Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:21]1[CH:22]=[C:23]([F:25])[CH:24]=[C:19]([Cl:18])[CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(Cl)c3)c(=O)n12
Temperature: 100 °C
Yield: 55.7 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (3-chloro-5-fluorophenyl)boronic acid (0.080 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.5 mL, 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-25% ethyl acetate/hexanes) to give the desired product (0.077 g, 55%). LCMS calculated for C15H12ClFN5OS (M+H)+: m/z=364.0. Found: 364.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:11]=[C:12]3[C:18]([NH:19][C:20](=O)[C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:23][C:22]=4[NH:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:11]=[C:12]3[C:18]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:23][C:22]=4[NH:34][CH:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[N:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(CNc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 17.2 %

Procedure:
100 mg (0.173 mmol) of N-(5-(3,5-difluorophenylthio)-1-H-pyrazolo[3,4-b]pyridine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide is added, in small fractions, to a solution of 19.64 mg (0.518 mmol) of LiAlH4 in 3 ml of anhydrous tetrahydrofuran under argon at 0° C. The reaction mixture is heated at 90° C. for 15 hours. An additional portion of 20 mg of LiAlH4 is then added and the reaction medium stirred at 90° C. for 5 hours. 45 μl of water at 0° C. is then added to the reaction mixture, followed by 45 μl of sodium hydroxide (15% wt) and finally 120 μl of water. The reaction mixture is stirred at 25° C. for 1 hour and then filtered on Dicalite. After evaporation of the solvents, the crude product is purified by chromatography. 16.80 mg (17%) of 5-(3,5-difluorophenylthio)-N-(4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzyl)-1H-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid is obtained.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:20]3[S:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:19]=3[CH3:18])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1csc2ccccc12
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccccc4c3C)c(C)nc12
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.145 mmol), 3-methyl-benzothiophene (7.25 mmol), Pd2 dba3 (0.0072 mmol), triphenylphosphine (0.029 mmol), and cesium carbonate (0.29 mmol) in previously degassed DMF (0.5 ml) is added to a pressure tube with a stirring bar. Mixture is degassed for 30 min. After heating for 16 h at 130° C., the reaction mixture is cooled, diluted with diethylether and washed with saturated aqueous ammonium chloride solution. The organic layer is dried over anhydrous magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography using mixtures of hexane-ethyl acetate as eluent to give the title compound (80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[NH:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]2=[CH:10][CH:9]=1.[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]3[CH2:42][O:41]B(O)[C:39]=3[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:21])[CH3:20].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]([CH2:42][OH:41])=[C:39]([N:14]3[C:12]4=[N:13][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[CH:9][CH:10]=[C:11]4[C:16]([C:17]#[N:18])=[CH:15]3)[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:20])[CH3:21]
Reactant: N#Cc1c[nH]c2nc(-c3ccccc3F)ccc12
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(-c6ccccc6F)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
In a 25 mL round-bottomed flask, 6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (200 mg, 843 μmol), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (297 mg, 843 μmol, Eq: 1.00) and copper acetate (207 mg,) were combined with 1,2-dichloroethane (10 ml) to give a blue suspension. Pyridine (133 mg, 136 μl, 1.69 mmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 50% to 60% EtOAc in hexanes), then by SFC gave 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (163 mg, 13%).
