Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1
Reactant: OCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reactant: NS(=O)(=O)c1cc(CCCl)ccc1O
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cc(CCN2CCC(c3nc(CO)c(-c4ccc(F)cc4)o3)CC2)ccc1O
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-2-piperidin-4-yl-oxazol-4-yl]methanol (0.20 g; 0.72 mmol) in dry dioxane (6 ml) is treated with 5-(2-chloroethyl)-2-hydroxy-benzenesulfonamide (0.36 g; 1.45 mmol), sodium iodide (0.22 g; 1.45 mmol) and diisopropylethylamine (0.50 ml; 2.88 mmol) and heated to 100 C. for 16 hours. The reaction is cooled and partitioned between ethyl acetate (30 ml) and water (10 ml). The aqueous phase is washed with ethyl acetate (2×15 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography using a methanol/ethyl acetate gradient (5%-40%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-30%). Crystallization from methanol/ethyl acetate afforded the product as a white solid (0.055 g; 16%). HNMR (CD3OD): 7.75 (m, 2H), 7.64 (d, 1H, J=2.1 Hz), 7.31 (dd, 1H, J=8.4; 2.1 Hz), 7.23 (t, 2H, J=8.8 Hz), 6.92 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 3.12 (m, 2H), 2.96 (m, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 2.34 (m, 2H), 2.17 (m, 2H), 1.99 (m, 2H). Mass spectrum: m/e calculated (MH+)=476.6; observed (MH+)=476.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Br:11][C:12]1[C:13]([S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18])=[CH:14][S:15][CH:16]=1>O1CCCC1>[Br:11][C:12]1[C:13]([S:17]([NH:20][C:21]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=2)=[O:22])(=[O:18])=[O:19])=[CH:14][S:15][CH:16]=1
Reactant: O=C=NS(=O)(=O)c1cscc1Br
Reactant: COc1nc(C)nc(N)n1
Solvent: C1CCOC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cscc2Br)n1
Temperature: 10 °C

Procedure:
To 1.1 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 20 ml of tetrahydrofuran was added 2 g of 4-bromo-3-thiophenesulfonyl isocyanate in 5 ml of tetrahydrofuran. The mixture was then stirred and warmed on a steam bath for 15 minutes and allowed to stir at ambient temperature for 70 hours. It was then heated to reflux for 2 hours, cooled to 10° C., filtered and the filtrate evaporated. The residual oil was triturated to yield the desired product as a solid which after recrystallization from acetonitrile melted at 180°-183°, yield 1.5 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C=O.[C:19]([BH3-])#N.[Na+]>>[CH3:19][NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Agent: C=O
Agent: [Na+]
Product: CNc1cccc(CNC(=O)OC(C)(C)C)c1

Procedure:
Tert-butyl 3-aminobenzylcarbamate was converted to the target molecule following standard reductive amination conditions using formaldehyde and sodium cyanoborohydride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>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.CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
To Trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (3.715 g, 11.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (336 mg, 0.478 mmol), cuprous iodide (168 mg, 0.882 mmol) was added dimethylformamide (45 mL), triethylamine (1.72 g, 17.0 mmol), and trimethylsilylacetylene (2.229 g, 22.70 mmol). The resulting mixture was heated at 90° C. under an atmosphere of nitrogen for 15 minutes. This was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography with elution with CH2Cl2 to yield (4-tert-Butyl-2-nitro-phenylethynyl)-trimethyl-silane (3.193 g, 11.61 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:30][CH2:29][CH2:28][N:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCN4CCOCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (60 mg, 0.21 mmol) was reacted with 2-morpholinoethanamine (CAS 2038-03-1) (55 mg, 0.42 mmol), HATU (166 mg, 0.42 mmol) and DIPEA (0.18 mL, 1.1 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-morpholinoethyl)benzamide 11. LC/MS (ESI+): m/z 397 (M+H). 1H NMR (400 MHz, DMSO) δ 8.70 (t, J=5.6 Hz, 1H), 8.62 (d, J=10.2 Hz, 1H), 8.54 (dd, J=17.5, 8.6 Hz, 2H), 8.44 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.72 (d, J=9.3 Hz, 1H), 3.67-3.52 (m, 4H), 3.46 (dd, J=13.1, 6.6 Hz, 2H), 2.55-2.51 (m, 2H), 2.47-2.41 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH:24]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[C:23][CH:24]([NH2:26])[CH3:25])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1

