Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[Cl:23])=[C:7]([Cl:14])[C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=O.Cl.[CH2:25]1COCC1>C(OCC)(=O)C.[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:6]2[C:5]([C:3](=[O:2])[CH3:25])=[CH:10][N:9]3[CH:11]=[CH:12][N:13]=[C:8]3[C:7]=2[Cl:14])=[C:17]([Cl:23])[CH:18]=1
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: C1CCOC1
Agent: [Ti+3]
Agent: C[Al+]C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
This compound is prepared from compound 29, the product of Example 9, Step H. Tebbe reagent (μ-chloro-μ-methylene[bis(cyclopentadienyl)titanium]dimethyl-aluminum, 1 M solution in toluene, 0.12 mL, 0.12 mmol) was added to a solution of 7-(4-bromo-2-chloro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (29) (25 mg, 0.061 mmol) in THF (1 mL) cooled to 0° C. The reaction mixture was warmed to room temperature and stirred for 1.5 hours. HCl (10% aqueous solution, 1 mL) was added and the mixture stirred for 16 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium carbonate, dried over MgSO4, and concentrated. The crude material was purified by flash column chromoatography (dichloromethane to 100:1 dichloromethane/methanol) to provide the desired product (6.8 mg, 28%). MS APCI (−) m/z 396, 398, 400 (M-, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 9.05 (br s, 1H), 8.81 (s, 1H), 7.71 (s, 2H), 7.55 (d, 1H), 7.22 (dd, 1H), 6.55 (d, 1H), 2.67 (s, 3H).
Reaction SMILES: N12CCN(CC1)CC2.C([Li])CCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C:21](=[O:23])=[O:22]>C(OCC)C>[F:14][C:15]1[C:16]([C:21]([OH:23])=[O:22])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=O
Reactant: Fc1cccnc1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1ncccc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 1,4-diazabicyclo[2.2.2]octane (1.15 g, 10.3 mmol) in diethylether (50 ml) is added n-butyllithium (2.6M in hexane) (3.95 ml, 10.3 mmol) at −78° C. The reaction mixture is stirred at −20° C. for 1 h followed by the addition of a solution of 3-fluoro-pyridine (1.00 g, 10.29 mmol) in diethylether (30 ml) at −78° C. The yellow suspension is stirred at −60° C. for 1 h and then cooled to −78° C. followed by the addition of excess dry ice. The resulting solution allowed to warm to to −10° C. over 20 min. The precipitate is filtered and the residue is washed with ether which yields pure 3-fluoro-pyridine-2-carboxylic acid (1.20 g, 8.51 mmol, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[O:20]C.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20]
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)c(O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
2-{[4-Chloro-3-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (7.0 g, 23 mmol) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. Boron tribromide (1.0 M solution, 46 mL) was added slowly then the solution was warmed to RT and stirred for 4 h. The reaction was cooled to 0° C. and ice water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, evaporated and triturated with hexanes to afford the title compound (6.5 g, 97%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.15 (s, 1H), 7.87 (d, 2H), 7.87 (ddd, 2H), 7.25 (d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 4.66 (s, 2H). MS: m/z 286.0 (M−1).