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH2:10][CH:5]([C:6]([CH3:11])=[CH:7][CH2:8]2)[CH:4]([OH:12])[CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][CH:4]1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH2:10][CH:5]1[C:6]([CH3:11])=[CH:7][CH2:8]2)(=[O:15])[CH3:14]
Reactant: CC1=CCC2CC1C(O)CC2C
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OC1CC(C)C2CC=C(C)C1C2
Yield: 86.9 %

Procedure:
To a solution of 10 g (60.2 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-ol [IA] in 40 ml of tetrahydrofuran were added 6.8 g (66.6 mmol) of acetic anhydride and 5.2 g (65.7 mmol) of pyridine and the resulting mixture was heated under reflux for 5 hours. After cooling, the tetrahydrofuran was distilled off, the residue was subjected to column chromatography and eluate with toluene gave 10.9 g of the title compound, which had a woody-like smell.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]5[NH:28][CH:29]=[CH:30][C:23]=45)=[CH:20][N:19]([CH2:31][C:32](O)=[O:33])[N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N=C=NCCCN(C)C)C.[CH3:46][O:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([NH2:54])[CH:49]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([NH:54][C:32](=[O:33])[CH2:31][N:19]2[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])=[CH:12][CH:13]=3)=[N:18]2)[CH:51]=[CH:52][CH:53]=1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: COc1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)Cn2cc(-c3ccnc4[nH]ccc34)c(-c3ccc(NC(=O)Nc4ccccc4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of [3-(4-{[(phenylamino)carbonyl]amino}phenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (0.166 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.249 mmol), 4-dimethylaminopyridine (0.249 mmol) and N,N-dimethylformamide (3.2 mL) at room temperature was added m-anisidine (0.415 mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, taken up in ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by Gilson reverse phase HPLC afforded the title compound as a white solid (26%). ESMS [M+H]+: 558.4
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([C:37]([N:39]3[CH2:42][CH:41]([O:43][C:44]4[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=4)[CH2:40]3)=[O:38])=[N:34][N:33]=2)=[CH:28][CH:27]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[N:8]1([CH2:48][C:47]2[CH:46]=[CH:45][C:44]([O:43][CH:41]3[CH2:42][N:39]([C:37]([C:35]4[O:36][C:32]([C:29]5[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)=[N:33][N:34]=4)=[O:38])[CH2:40]3)=[CH:51][CH:50]=2)[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: C1CNC2(C1)CCOC2
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCCC56CCOC6)cc4)C3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
7-Oxa-1-azaspiro[4.4]nonane TFA salt (0.07 g, 0.29 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.044 ml, 0.32 mmol) was added, followed by 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.11 g, 0.29 mmol) and finally sodium triacetoxyhydroborate (0.123 g, 0.58 mmol). The mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.072 g (51%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62-1.74 (m, 3H), 1.79-1.9 (m, 2H), 2.10 (dd, 1H), 2.42 (dd, 1H), 2.53-2.55 (m, 1H), 3.41 (d, 1H), 3.48 (d, 1H), 3.63 (d, 1H), 3.69 (q, 1H), 3.80 (d, 1H), 3.88 (s, 3H), 3.91 (td, 1H), 4.09 (dd, 1H), 4.54 (dd, 1H), 4.62 (ddd, 1H), 5.08 (ddd, 1H), 5.15 (ddd, 1H), 6.84 (d, 2H), 7.17-7.21 (m, 2H), 7.25 (d, 2H), 8-8.05 (m, 2H). MS (APCI+) m/z 491.2 [M+H]+, LC purity: 96%
Reaction SMILES: [CH:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[N:5])=O.C([O-])(=O)C.[Na+].Cl.[NH2:17][CH2:18][C:19]#[N:20].CO>CO.O.C(OCC)(=O)C.CCCCCC>[C:18]([CH2:19][NH:20][CH:1]=[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[N:5])#[N:17]
Reactant: CCCCCC(C#N)C=O
Reactant: N#CCN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CCCCCC(C#N)=CNCC#N

Procedure:
2-Formylheptanonitrile (10.7 g), sodium acetate (7.9 g) and aminoacetonitrile hydrochloride (8.9 g) were mixed together in 200 ml of methanol: water (8:2). After stirring for 2 hours at ambient temperature the methanol was removed under aspirator vacuum and the residue partitioned between ethyl acetate and water. The layers were separated and the ethyl acetate layer was washed with brine, dried (Na2SO4) and concentrated to leave a yellow oil. Chromatographic purification of the material over silica gel using ethyl acetate/hexane as the eluent afforded a light yellow solid as a mixture of isomers (11.6 g, 85%): tlc, Rf =0.37 and 0.50 silica gel, ethyl acetate:hexane (1:1).
