Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:40]1[CH:49]=[CH:48][C:47]2[N:46]=[C:45]([NH2:50])[C:44]3[N:51]=[CH:52][N:53]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:43]=3[C:42]=2[CH:41]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:50][C:45]1[C:44]2[N:51]=[CH:52][N:53]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:43]=2[C:42]2[CH:41]=[C:40](/[CH:3]=[CH:2]/[CH2:1][N:4]3[CH2:8][CH2:7][CH2:6][C:5]3=[O:9])[CH:49]=[CH:48][C:47]=2[N:46]=1
Reactant: C=CCN1CCCC1=O
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1cnc2c(N)nc3ccc(/C=C/CN4CCCC4=O)cc3c21
Temperature: 120 °C

Procedure:
A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (15 mL), N-allyl-2-pyrrolidone (650 mg, 5.17 mmol), triethylamine (2.1 ml, 15.65 mmol), tri-o-tolylphosphine (275 mg, 0.9 mmol) and 8-bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 11, 1.5 g, 4.7 mmol). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. for 24 hours. The reaction mixture was concentrated to dryness. The reaction mixture was slurried in a mixture of 1% aqueous sodium carbonate (75 mL) and chloroform (100 mL). The layers were separated. The aqueous layer was extracted with chloroform (2×25 mL). The combined organic fractions were concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% methanol/dichloromethane) to provide 1-{(2E)-3-[4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enyl}pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]1[CH:10]=[CH:9]O[CH:7]=1)[CH2:2][CH2:3][CH3:4].BrC1C=C[S:22]C=1>>[CH2:1]([Sn:5]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]1[CH:10]=[CH:9][S:22][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccoc1
Reactant: Brc1ccsc1
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1

Procedure:
Using the method for the preparation of 3-tributylstannylfuran, 2.50 g (15.39 mmoles) of 3-bromothiophene gave 1.31 g (Y: 23%) of the title product. 1H NMR (CDCl3): δ7.46 (m, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.16 (d, J=4.6 Hz, 1H), 1.52 (m, 6H), 0.132 (m, 6H), 1.05 (t, J=8.2 Hz, 6H), 0.89 (t, J=7.2 Hz, 9H). MS (DCI)m/e: 375 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1)(=[O:26])[CH3:25]>>[C:24]([O:27][CH2:28][C:29]1[C:34]([N:35]2[CH2:47][CH2:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[CH:33][C:32]([F:49])=[CH:31][C:30]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)CC1
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(C4CCN(C)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 41 %

Procedure:
Following Example 247c, 282c and 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d were reacted to give 282d in 41% yield.
Reaction SMILES: O.[O:2]=[S:3]1(=O)[C:7](C)(C)[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:4]1C>C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:5]3[C:6](=[O:10])[CH2:7][S:3](=[O:2])[CH2:4]3)[CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: CC1N(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)C(C)(C)S1(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CS(=O)CN1CCCCN1CCN(c2ccc(F)cc2)CC1
Yield: 52.5 %

Procedure:
A second run using NaIO4 (1.41 g), H2O (13 ml), 1 (2.02 g) and THF (20 ml) was conducted in a similar manner yielding 0.910 g of product.
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C@@H:14]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@@H:16]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:15]1=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:21]([O:20][CH:18]1[CH2:17][C@@H:16]([O:28][Si:29]([C:32]([CH3:35])([CH3:33])[CH3:34])([CH3:30])[CH3:31])[C:15](=[CH2:1])[C@H:14]([O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:19]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(OCc2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(OCc2ccccc2)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (1.55 g, 4.34 mmol) in dry THF (10 mL) cooled to 0° C. was added n-butyl lithium (n-BuLi, 2.71 mL, 4.34 mmol, 1.6 M solution in hexane), and the mixture was stirred for 10 min, and further stirred for 1 h at room temperature. To the resulting orange mixture was added over ca. 20 min period a solution of Compound 6 (1.0 g, 2.15 mmol) dissolved in dry THF (10 mL). After being stirred for 1 h at 0° C. and for 17 h at room temperature, the reaction mixture was poured into ice water, and extracted with AcOEt. The organic layer was rinsed with saturated brine, and dried over anhydrous MgSO4. The solvent was removed by evaporation. The residue was purified by silica gel column chromatography (5 g; 2% AcOEt/hexane), to yield Compound 7 (978.5 mg, 98%, single compound).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH:32]1([CH2:31][CH2:30][O:29][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:39])=[O:3])=[C:8]([CH3:38])[CH:9]=3)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:17]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg (57%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.06 min.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1)[CH3:30]>>[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1)[CH3:30]
Reactant: CCn1[nH]c2ccccc2c1=O
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-ethyl-1,2-dihydroindazol-3-one were reacted to give 252. LCMS m/z: 535.3 (MH+)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cn[nH]c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCn1cc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A solution of methyl pyrazole-4-carboxylate (10 g) in N,N-dimethylformamide (100 ml) was treated with potassium carbonate (10.95 g) and 1-bromodecane (19.31 g) and the mixture was stirred for 16 hours at room temperature. Ethyl acetate was added and the solution was washed with water (6x), dried over magnesium sulfate and the evaporated residue was purified by silica gel chromatography (5:1 hexane-ethyl acetate elution) to give methyl 1-decylpyrazole-4-carboxylate (19.4 g) as a white solid.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>>[C:12]1([N:11]2[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[S:1][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Reactant: BrCc1cccs1
Product: O=c1c2ccccc2nc(SCc2cccs2)n1-c1ccccc1
Yield: 37.4 %