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[O:6][CH2:5][CH2:4][N:3]4[C:2]2=[N:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=c1n(Cc2ccc(C(F)(F)F)cc2)c2cccc3c2n1CCO3)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h and then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide (2nd compound to elute off the column); which was further purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide trifluoroacetic acid salt. MS 474 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:25][C:8]=2[C:7]1=[O:30])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[S:25][C:8]=2[C:7]=1[OH:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(C(C)(C)C)nc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2nc(C(C)(C)C)sc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A solution of 2-tert-butyl-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (1 g, 2.3 mmol) in 23 mL of dichloromethane was cooled to 0° C. with an external ice bath and thionyl chloride (253 μL, 3.47 mmol) was added. The ice bath was removed and the reaction was allowed to stir at room temperature for 16 h. Pyridine (500 μL) was added and the mixture was stirred for 5 min before concentrating on silica gel under reduced pressure and purification by column chromatography. The desired product was eluted from silica gel with a gradient of 10-50% ethyl acetate in hexanes to give 363 mg of pale yellow solid. MS (ESI−): m/z 279.3 (M−1).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:36])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:21]=3)[CH:15]=2)[N:10]([C:32](=[O:34])[CH3:33])[C@@H:9]([CH3:35])[CH2:8]1)[CH3:3].[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[C:32]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:18]=[CH:19][N:20]([CH2:22][CH2:23][NH2:24])[CH:21]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:36])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:35])(=[O:34])[CH3:33]
Reactant: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N1c2ccc(-c3cn(CCN)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
A solution of 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-imidazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 79) (47 mg, 0.094 mmol) in 1,4-dioxane (0.5 mL) was treated with HCl (4M in 1,4-dioxane, 2 mL, 8 mmol) and the resulting mixture was stirred at room temperature for 4 h. Et2O (10 mL) was added and the resulting mixture stirred for 15 min. The solid formed was filtered off, washed with Et2O and dried under house vacuum to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-aminoethyl)-1H-imidazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (25 mg, 0.057 mmol, 61%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 568.8 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)=[O:9].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>O1CCCC1>[OH:18][C:15]1[CH:16]=[CH:17][C:12](/[CH:11]=[CH:10]/[C:8](=[O:9])/[CH:7]=[CH:6]/[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: CCCCC/C=C/C(=O)CCc1ccc(O)c(OC)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC/C=C/C(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
[6]-Shogaol (276 mg, 1.0 mmol) was dissolved in tetrahydrofuran (THF) and cooled down to 0° C. To this mixture, a solution of DDQ (181 mg, 0.8 mmol) in THF was added. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature (RT) for 3 hours. Then water was added and the resulting mixture was extracted with EtOAc (×3). The organic phase was washed with water (×1) and brine (×1), dried over anhydrous NaSO4, and filtered. The filtration was evaporated and the residue was purified by chromatography column (CC) (hexane/ethyl acetate=8:1 and 6:1) to give the desired compound as a yellow oil (170 mg, yield: 62%); 1H NMR (600 MHz, CDCl3) δ 7.59 (1H, d, J=15.9 Hz, H-1), 6.82 (1H, d, J=15.9 Hz, H-2), 6.44 (1H, d, J=15.6 Hz, H-4), 6.99 (1H, dt, J=15.6, 7.0 Hz, H-5), 2.27 (2H, q, J=7.0 Hz, H-6), 1.51 (2H, m, H-7), 1.34-1.29 (4H, m, H-8 and H-9), 0.90 (3H, t, J=6.8 Hz, H-10), 7.07 (1H, d, J=1.4 Hz, H-2′), 6.93 (1H, d, J=8.2 Hz, H-5′), 7.14 (1H, dd, J=8.2, 1.4 Hz, H-6′), and 3.93 (3H, s, OMe-3′); 13C NMR (150 MHz, CDCl3) δ 143.3 (d, C-1), 123.3 (d, C-2), 189.3 (s, C-3, C═O), 129.1 (d, C-4), 148.0 (d, C-5), 32.7 (t, C-6), 27.9 (t, C-7), 31.4 (t, C-8), 22.4 (t, C-9), 14.0 (q, C-10), 127.4 (s, C-1′), 109.7 (d, C-2′), 148.1 (s, C-3′), 146.8 (s, C-4′), 114.8 (d, C-5′), 122.9 (d, C-6′), and 56.0 (q, OMe-3′); positive ESI-MS, m/z 275 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25](C4C=CC=C(C5CNCCN5)C=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].Cl[C:44]1[CH:45]=[C:46]([CH:50]2CNC[CH2:52][NH:51]2)[CH:47]=[CH:48][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:45]4[CH:44]=[CH:49][CH:48]=[CH:47][C:46]=4[CH2:50][NH:51][CH3:52])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C5CNCCN5)c4)cc23)CC1