Reaction SMILES: [CH2:1]([NH:7][C@@H:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].C([Li])CCC.[C:21]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])/[CH:22]=[CH:23]/[CH:24]=[CH:25]/[CH3:26]>>[CH2:1]([N:7]([C@@H:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@@H:23]([CH:24]=[CH:25][CH3:26])[CH2:22][C:21]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: C/C=C/C=C/C(=O)OC(C)(C)C
Reactant: C/C=C/C=C/CN[C@@H](C)c1ccccc1
Agent: [Li]CCCC
Product: CC=CC=CCN([C@@H](C=CC)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Yield: 128.9 %

Procedure:
(S)-(E,E)-N-Hexa-2,4-dienyl-α-methylbenzylamine (3) (0.500 g, 2.49 mmol), 1.6M butyllithium (1.35 ml, 2.16 mmol) and t-butyl sorbate (11) (0.279 g, 1.66 mmol) were reacted according the procedure of Example 1. Flash chromatography of the product on silica gel [ethyl acetate/petroleum ether (1:19)] afforded the title compound as a colourless oil (0.791 g, 72%). δH (200 MHz; CDCl3) 7.39-7.18 (5H, m, Ph), 6.12-5.93 (2H, m, CH=CH--CH=CH), 5.69-5.41 (4H, m, CH3CH=CH and CH=CH--CH=CH), 4.0 (1H, q, J=6.8, PhCHCH3), 3.87-3.75 (1H, m, CH3CH=CHCH), 3.21-3.09 (2H, m, NCH2), 2.40 (1H, dd, J=14.1 and 6.4, CH2CO2), 2.25 (1H, dd, J=14.1 and 8.5, CH2CO2), 1.76-1.71 (6H, m, CH3CH=CHCH and CH=CHCH3), 1.41 (9H, s, (CH3)3C), 1.37 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]=[O:11])=[CH:2]1.[C-]#N.[Na+].[CH3:15][OH:16]>[O-2].[O-2].[Mn+4]>[CH3:15][O:16][C:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)=[O:11]
Reactant: CO
Reactant: O=Cc1csc2ccccc12
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To a methanol (500 mL) solution of 1-benzothiophene-3-carbaldehyde (51.3 g, 300 mmol), sodium cyanide (22.0 g, 449 mmol) was added thereto at room temperature. Then, manganese dioxide (89.0 g, 901 mmol) was added at 0° C. The reaction mixture was stirred for 20 hours at room temperature, and then the reaction liquor was filtered. The filtrate was concentrated under reduced pressure. To the obtained residue, diethyl ether (200 mL), a saturated aqueous solution of sodium hydrogen carbonate (150 mL) and water (150 mL) were added, and the mixture was partitioned. The aqueous layer was extracted with diethyl ether (200 mL), and the organic layer was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography using silica gel (silica gel 300 g, hexane:diethyl ether=100:0 to 85:15), to obtain the title compound (52.1 g, 90%) as a transparent oily matter.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (800 mg) was dissolved in DMF (8 mL) and tert-butyl bromoacetate (452 mg) was added. Potassium carbonate (336 mg) was further added, and the mixture was stirred at room temperature overnight. After water was added carefully to the reaction solution, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further recrystallization with IPE afforded 704 mg of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.[Cl-].[Na+].O.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[O:19][CH3:20]
Reactant: Oc1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1Oc1cccc(Cl)c1
Temperature: 95 °C
Yield: 91.8 %

Procedure:
In a 250 mL round-bottom flask was added 3-chlorophenol (4.13 g, 32.1 mmol), 1-fluoro-2-methoxy-4-nitrobenzene (5.00 g, 29.2 mmol), potassium carbonate (6.06 g, 43.8 mmol) and acetonitrile (25 mL). The reaction was heated to 95° C. for 48 hours. The reaction was cooled to room temperature and was purified by column chromatography on silica gel (hexane/ethyl acetate=3:1). The reaction was poured into sodium hydroxide (2 mol) and extracted with ethyl acetate. The ethyl acetate layers were washed with sodium hydroxide (2 mol), water and brine. The combined organic layers were dried over sodium sulfate, filtered and solvent removed. A small amount of methanol added and oil was triturated to obtain the title compound (7.5 g) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.C[C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:11]2[CH:2]=[N:3][C:4]([N:18]3[CH2:17][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:9][CH:10]=2)[C:11]=1[CH3:12]