Procedure:
2-{3-[4-(6-Benzyloxypyridin-3-yloxy)phenyl]-1-methylprop-2-ynyl}isoindole-1,3-dione (2.0 g, 2.32 mmol) and hydrazine hydrate (0.57 ml, 11.82 mmol) were stirred in 40 ml of ethanol at 100° C. for 2 h. The reaction mixture was concentrated, heated with ethyl acetate and filtered hot. The filtrate was concentrated. Yield: 800 mg (100%), M+H+: 345.15.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:11]1([CH2:21][CH2:22]O)[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:22][CH2:21][C:11]2[CH:20]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: OCCc1cccc2ccccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(OCCc2ccccc2)c1
Reaction time: 8 h

Procedure:
A stirred solution of 3-nitrophenol (1.39 g, 10 mmol), 1-naphthaleneethanol (1.89 g, 11 mmol), and triphenylphosphine (2.9 g, 11 mmol) in 100 ml of tetrahydrofuran was treated with a solution of 2.22 g (11 mmol) of diisopropylazodicarboxylate added dropwise. The resulting mixture was stirred overnight, and then concentrated and redissolved in a minimum amount of ethyl acetate. Purification on a silica gel column, eluting with 10% ethyl acetate in hexane, delivered 2.0 g of the ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:20])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (15.0 g, 64.0 mmol) in THF was added sodium hydride (55 wt % paraffin oil, 3.35 g, 77.0 mmol) at room temperature and methyl iodide (8.01 mL, 128 mmol) was successively added at room temperature. After stirring at room temperature for 15 min, the reaction mixture was poured into ice water. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent; 33% ethyl acetate/hexane) to give a mixture (1:1 (mol/mol), 14.2 g, 90%) of ethyl 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxylate and ethyl 3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxylate as a brown oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([F:21])=[C:10]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:6].[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:21][C:9]1[C:8]([N:7]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(NC(=O)CCCCl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCC2=O)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of methyl 3-[(4-chlorobutanoyl)amino]-2-fluoro-5-nitrobenzoate (D139) (8.5 g, 26.7 mmol, 1 equiv) in THF (100 ml) was added NaH (60% dispersion in mineral oil, 1.17 g, 29.4 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 1.5 h then diluted with AcOEt. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 2-fluoro-5-nitro-3-(2-oxo-1-pyrrolidinyl)benzoate (D140) (3.3 g, 43%) as a yellow solid. [M+H]+=283.1, RT=2.53 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=O)[C:31]2=[CH:30][CH:29]=1)[CH2:25][CH3:26])[CH3:23].Cl>C1COCC1>[CH2:22]([N:24]([CH2:27][C:28]1[N:33]=[C:32]2[CH2:34][O:35][C:36](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:31]2=[CH:30][CH:29]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (88 mg, 0.58 mmol.) in THF (4 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (1.55 mL of a 1M solution in THF, 1.55 mmol) is added slowly at 0° C. and the resulting solution is stirred for 20 min. The ice-bath is then removed and a solution of 2-diethylaminomethyl-7H-furo[3,4-b]pyridin-5-one (85 mg, 0.39 mmol) in THF (1 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 3 h and then poured into 10% aqueous HCl solution (20 mL) and stirred for 48 h at room temperature. The solid which precipitated from solution is collected by filtration. The solid is purified by chromatography (silica gel, gradient elution, 100:1 Chloroform/MeOH to 10:1 Chloroform/MeOH). The product containing fractions are concentrated to give the title compound (54 mg, 39%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.[C-:16]#[N:17].[K+]>CN(C=O)C>[F:15][C:4]1[C:3]([CH2:2][C:16]#[N:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(F)c(CC#N)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (20.0 g, 74 mmol; prepared as in WO 2007/081597) in DMF (530 mL) was added KCN (22.1 g, 339 mmol) and the mixture was stirred at 70° C. overnight. The mixture was concentrated, water and EA were added and the aq. layer was extracted with EA. The combined org layers were washed with brine, dried over MgSO4 and concentrated to afford the title intermediate as a beige solid (16.13 g, 100% yield).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([C:33]([F:35])([F:34])[F:36])[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC(C)C)nn1
Reactant: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)cn1
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC(C)C)nn4)c3)cc2C(F)(F)F)cn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:133-135° C.; 1H NMR (300 MHz, CDCl3) δ: 10.46 (1 H, s), 8.40 (1 H, s), 8.28-8.31 (1 H, d, J=8.1 Hz), 8.04 (1 H, s), 7.82-7.84 (1 H, d, J=8.1 Hz), 7.53 (1 H, s), 7.41-7.43 (1 H, d, J=8.4 Hz), 7.34-7.36 (2 H, m), 6.81 (1 H, s), 6.66-6.69 (1 H, d, J=9.3 Hz), 5.13-5.15 (1 H, d, J=6.3 Hz), 4.08 (1 H, m), 2.29 (3 H, s), 1.30-1.32 (6 H, d, J=6.0 Hz). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C27H23ClF3N6O: 539.1568. found: 539.1592.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=1)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:11]=[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[N:10][N:9]3[CH:13]=2)=[CH:21][CH:20]=1
Reactant: CCCOc1ccc(N)nn1
Reactant: COCCOc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 41 %

