Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][OH:25])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][O:25][S:41]([CH3:40])(=[O:43])=[O:42])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ncc2c(n1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(4-fluorophenyl)-N-[2-(2-hydroxy-ethyl)-5,6,7,8-tetrahydro-quinazolin-5-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (56.6 mg, 0.1 mmol) in dry CH2Cl2 at 0 C was added MsCl (34 mg, 0.3 mmol), followed by Et3N (50 mg, 0.5 mmol). After stirring at 0° C. for 20 min, the reaction was quenched with Sat. NaHCO3 solution, extracted with EtOAc, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:3 to 100:5 to 100:7) gave the title compound as a white solid. MS: 645.0 (M+1).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:36])[CH2:31][CH2:32][C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added succinimide (525 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (1.79 g, yield 100%) as pale yellow oil.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:23]([CH2:25][NH2:26])O.O>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:26]3[CH2:25][CH2:23][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: NCCO
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Yield: 66.3 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 40 ml of dimethylsulfoxide was added 3.05 g of monoethanolamine, and the resultant mixture was heated at about 90°C for 3 hours. After cooling, the reaction mixture was poured into 300 ml of water and extracted with chloroform. The extract was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.0 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one. Recrystallization from ethanol gave pale yellow prisms, having a melting point of 219° - 220°C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.[N:24]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2[O:32][CH2:31][CH2:30][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Reactant: OCCN1CCCCC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(OCCN2CCCCC2)c2cc(C3OCCO3)ccc21

Procedure:
The title compound was prepared from 600 mg (1.344 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) in analogy to the procedure described in Example 21A. The procedure was modified by using 5 equivalents of 2-(piperidin-1-yl)ethanol as the alcohol reactant and by switching to toluene as solvent. Instead of using microwave irradiation, the reaction mixture was refluxed for 5 days employing conventional heating. During this time, the same amounts of catalyst and ligand were added again on day 3. The crude product thus obtained was purified by chromatography on silica gel (cyclohexane/ethyl acetate gradient) to afford 244 mg (32% of th.) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=3)[N:25](S(C3C=CC=CC=3)(=O)=O)[CH:24]=2)[CH:3]=1.[OH-].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=3)[NH:25][CH:24]=2)[CH:3]=1
Reactant: CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](N)CC4)c3)c2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of Example 224b (76.1 mg, 0.122 mmol) in dioxane (1.5 mL) was treated with 20% sodium hydroxide (0.10 mL, 0.122 mmol). The mixture was heated at 90° C. for 1 hour. The solvent was evaporated. The residue was treated with 20% brine and extracted with EtOAc (2×). The combined organic layers were dried. The crude intermediate was dissolved in CH2Cl2 (1.0 mL) and treated with TFA (0.19 mL, 2.4 mmol). After 1 hour, the reaction mixture was concentrated and purified by reverse-phase HPLC as described in Example 56 to give the title compound (6.5 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.29-1.43 (m, 2H), 1.43-1.49 (m, 3H), 1.52-1.72 (m, 2H), 2.02-2.17 (m, 2H), 2.17-2.32 (m, 2H), 3.13 (m, 1H), 3.80 (m, 1H), 4.18 (q, J=7.02 Hz, 2H), 6.75 (d, J=1.22 Hz, 1H), 6.86 (d, J=1.22 Hz, 1H), 7.86 (s, 1H), 7.90 (d, J=2.44 Hz, 1H), 8.06 (d, J=2.44 Hz, 1H). MS (DCI+) m/z 386.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][OH:15])[O:10][C@H:9]1[N:16]1[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]1=[O:18])=[O:4].[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([O:15][CH2:14][C@H:11]2[O:10][C@@H:9]([N:16]3[CH:23]=[CH:22][C:20](=[O:21])[NH:19][C:17]3=[O:18])[C@H:8]([O:7][CH2:6][CH2:5][C:3](=[O:4])[NH:2][CH3:1])[C@@H:12]2[OH:13])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:29]2[CH:46]=[CH:47][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNC(=O)CCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CNC(=O)CCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Yield: 71 %

Procedure:
The compound (558 mg, 1.67 mmol) prepared in Example 6 was dissolved in dried pyridine (8 mL). To the solution was added 4,4′-dimethoxytrityl chloride (622 mg, 1.84 mmol), followed by stirring at room temperature. The reaction system was concentrated under reduced pressure, diluted with ethyl acetate, and then washed with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography eluting with chloroform:methanol (98:2, v/v) containing 0.5% triethylamine to give the title compound (749 mg, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>O>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Solvent: O
Solvent: CO
Product: Cc1cc(NCCOC(=O)c2ccccc2)c2[nH]ncc2n1

