Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[CH3:14].C(O)C.S(=O)(=O)(O)O>CCOCC>[CH:13](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[CH3:14]
Reactant: CC=O
Reactant: NNC1=NCCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: CC=NNC1=NCCc2ccccc21

Procedure:
A mixture of 1-ethoxy-3,4-dihydroisoquinoline (1.0 g.), hydrazine monohydrochloride (0.4 g.) and absolute ethanol (15 ml.) was heated under reflux (for 40 min.). The solution was cooled, filtered and concentrated and the residue was recrystallized from ethanol-ether, affording 1-hydrazino-3,4-dihydroisoquinoline hydrochloride (0.9 g., m.p. 205°-207° C.). C. A mixture of 1-hydrazino-3,4-dihydroisoquinoline (8.0 g.), acetaldehyde (20 ml.) and ethanol (20 ml.) was allowed to stand at room temperature (for 45 min). Ethanolic sulfuric acid was added until the solution was distinctly acidic. Ether was added. The resulting oil crystallized and the crystals were recrystallized from ethanol-ether, affording 1-(2-ethylidenehydrazino)-3,4-dihydroisoquinoline (I: X=CH3, X'=Y=Y'=Z=Z'=H) sulfate in two crops (8.3 g., m.p. 152°-154° C.; 0.5 g., m.p. 152°-155° C.).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)[OH:32].COCCOC>O>[CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][OH:32])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Solvent: O
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A mixture of 100 mg of 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, 0.2 ml of 1N sulfuric acid, and 1.0 ml of 1,2-dimethoxyethane is heated under reflux for one hour, diluted with water, and filtered to yield 2,3-dihydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, mp 112°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[BH4-].[Na+].N.O>C(O)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:12]2[CH2:13][CH2:14][N:15]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][CH2:17]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: O=C1CCCCC1
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C3CCCCC3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A mixture of compound 6 (100 mg, 0.29 mmol), cyclohexanone (36 ul, 0.35 mmol) and Ti(OPr-i)4 (0.17 ml, 0.58 mmol) was ultrasonicated for 1 hr and then stirred at rt overnight under a nitrogen atmosphere. The mixture was diluted with ethanol (5 ml) and followed by addition of NaBH4 (33 mg, 0.87 mmol). The resulting mixture was stirred for 12 hr at rt. 2N NH3.H2O was added to quench the reaction and the mixture filtered through celite. The filtrate was extracted with ethyl acetate several times and the combined organic phases washed with water and brine, and dried over Na2SO4. Concentration in vacuo and MPLC purification (0:100 to 100:0 EtOAc:Heptane eluting on silcal gel 60) gave the title compound (24 mg, 20%).
Reaction SMILES: [C:1]([C:3](=[C:8](C(OC(F)(F)F)=O)[C:9]([F:12])([F:11])[F:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.N1C=CC=CC=1.O>[Cl:23][C:8]([C:9]([F:12])([F:11])[F:10])=[C:3]([C:1]#[N:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C(C#N)=C(C(=O)OC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(C#N)=C(Cl)C(F)(F)F

Procedure:
To a mixture of the compound 2a and 2b obtained in the above step (1) (27.6 g) in methylene chloride (200 mL) were gradually added dropwise oxalyl chloride (31.6 mL) and a few drops of pyridine, and the mixture was refluxed under heating for 4 hours. The reaction mixture was gradually poured in water, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give methyl 3-chloro-2-cyano-4,4,4-trifluoro-2-butenoate as a crude product.
Reaction SMILES: CC[N:3]([C:6]1C=C[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[N:3]1[CH:6]=[CH:11][C:10]([C:9]#[C:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: CCN(CC)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(C#Cc2ccncc2)cc1
Reaction time: 16 h