Procedure:
A stirred mixture of 6-propoxypyridazin-3-amine (4.50 g, 29.4 mmol), 2-bromo-1-[4-(2-methoxyethoxy)phenyl]ethanone (8.03 g, 29.4 mmol) and ethanol (280 mL) was heated under reflux for 2.5 hours. The mixture was cooled and sodium bicarbonate (2.50 g, 30 mmol) added. The mixture was stirred at room temperature for 15 hours, heated under reflux for 1 hour, then cooled and evaporated. The residue was extracted with chloroform (150 mL) and the extract washed with saturated, aqueous, sodium chloride solution (50 mL), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-2% methanol in dichloromethane afforded a green/brown solid. Treatment with decolourising charcoal in diethyl ether solution (three times) and recrystallization from cyclohexane gave Compound 63 (3.95 g, 41%) as pale green crystals. M.p. 82.5-84° C. 1H n.m.r. (CDCl3) δ 1.06, t, J=7.2 Hz, 3H; 1.75-1.94, m, 2H; 3.47, s, 3H; 3.74-3.81, m, 2H; 4.14-4.21, m, 2H; 4.27, t, J=6.6 Hz, 2H; 6.68, d, J=9.3 Hz, 1H; 7.00, d, J=8.8 Hz, 2H; 7.76-7.88, m, 3H; 7.94, s, 1H. Mass spectrum (APCI+) m/z 328 (M+H, 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N12CCN(CC1)CC2>CCO>[C:13]([O:17][C:18]([N:20]([CH3:26])[CH:21]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
4,7-Dichloroquinoline (0.49 g, 2.0 mmol), 3-[tert-butoxycarbonyl(methyl)amino]pyrrolidine (1.96 mL, 10.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.12 g, 10.0 mmol) are heated in EtOH for 15 h at reflux. The reaction mixture is concentrated, diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][C:44]([F:47])([F:46])[F:45])[CH:40]=[CH:39][C:38]=1[S:48](Cl)(=[O:50])=[O:49]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:48]([C:38]1[CH:39]=[CH:40][C:41]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:42][C:37]=1[O:36][CH3:35])(=[O:49])=[O:50])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 31.7 %