Procedure:
The title compound was prepared from 7-(2-hydroxyethyl-amino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (2 g) and benzoyl chloride by the general method of Example 4 without the addition of methanol. The crude reaction mixture was poured into a large excess of water and extracted with ethyl acetate (×3). The combined organic layers were washed with water (×2), dried with anhydrous sodium sulphate, filtered and evaporated to dryness. The resulting intermediate dibenzoylated compound was recrystallized from carbon tetrachloride/60°-80° C. petrol to give a pale yellow solid, m.p. 136°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][CH:26]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]([F:45])([F:44])[F:43])[C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:34])=[O:33])[CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:16])([F:17])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:25][CH:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]([F:43])([F:44])[F:45])[C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:34])=[O:33])[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reactant: CC(C)(NC(=O)C(N)c1ccccc1C(F)(F)F)C(N)=O
Agent: Cl
Product: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F)C(N)=O

Procedure:
Analogously to Example 1, 25 mg (72 μmol) of the compound of Example 11A and 29 mg (79 μmol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 32 mg (70% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1C=C(C)C2C(=CC=C(C#CC3C=CC(C4C=CC(Cl)=CC=4)=CN=3)C=2)[N:3]=1.Br[C:29]1[CH:38]=[C:37]([CH3:39])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)=[CH:44][N:43]=3)[CH:35]=2)[N:30]=1>CN1C(=O)CCC1.CN(C=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C:45]2[CH:46]=[CH:47][C:42]([C:41]#[C:40][C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([CH2:2][NH2:3])[CH:38]=[C:37]4[CH3:39])=[N:43][CH:44]=2)=[CH:49][CH:50]=1
Reactant: Cc1cc(Cl)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Reactant: Cc1cc(Br)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1cc(CN)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
Analogously to Example 1k, the following Examples may be prepared starting from 2-chloro-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1h) or 2-bromo-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1i) and the corresponding amines: Examples 1.8-1.9, 1.11, 1.15-1.21, 1.23 and 1.28 were prepared by heating in NMP in the microwave (300 W, 190° C.; 30-60 min); Example 1.13 was prepared by heating in DMF in the microwave (150 W, 170° C.; 10 min); and Example 1.51 was obtained as a by-product.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH2:21][CH3:22])=[O:5]
Reactant: CCO
Reactant: Cc1cc(C(=O)O)c(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(C)cc([N+](=O)[O-])c1O

Procedure:
2-Hydroxy-5-methyl-3-nitrobenzoic acid (10.0 g) was dissolved in absolute ethanol (50 ml) and the solution was treated with concentrated sulphuric acid (3.0 ml), slowly with stirring. The mixture was heated at reflux for 20 hours and then poured into water (250 ml). The resulting yellow solid was recrystallised from ethanol to give ethyl 2-hydroxy-5-methyl-3-nitrobenzoate (7.5 g), m.p. 97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]3[O:20][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[O:13]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(=O)O
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccc(-c3ccc(Cl)cc3)cc2)OC1=O
Yield: 69.7 %