Procedure:
The title compound was prepared in a yield of 37.4%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3-isobutyl-2-mercapto-4(3H)-quinazolinone and 2bromomethylthiophene in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]>>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CC(C)CCCBr
Agent: [H-]
Agent: [Na+]
Product: Cc1c(F)c(NCCCC(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 57.9 %

Procedure:
Substantially the same manner as that in Example 114 (1) was repeated except that 1.02 g (2.54 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1), 306 mg (7.65 mmol) of sodium hydride (60% oil dispersion) and 0.90 mL (6.3 mmol) of 1-bromo-4-methylpentane were used under argon atmosphere, to give 718 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-(4-methylpentylamino)-4H-1-benzopyran-4-one (yield: 58%).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([CH3:8])[N:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:3]([C:15]#[N:16])=[N:4][C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:6]([CH3:8])[N:7]=3)[CH2:28][CH2:29]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(Cl)c(C#N)nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75c, the 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was treated with 4-(4-fluoro-phenyl)-piperidine and N-ethyldiisopropylamine in N,N-dimethylformamide at room temperature to yield the 3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-5-methyl-6-phenyl-pyrazine-2-carbonitrile as yellow oil; MS: 373 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[ClH:1].[C:2]1([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2CCNCC2)cc1
Yield: 95 %

Procedure:
1,2,3,6-Tetrahydro-4-phenylpyridine hydrochloride (200 mg, 1.0 mmol) and 10% palladium-carbon (30 mg) were stirred in methanol (2 ml) for 19 hours in an atmosphere of hydrogen. The reaction solution was filtered and the resulting residue was thoroughly washed with methanol. Then the filtrate and washed solution were combined and evaporated under a reduced pressure to obtain 190 mg of the title compound (0.95 mmol, 93% in yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:23]([OH:25])=O)[S:5][C:6]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N:12][N:11]=[CH:10]2.C([N:29]([CH:32]([CH3:34])[CH3:33])CC)(C)C.C1(N)CC1>S(Cl)(Cl)=O.CCOC(C)=O>[CH:32]1([NH:29][C:23]([C:4]2[S:5][C:6]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:12][N:11]=[CH:10]4)=[C:2]([CH3:1])[CH:3]=2)=[O:25])[CH2:34][CH2:33]1
Reactant: Cc1cc(C(=O)O)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NC2CC2)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
4-Methyl-5-(1-morpholinophthalazin-6-yl)thiophene-2-carboxylic acid (140 mg, 309 μmol) was suspended in thionyl chloride (3.1 mL) and heated to 65° C. for 1 h. The reaction mixture was concentrated in vacuo and azeotropically dried with toluene, before being dissolved/suspended in tetrahydrofuran 99.9% (3.1 mL), diisopropylethylamine (216 μl, 1238 μmol) and cyclopropylamine (71 μl, 1238 μmol). The reaction was stirred at RT for 2 h, diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated via rotovap to give a crude yellow product. The crude was purified by chromatography, to obtain the title compound. Found MS (ES+): 395(M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CCOCC>[CH2:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C1COCCN1
Reactant: C#CCCCI
Solvent: CCOCC
Product: C#CCCCN1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 5-iodo-pent-1-yne (2.40 g, 12.3 mmol) and morpholine (2.70 g, 30.9 mmol) was heated to 80° C. for 15 min. The mixture was diluted with Et2O and filtered. The solid residue was discarded, and the mother liquor was extracted with 3N HCl. The aqueous layer was made basic with NaOH, and back-extracted into EtOAc. Drying (Na2SO4), and concentration gave the title compound as a pale orange oil. 1H NMR (CDCl3) δ 3.67 (t, 4H), 2.39 (m, 6H), 2.21 (td, 2H), 1.93 (t, 1H), 1.67 (quint., 2H).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3]([NH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Br)C(Br)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)C(Br)CCCBr)CC1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
To a solution of crude 2,5-dibromopentanoyl bromide (6.50 g, 20 mmol) and triethylamine (3.06 g, 30.2 mmol) in CH2Cl2 (40 mL) cooled to 0° C. was added tert-butyl-4-aminopiperidine-1-carboxylate (4.23 g, 21.1 mmol) in one portion. The reaction was allowed to stir for 4 hours at which point the reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (10 mL). The organic layer was separated and the aqueous layer washed with additional CH2Cl2 (3×15 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude material was purified over silica gel (3:1 hexanes/EtOAc) to give tert-butyl 4-(2,5-dibromopentanamido)piperidine-1-carboxylate (8.00 g, 90%) as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15].[CH3:16]I.O>CN(C)C=O>[CH3:16][N:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:5]3[C:4]1=[O:15]
Reactant: CI
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n2c3c(cccc31)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.36 g) was added to a solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10 g) obtained in Reference Example 131 in dimethylformamide (100 ml), the mixture was stirred at room temperature for 1 hour, methyl iodide (3.68 ml) was added, and the mixture was stirred at room temperature for 18 hours. Water (200 g) was poured into the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow solid (9.7 g). Further recrystallization from water-ethyl acetate afforded the title compound as colorless crystals (9.0 g).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[C:11]([Cl:18])[N:10]=[C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])=[CH:22][CH:21]=2)[N:8]=1.[OH-].[Na+]>O>[Cl:18][C:11]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([Cl:6])[N:8]=[C:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=3)=[O:28])=[CH:24][CH:25]=2)[N:10]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A THF (1.5 mL) solution of methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.048 g, 0.10 mmol) at room temperature was treated with 1N NaOH (1 mL). After stirring for 16 hours at room temperature, the reaction mixture was poured into water and washed with EtOAc. The aqueous layer was acidified with 1N HCl and back extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The remaining residue was chromatographed over silica gel eluting with 10% THF in CH2Cl2 containing 0.5% AcOH to give {4,6-dichloro-2-[4-(2-naphthoyl-amino)benzyl]pyrimidin-5-yl}acetic acid (0.007 g, 15% yield) as a white solid.
Reaction SMILES: [OH-].[K+].O.C([O:6][C:7](=[O:22])[CH:8](Br)[CH:9](Br)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)C>C(O)C>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:7]([OH:22])=[O:6])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C#CC(=O)O)cc1OC
Temperature: 10 °C