Procedure:
With 150 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyridin-4-yl piperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one, which is the compound described in EXEMPLE 1 of Publication No. WO03/008407, and 100 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 73 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[N:20]=[C:21]=[S:22])([CH3:10])[CH3:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:18])[CH3:19])[C:12]=1[N:20]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:21]1=[S:22])([CH3:9])[CH3:10]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2c(C(C)C)cccc2C(C)C)C1=S
Yield: 27 %

Procedure:
A mixture of the crude N-ethyl glycine (18.4 g), 2,6-diisopropylphenyl-isothiocyanate (21.9 g), triethyl amine (20.2 g) and chloroform (300 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (8.2 g) was obtained as a light yellow solid, m.p. 159°-161° C. Anal. Calcd. for. C17H24N2OS: C, 67.07; H, 7.94; N, 9.20. Found: C, 66.92; H, 8.03; N, 9.13. Mass spectrum (PBEI, M.+) m/z 304.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][CH2:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:24][OH:25].[OH-].[NH4+]>CO.O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[N:24][OH:25])[CH2:16][CH2:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCC(=O)c1cccc2c1CC(N(CCC)CCC)CC2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(=NO)c1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.3 %

Procedure:
2-Di-n-propylamino-8-butyryl-1,2,3,4-tetrahydronaphthalene (1 g; 3.3 mmol) (prepared as in Example 22) was dissolved in 40 ml of methanol, and 2.3 g (33 mmol) of hydroxylamine hydrochloride dissolved in water were added. The mixture was stirred at room temperature for 20 hours after which it was poured into water, and the pH was adjusted to 10 using ammonium hydroxide. The mixture then was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated. The residue was placed on a silica gel column and was eluted with a gradient mixture of 3-5% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined and evaporated to give 1.1 g of 2-di-n-propylamino-8-(1-oximino-butyl)-1,2,3,4-tetrahydronaphthalene. (Rf=0.30 in 4% methanol and methylene chloride containing a trace of ammonium hydroxide) MS(FD): 316(100).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]([NH2:13])([CH3:12])[CH3:11]>>[CH:10]([NH:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:12])[CH3:11]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)N
Product: CC(C)Nc1ccccc1C#N

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and isopropylamine.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:4]1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:19]2[CH2:18][CH2:17][C:5]3([O:4][C:3](=[O:2])[N:7]([C:8]4[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=4)[CH2:6]3)[CH2:21][CH2:20]2)=[CH:25][C:24]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Product: O=C(O)c1ccc(N2CC3(CCN(Cc4ccc(Cl)c(C(F)(F)F)c4)CC3)OC2=O)cc1

Procedure:
The title compound was prepared from 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid hydrochloride salt (20 mg, 0.064 mmol; Example 5-1, Step 4) and 4-chloro-3-trifluoromethylbenzaldehyde (14.68 mg, 0.071 mmol), following essentially the same procedure described in Example 7-1. The title compound was obtained as a white solid (17.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]=[O:21])[CH:6]=[CH:5]2.[CH2:22]([Mg]Br)[CH:23]([CH3:25])[CH3:24].C1COCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:20]([OH:21])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C=O)nc12
Reactant: CC(C)C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(Br)cc2ccc(C(O)CC(C)C)nc12
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of diethyl 6-bromo-2-formyl-8-quinolylphosphonate (293 mg, 0.78 mmol) in toluene (6 mL) at −10° C. was added a 2M solution of isobutylmagnesium bromide in THF (1.59 mL, 3.12 mmol). The mixture was stirred at −10° C. to −5° C. for 2 h. Aqueous NH4CL was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 179 mg (53%) of the title compound