan-5-yl-2-(3-methoxy-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 8.47 (s, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.01 (br, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.34 (t, J=5.7 Hz, 2H), 3.29 (s, 3H), 3.24 (q, J=6.1 Hz, 2H), 2.99 (m, 4H), 2.18 (m, 2H), 1.71 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([C:22](O)=[O:23])[C:5]=1[C:25](O)=[O:26])[CH3:2].[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:29]>C(O)(=O)C.[Cl-].[Na+].O>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[C:22](=[O:23])[C:6]3[C:7]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]4=[C:4]([O:3][CH2:1][CH3:2])[C:5]=3[C:25]2=[O:26])=[CH:37][CH:38]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCc2ccccc2)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCC)C2=O)cc1
Yield: 74.2 %

Procedure:
A mixture of 1-(ethyloxy)-4-[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.55 g, 6.97 mmol) and ethyl(4-aminophenyl)acetate (2.49 g, 13.9 mmol) were heated to 120° C. in acetic acid (20 ml) for 18 hours. The reaction mixture was diluted with brine and extracted with ethyl acetate twice. Combined organics were washed with water then dried over magnesium sulphate, the solvent evaporated to give a brown oil. This was purified by chromatography on silica gel, eluting with ethyl acetate (0-30%) in hexane to give the title compound as a peach coloured solid (2.63 g, 5.17 mmol). LC/MS: Rt=3.95, [MH]+ 510.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:33][O:34][CH3:35]>CCOC(C)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:33][O:34][CH3:35])[C:7]([CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[N:8][C:4]=2[CH:3]=1
Reactant: COCCl
Reactant: CN(Cc1nc2cc(Br)ccc2[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCn1c(CN(C)C(=O)OC(C)(C)C)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl [(5-bromo-1H-benzimidazol-2-yl)methyl]methylcarbamate (1.54 g) and DMF (20 mL) were added K2CO3 (1.88 g) and chloromethylmethyl ether (516 μL) under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: Hex/EtOAc=80/20-55/45) to obtain a mixture (1.25 g) of tert-butyl {[5-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate and tert-butyl {[6-bromo-1-(methoxymethyl)-1H-benzimidazol-2-yl]methyl}methylcarbamate.
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]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.C(N(CC)CC)C.CN(C=O)C.[C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)#[CH:46]>C(OCC)(=O)C.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>[C:47]1([C:45]#[C:46][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[N:4]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3c(n2)c(C#Cc2ccccc2)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 100 °C
Yield: 73.8 %

Procedure:
7-Iodo-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (275 mg, 0.49 mmol), PdCl2(PPh3)2 (17 mg, 0.02 mmol), and cuprous iodide (5 mg, 0.02 mmol) were placed in a 5 ml microwave vial. The vial was capped and purged with nitrogen. Triethylamine (0.35 ml, 2.45 mmol) and 2.5 ml of DMF were added through the septum and the flask was purged again with nitrogen three times. Ethynyl-benzene (0.19 ml, 1.75 mmol) was added and the reaction was heated in a microwave reactor at 100° C. for 30 minutes. The crude reaction mixture was diluted with ethyl acetate, washed with water two times, dried and concentrated. The mixture was purified by flash chromatography using a gradient of 0% ethyl acetate in hexanes up to 30% to yield 195 mg of 7-phenylethynyl-5-(toluene-4-sulfonyl)-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine. MS: (M+H)+=540.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH2:8][CH:9]=[CH:10][CH3:11]
Reactant: C=CC=C
Reactant: Cc1ccncc1
Product: CC=CCCc1ccncc1
Temperature: 140 °C
Yield: 86 %

Procedure:
220 g of 4-methylpyridine and 1.0 g of solid base A were fed into a 1000 ml autoclave equipped with an electromagnetic stirrer under an atmosphere of nitrogen, and then heated to 140° C. with stirring at 700 r.p.m. subsequently, 16.5 g of butadiene was added to the mixture in 1 hour. After the reaction, the autoclave was cooled and the catalyst was removed by filtration. The reaction solution was analyzed by gas chromatography. 4-(3-pentenyl)pyridine was obtained in a 86% yield based on 4-methypyridine consumed.