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.442 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][N:6]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN=Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 77.46 g (0.617 mol) of glycine methylester hydrochloride in CH2Cl2, 92 ml (0.66 mol) of triethylamine, a solution of 60 g (0.44 mol) of p-anisaldehyde in 50 ml of CH2Cl2 and 40 g of MgSO4 are successively added at 0–5° C. under N2 atmosphere. After stirring for 18 h at r.t. the reaction mixture is filtered through celite and washed with CH2Cl2. The filtrate is concentrated under reduced pressure and then the crude mixture is diluted with AcOEt. The AcOEt solution is filtered again to remove triethylamine hydrochloride and the filtrate diluted with toluene and concentrated under reduced pressure (azeotropic removal of H2O) to give 91.3 g of [(4-methoxy-benzylidene)-amino]-acetic acid methyl ester as light yellow crystals; NMR (C6D6): 3.18 (s, 3H), 3.34 (s, 3H), 4.13 (s, 3H), 6.69 (d, 2H, J=8.56 Hz), 7.70 (d, 2H, J=8.56 Hz), 7.79 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:36][CH2:35][C:11]2([C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH3:34])[CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1.CO.C(Cl)Cl>[ClH:37].[CH3:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:29]1[CH:26]1[CH2:27][CH2:28][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([N:15]3[CH2:14][CH2:13][CH2:12][C:11]4([CH2:35][CH2:36][NH:8][CH2:9][CH2:10]4)[C:16]3=[O:17])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)cc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCNCC4)C3=O)cc2)C1
Yield: 105.2 %

Procedure:
2-{4-[3-(2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxyl ic acid tert-butyl ester (example 3) (22 mg, 0.044 mmol) was treated with 4 M HCl (0.5 mL, 2 mmol, excess) in dioxane and methanol (0.5 mL) at rt for 4 h when TLC (10% MeOH in DCM) showed the reaction was complete. The volatiles were removed in vacuo and the residue was dried under high vacuum for 2 h to obtain 20 mg (100% yield) of the title compound as a gummy solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([CH2:8][Br:18])[CH:7]=1
Reactant: COc1ncc(C)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: O
Product: COc1ncc(CBr)cc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-2-methoxy-5-methyl-pyridine (Step AM3) (3.0 g, 14.7 mmol), was added NBS (3.1 g, 17.6 mmol) and AIBN (121 mg, 0.7 mmol) and the mixture was stirred at 80° C. for 1 h. H2O and CH2Cl2 were added and the phases were separated. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (heptane/EtOAc, 95:5→0:100). tR: 1.10 min (LC-MS 1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].C([O:13][C:14]([C:16]1[C:25]([Br:26])=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)C.O.N>O1CCCC1>[Br:26][C:25]1[C:16]([CH2:14][OH:13])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CCOC(=O)c1cc2ccccc2cc1Br
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccccc2cc1Br
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To the mixture of lithium aluminum hydride (430 mg, 9.0 mmol) and tetrahydrofuran (15 ml) under nitrogen atmosphere, aluminum chloride (1.7 g, 13 mmol) was added at 0° C. (an outer temperature), and the obtained reaction mixture was stirred at the same temperature for 1 hour. Subsequently, 3-bromo-naphthalene-2-carboxylic acid ethyl ester (500 mg, 1.8 mmol) was added to the reaction mixture at 0° C. (an outer temperature), and the reaction mixture was stirred at the same temperature for 1.5 hours. 28% ammonia water was added to the reaction mixture, followed by filtration with Celite. The solvents were evaporated under reduced pressure from the filtrate, and then the obtained residue was purified with NH-silica gel column chromatography (heptane:ethyl acetate=3:1), thereby obtaining the entitled compound (280 mg, 67%).