Procedure:
4-pyridyl-hydroxymethyldiphenylphosphonate (6) (15.3 g, 46 mmol), diethylaniline (4 mL), and phosphorous oxychloride (50 mL) were warmed to 90° C. for 16 h. The reaction was quenched by pouring the reaction mixture over ice (400 g). Potassium carbonate was added until a pH of 8 was obtained for the solution followed by extraction with methylene chloride (3×200 mL). After drying (MgSO4), the reaction was concentrated to afford crude 4-pyridyl-chloromethyldiphenylphosphonate (7) as a solid which was used in the next step without further purification: Mass Spectrum (CI) 360 (MH+). Potassium t-butoxide (3.30 g, 29.2 mmol) was added as a solid to 4-pyridyl-chloromethyldiphenylphosphonate (7) (5.00 g, 13.9 mmol), 4-fluorobenzaldehyde (8) (2.00 g, 15.3 mmol), and THF (70 mL) at 23° C. under argon. After 16 h, the reaction was quenched by adding to water (200 mL) over 3 mm. After adjusting the pH of the solution to 7 with 1 N HCl, the mixture was extracted with ethyl acetate (3×350 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) as a solid: Mass Spectrum (CI) 198 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH3:41]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH:35]3[CH2:39][CH2:38][CH2:37][N:36]3[CH2:40][CH3:41])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CCN1CCCC1CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.76 g, 0.020 mole), 1,1'-carbonyldiimidazole (3.24 g, 0.020 mole), and anhydrous tetrahydrofuran (250 ml) was stirred at room temperature with a stream of nitrogen bubbling through for 2 hrs. The nitrogen flow was stopped and a solution of 2-(aminomethyl)-1-ethyl pyrrolidine (2.56 g, 0.02 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stoppered and stirred at room temperature over the weekend. The reaction was concentrated in vacuo and partitioned between ethyl acetate (100 ml) and 5% potassium hydroxide solution (50 ml). The layers were separated and the aqueous portion washed with ethyl acetate (50 ml), water (25 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The solid residue was converted to the dihydrochloride salt and crystallized from isopropyl alcohol-diethyl ether. Recrystallization from isopropyl alcohol-isopropyl ether gave 1.38 g (15%) of an off-white solid, mp 186°-190° C. with decomposition.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.[O:8]=[C:9]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([F:44])([F:43])[F:42].O>CN(C=O)C>[O:8]=[C:9]([N:27]1[CH2:28][CH2:29][N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:42])([F:43])[F:44])[CH2:31][CH2:32]1)[CH2:10][NH:11][C:12](=[O:26])[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
K2CO3 (130 mg, 0.95 mmol) was added to N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (141 mg, 0.38 mmol) in 5 mL of DMF. After 10 minutes atr room temperature, 1-Bromomethyl-2-trifluoromethyl-benzene (75 mg, 0.32 mmol) was added and the resulting mixture was stirred at 60° C. for 4 hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulphate and concentrated. Purification by column chromatography (60-120 mesh silica gel using 6:4 EtOAc and Hexane as the eluent) afforded N-{2-Oxo-2-[4-(2-trifluoromethyl-benzyl)-piperazin-1-yl]-ethyl}-4-phenoxy-benzamide in 39% yield. LC-MS purity: 86%. 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.7 (q, 2H), 7.4 (m, 3H), 7.2 (t, 1H), 7.1 (m, 2H), 7 (m, 2H), 4.1 (d, 2H), 3.7 (s, 2H), 3.5 (m, 4H), 2.4 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:58])([CH3:59])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COc2ccc(CC(NC(=O)c3cccc4c(Cl)cccc34)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (260 mg, 1.26 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (242 mg, 1.26 mmol) and 1-hydroxybenzotriazole monohydrate (193 mg, 1.26 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.20 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-1-naphthamide (473 mg, 76%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:7]1=[O:34])=[O:4].[C:40](OC(=O)C)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl>[C:40]([NH:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][C:20]=3[S:19](=[O:32])(=[O:33])[N:18]=2)[C:7]1=[O:34])=[O:4])(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CCC1(NC(=O)CN)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC(=O)NC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of the product of Example 46 (10 mg, 0.017 mmol) in dichloromethane (0.25 mL) was added acetic anhydride (8 μL, 0.087 mmol) followed by addition of triethylamine (7 μL, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was then diluted with dichloromethane (1 mL) and washed with aqueous 1 N HCl (2×0.5 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was dissolved in methanol (0.5 mL) and treated with excess K2CO3 for 30 min. The heterogeneous solution was filtered and the filtrate concentrated in vacuo. The residue was then taken up in ethyl acetate (1 mL), washed with aqueous 1 N HCl (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10% methanol/dichloromethane) afforded the title compound as a light yellow solid (5 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.61-0.75 (m, 6H), 0.79-0.97 (m, 1H), 1.16-1.35 (m, 2H), 1.56-1.71 (m, 1H), 1.78 (s, 3H), 1.83-1.97 (m, 1H), 2.99 (s, 3H), 3.64-3.88 (m, 2H), 7.26-7.34 (m, 2H), 7.35-7.44 (m, 2H), 7.46 (d, J=2.21 Hz, 1H), 7.91 (t, J=5.52 Hz, 1H), 7.96-8.02 (m, 1H), 8.36 (s, 1H), 9.86 (s, 1H), 15.39 (s, 1H); MS m/z 618.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:4]2[CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([N:54]([CH2:53][C:52]3[CH:51]=[CH:50][C:49]([O:48][CH3:47])=[CH:65][CH:64]=3)[CH2:55][C:56]3[CH:57]=[CH:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=3)=[O:13])=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnn2ccc(Br)cc12
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(Br)cc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (I-25) (66 mg, 0.27 mmol) in DMF (3 mL) was added DIEA (0.14 mL) and HATU (0.10 g, 0.27 mmol). The reaction was stirred for 30 minutes at room temperature then bis(4-methoxybenzyl)amine (70 mg, 0.27 mmol) was added. Stirring was continued at room temperature for 12 hours. The reaction was diluted with EtOAc, washed with brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by flash column chromatography on silica with hexanes/EtOAc gradient as eluant to yield 5-bromo-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-26). 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=2.4 Hz, 1 H), 8.26 (dd, J=0.4, 7.2 Hz, 1 H), 7.88 (s, 1 H), 7.22 (d, J=8.0 Hz, 4 H), 7.00 (dd, J=2.0, 7.2 Hz, 1 H), 6.91 (d, J=8.4 Hz, 4 H), 4.67 (s, 4 H), 3.82 (s, 6 H). MS m/z 480.1, 482.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][C:31]#[N:32]>C1COCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[C:6]([F:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2)[CH2:30][C:31]#[N:32]
Reactant: N#CCBr
Reactant: COC(=O)Cc1c(F)ccc2ccc(OC)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1c(F)ccc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (7-fluoro-2-methoxy-quinolin-8-yl)-acetic acid methyl ester (1.0 g, 4.0 mmol; prepared as in WO 2007/081597) in THF (10 mL) cooled to −78° C. was added LiHMDS (1M, 4.43 mL, 1.2 eq.) dropwise over 15 min. The resulting orange mixture was stirred at −78° C. for 2 h. Bromoacetonitrile (1.5 eq.) was added dropwise over 20 min and stirring was continued at −78° C. for an additional 2 h. The reaction was quenched with water and extracted with EA (3×). The combined org. phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by CC (Hept/EA 2:1 to 1:1) to afford the title intermediate as a colourless solid (953 mg, 82% yield). MS (ESI, m/z): 289.4 [M+H+].
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]>>[C:1]([S:3][CH2:7][CH:6]([CH3:8])[C:5]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(C)C(=O)O
Product: CC(=O)SCC(C)C(=O)O
Reaction time: 18 h