Procedure:
To a solution of 52.7 g (0.80 mol) of potassium hydroxide (85%) in 300 ml of ethanol and 30 ml of water 59.4 g (0.15 mol) of 2,3-dibromo-3-(3,4-dimethoxyphenyl)propionic acid ethyl ester are added at 25° C. over 10 minutes. The mixture is stirred under reflux for 2.5 hours. The solvent is evaporated, the residue dissolved in 200 ml of water and, with cooling to 10° C., the solution acidified with 2N hydrochloric acid. The resulting crystals are filtered off, washed with water and recrystallized from methanol/water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CN)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2ccccc2)cc1OC
Temperature: 15 °C
Yield: 85.2 %

Procedure:
To a mixture of 3,4-dimethoxybenzylamine (24.0 g, 0.144 mol), tetrahydrofuran (192 mL) and triethylamine (15.5 g, 0.153 mol) was added dropwise benzoyl chloride (20.7 g, 0.147 mol) at −7-0° C. During addition dropwise, tetrahydrofuran (24 mL) was added thereto to stir the mixture. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (12 mL), and tetrahydrofuran (24 mL) was added again thereto. The reaction mixture was gradually warmed to about 15° C. The reaction was monitored by TLC (eluent: hexane/ethyl acetate (1:1)). To the reaction mixture was added water (48 mL) at 5-8° C., and then added ethyl acetate (144 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (48 mL×2). The combined organic layers were washed successively with 10% hydrochloric acid (48 mL), saturated aqueous sodium hydrogen carbonate solution (48 mL), water (48 mL) and saturated brine (48 mL), and dried over magnesium sulfate (12 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. To the concentrate (40 g) was added ethyl acetate (89 g), and the mixture was homogenized with warming at 50° C., and cooled to 11° C. The solid was collected by filtration, washed with cold ethyl acetate (15 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-3,4-dimethoxybenzylamine (33.3 g, 85.4%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11](OCC)(=[O:14])[C:12]#[CH:13].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[OH:14][C:11]1[CH:12]=[CH:13][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(NN)cc1
Reactant: C#CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(-n2ccc(O)n2)cc1
Reaction time: 12 h
Yield: 60.3 %

Procedure:
A solution of 72.7 g of 4-methoxyphenylhydrazine in 700 ml of tert-butanol was treated dropwise at 30° C. with 56.8 g of ethyl propiolate. A total of 118 g of potassium tert-butoxide was then introduced in portions with ice cooling into the mixture thus obtained. After 12 h at 25° C., the solvent was distilled off under reduced pressure and the residue thus obtained was taken up in water. The aqueous solution was washed with dichloromethane and then acidified with conc. acetic acid with cooling to a pH of 9, the product being deposited as a solid. After washing and drying, 60.3 g of the title compound (60% of theory) were obtained; m.p.: 167°-170° C.