Procedure:
A mixture of 4-(4-chlorophenyl)benzaldehyde (15.0 g.), 2-hydroxy-2-methylpropionic acid (10.0 g.) and p-toluenesulphonic acid monohydrate (0.2 g.) was heated in toluene (200 ml.) under reflux for 6 hours with continuous removal of water by azeotropic distillation. The solution was then cooled, washed with 10% w/v sodium hydrogen carbonate solution (100 ml.) and then with water (2×100 ml.) before it was dried (Na2SO4). The dried toluene solution was filtered and evaporated to give 2-[4-(4-chlorophenyl)phenyl]-5,5-dimethyl-1,3-dioxolan-4-one (14.6 g.), m.p. 108°-110° C. (after recrystallisation from cyclohexane and then from toluene).
Reaction SMILES: Cl[C:2]1([F:10])[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].NCCN>[Ni].C(O)C>[F:10][CH:2]1[CH2:4][CH:3]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C1CC1(F)Cl
Agent: [Ni]
Solvent: NCCN
Solvent: CCO
Product: CCOC(=O)C1CC1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An internal glass tube was introduced into an autoclave and 0.5 g of ethyl 2-chloro-2-fluoro-1-cyclopropanecarboxylate (cis:trans=1.4:1), 0.5 ml of Raney nickel and 5 ml of ethanol were fed thereinto. Then 0.54 g of 1,2-diaminoethane was further added and the mixture was stirred at room temperature under an elevated hydrogen gas atmosphere (50 kgf/cm2) for 24 hours. After the completion of the reaction, the catalyst was filtered off. Then the reaction mixture was analyzed by gas chromatography. As a result, it was found out that the reaction conversion rate was 100%, the yield was 88.9% and the cis:trans ratio was 1.4:1. The analytical data of the title compound are as follows.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[C:12]([OH:21])=[CH:11]1)[CH3:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:21][C:12]1[C:13](=[O:20])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([CH2:8][CH3:9])[CH:11]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1cc(O)c(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(OS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
Triethylamine (5.6 ml) was added to a stirred suspension of 1-ethyl-3-hydroxy-4-quinolone (3.74 g) and methanesulphonyl chloride (2.3 ml) in dichloromethane (80 ml) and the resultant solution was stirred for 90 minutes. The solution was washed with water (50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (10 ml) to give the novel compound 1-ethyl-4-oxo-1,4-dihydro-quinol-3-yl methanesulphonate, m.p. 141°-143°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:16]2[CH:17]=[C:18]([O:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[O:27])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(OS(C)(=O)=O)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1cccc(C(=O)NC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above prepared 4-(3-methanesulfonyloxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.920 g, 1.85 mmol) was dissolved in 9.5 ml of CH2Cl2 and treated with 2.4 ml of trifluoroacetic acid. After stirring for 4 h at ambient temperature, TLC indicated the absence of starting material. Evaporation of all volatiles left 1.47 g of the title compound as trifluoroacetate as off-white viscous oil.
Reaction SMILES: [C:1]([Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:11]1[C:16]([F:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:18][C:14]1[CH:15]=[C:16]([F:17])[C:11]([C:9]#[C:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[N:12][CH:13]=1
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: Fc1cc(Br)cnc1Br
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, 2.62 mL (13.811 mmol) of tert-butylethynyldimethylsilane was added to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine, 5.22 mL of triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) of CuI, and 220.3 mg (0.31 mmol) of bis(triphenylphosphane)palladium (II) chloride in 30 mL of absolute THF at 15° C. and the mixture was stirred for 2 hours at RT. 1 mL of tert-butylethynyldimethylsilane was added and the mixture was again stirred for 1 hour at RT. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semisaturated aqueous sodium bicarbonate solution, 5% aqueous ammonia, and water, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/DCM 9:1). Yield: 1.62 g (41% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+: 314/316 (Br); found: molpeak (M+H)+: 314/316 (Br); HPLC-MS: 7.85 minutes (method B).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:28][C:27]1[CH:26]=[C:25]([CH3:29])[CH:24]=[C:23]([CH3:30])[C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Cc1cc(C)c(C(Cl)Cn2ccnc2)c(C)c1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
947 mg of methyl 4-mercaptobenzoate were dissolved in 6 ml of dry dimethylformamide, and 245 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to the resulting solution. The mixture was then stirred at room temperature for 30 minutes. 1.4 g of 1-[2-chloro-2-(2,4,6-trimethylphenyl)ethyl]imidazole dissolved in 7 ml of dry dimethylformamide was added to the solution, and the mixture was then heated at 60° to 65° C. for 20 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 1.72 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](OC)([O:17]C)[CH2:13][CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:15][CH2:14][CH2:13][C:12]([O:11][CH3:10])=[O:17]
Reactant: COC(CCCBr)(OC)OC
Reactant: Cc1cc(Cl)ccc1Cl
Product: COC(=O)CCCCc1cc(Cl)ccc1Cl

Procedure:
The anion of 2,5-dichlorotoluene was reacted with trimethyl 4-bromoorthobutyrate to produce methyl 5-(2,5-dichlorophenyl)pentanoate after mild hydrolytic work-up. Competitor A was prepared by LiOH hydrolysis of the methyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:15]=[C:9]2[CH:8]=1.[OH-].[NH4+].CN(C)[CH:27]=[O:28]>>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:15]([CH:27]=[O:28])=[C:9]2[CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added to N,N-dimethylformamide (10 mL) and the resulting mixture stirred at room temperature for 10 minutes. 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (1.0 g, 4.1 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-water and neutralized to pH 7 with aquous ammonium hydroxide. The resulting slurry was extracted with dichloromethane (3×40 mL). The combined organics were washed with brine, dried (magnesium sulfate), filtered and concentrated to give, after recrystallization from acetonitrile, 5-chloro-2-(4fluorophenyl)pyrazolo [1,5-α]pyridine-3-carbaldehyde (0.95 g, 85%) as a white solid. 1H-NMR (CDCl3): δ10.07 (s, 1H),18.49 (d, 1H), 8.44 (d, 11H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1 H); MS m/z 275 (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][NH:18][C:17](=O)[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:17]1[N:18]=[N:19][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)N1CCN(c2cc(=O)[nH]nc2-c2ccccc2)CC1
Product: O=C(c1ccccc1)N1CCN(c2cc(Cl)nnc2-c2ccccc2)CC1
Temperature: 80 °C

Procedure:
To 5-(4-benzoylpiperazin-1-yl)-6-phenylpyridazin-3(2H)-one (1.3 g) taken in single necked round bottom flask, phosphorusoxychloride (10 ml) was added and the mixture was heated to 80° C. for 4 hrs. Reaction mixture was cooled to room temperature and concentrated to remove excess phosphorus oxychloride. Residue was slowly poured into ice and neutralized with solid sodium bicarbonate. The mixture was extracted with Ethyl acetate (3×100 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated to afford (4-(6-chloro-3-phenylpyridazin-4-yl)piperazin-1-yl)(phenyl)methanone as white solid.