Procedure:
A mixture of thioacetic acid (50 g.) and methacrylic acid (40.7 g.) is heated on the steam bath for one hour and then stored at room temperature for 18 hours. After confirming by nmr spectroscopy that complete reaction of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic acid is separated in the fraction with boiling point 128.5°-131° (2.6 mmHg.), yield 64 g.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1>CN(C=O)C.O>[CH2:2]([CH:3]([O:6][C:10]1[C:11]2[CH:20]=[CH:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[C:13](=[O:17])[N:14]([CH3:16])[N:15]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-pentanol (0.093 ml, 0.86 mmol) in DMF (2 ml) was added sodium hydride (60% in oil, 34 mg, 0.86 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (64.8 mg, 0.20 mmol). The mixture was stirred at 60° C. for 1.5 hours, then diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 52 mg (69%) of the title compound as crystals.
Reaction SMILES: N[C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C([N:37](CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][CH:2]=[CH:24][C:23]=3[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[C:26]([NH2:37])=[O:33])=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1cnccc1-c1ccccc1C(=O)N1Cc2ccccc2Cc2ccccc21
Yield: 14.3 %

Procedure:
A mixture of 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.551 g (3 mmol) of nicotinoyl chloride, hydrochloride, 0.606 g (6 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 17 ml of dichloromethane is refluxed for 7 hours. The mixture is washed with H2O, 2N citric acid, H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from hexane-dichloromethane to give 0.12 g of crystals, m.p. 217°-220° C. Anal Calc'd for C27H21N3O2H2O: C,74.1; H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cc(CCl)on1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C(=O)CCl)c2c(C)cccc2C)on1
Yield: 30 %

Procedure:
A mixture of 4.54 g N-chloroacetyl-2,6-dimethylaniline and 3 g 3-methyl-5-chloromethylisoxazole (prepared as in Example 8 above) in 100 ml dry dimethylformamide was treated with 1.33 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield 2.0 g pure product, m.p. 78°-82° C. This product is shown as Compound 1 in Table I. C15H17ClN2O2 : calc., %C 61.54, %H 5.81, %N 9.57; found, %C, 63.37, %H 6.16, %N 9.65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1.[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[NH2:20])([CH3:16])[CH3:15]>>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([NH:20][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)([CH3:13])[CH3:15]
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: COc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Yield: 12.7 %

Procedure:
Using 5-methoxysalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C.CN(C)C=O>ClCCl>[CH3:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1NCCc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1c2ccccc2CCN1c1ccnc(Cl)n1
Yield: 28.9 %

Procedure:
A mixture solution of 2,4-dichloropyrimidine(3.0 g, 20 mmol), 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.3 g, 22 mmol), triethylamine(3.4 ml, 24.4 mmol) and N,N-dimethyl formamide(20 ml) was stirred for 5 hours, diluted with dichloromethane, washed with water several times. The dichloromethane layer was separated, dried over anhydrous sodium sulfate and then concentrated under a reduced pressure. The resulting residue was crystallized by silica gel column chromatography to give 1.5 g of the titled compound. (Yield: 28.9%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 16.2 %

Procedure:
A mixture of tert-butyl 3-(3-cyanophenyl)propionate (0.74 g, 3.2 mmol), methyl thiosalicylate (1.1 g, 6.4 mmol), triethylamine (0.67 ml, 4.8 mmol) and toluene (3 ml) was heated and refluxed for 27 hours under a nitrogen flow. The reaction mixture was applied to column chromatography using silica gel (50 g). Fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the title compound (0.19 g, 16%) as crystals.