Reactant: Clc1cccc(C2CNCCN2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4CNC)cc23)CC1
Yield: 19.8 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperazinyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-(2-bromophenyl)-N-methylmethanamine (65 mg, 0.325 mmol) for 2-(3-chlorophenyl)piperazine to afford 14.6 mg of the title compound (19.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:21][OH:22]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:21][OH:22])[CH2:8][CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCCC2=NO
Yield: 47 %

Procedure:
A solution of 6-methoxy-1-tetralone (40 g, 227 mmol), potassium carbonate (64 g, 462 mmol) and hydroxylamine.hydrochloride (63.2 g, 909 mmol) in methanol (500 mL) and water (56 mL) was refluxed for 2.5 hours. The potassium carbonate was filtered off, poured into ice (300 g) and water was added to total 1.5 L. The precipitate was collected to give 34.79 g (80%) of crude product, which recrystallized in methanol to give 20.4 g (47%) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[O:11][CH2:12][CH2:13][N:14]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC1=NCCO1
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(C)cc1

Procedure:
Combine 5.0 g (0.046 mol) 4-methylphenol and 3.9 g (0.46 mol) 2-methyl-2-oxazoline under a nitrogen atmosphere and heat to 175° C. for 18 hours. After this time, cool the reaction mixture and add 50 mL of methylene chloride. Wash the organics with 3×10 mL of 10% potassium hydroxide, dry over sodium sulfate and remove the solvents to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[OH:35][CH2:34][CH2:33][N:32]([CH:29]1[CH2:30][CH2:31][N:26]([C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:14]([C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:12]=3[CH3:13])=[O:16])=[CH:25][C:22]=2[C:23]#[N:24])[CH2:27][CH2:28]1)[CH2:36][CH2:37][OH:38]
Reactant: N#Cc1cc(N)ccc1N1CCC(N(CCO)CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(CCO)CCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 9.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-{4-[N,N-bis(2-hydroxyethyl)amino]piperidin-1-yl}benzonitrile (1.2 g), the title compound (0.2 g) was obtained, melting point: 230–233° C.
Reaction SMILES: [C:1]([C:4]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:5]=1[CH2:6][C:7]1[C:11]([C:12](=[O:25])[CH:13]([C:23]#[N:24])[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:15])=[N:10][N:9]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=12)([OH:3])=[O:2].[CH2:36](I)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([CH:13]([C:12]([C:11]1[C:7]2[CH2:6][C:5]3[C:32](=[CH:33][CH:34]=[CH:35][C:4]=3[C:1]([O:3][CH2:36][CH3:37])=[O:2])[C:8]=2[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:10]=1)=[O:25])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])#[N:24]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1c(C(=O)O)cccc1-2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1Cc1c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn(-c3ccccc3)c1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
3-(5-Carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) dissolved in dimethylformamide (25 ml) is reacted with ethyl iodide (1.55 g) in the presence of anhydrous potassium carbonate (1.4 g) under stirring at room temperature for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, dissolved in chloroform and washed with 1N HCl and then with water. Evaporation of the solvent in vacuo gives a residue which is crystallized from CH2Cl2 /methanol to yield 1.9 g of 2-cyano-3-(5-ethoxycarbonyl-1,4-dihydro -1-phenyl-indeno[1,2-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 233°-236° C. dec.
Reaction SMILES: Br[C:2]1[C:7]([O:8][C@H:9]([CH2:11][CH:12]=[CH2:13])[CH3:10])=[CH:6][C:5]([F:14])=[CH:4][C:3]=1[F:15].CC(O)C.C(=O)=O.[Li]CCCC.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>C1COCC1.CCCCCC>[CH2:37]([Sn:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[C:2]1[C:7]([O:8][C@H:9]([CH2:11][CH:12]=[CH2:13])[CH3:10])=[CH:6][C:5]([F:14])=[CH:4][C:3]=1[F:15])[CH2:38][CH2:39][CH3:40]
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1[Sn](CCCC)(CCCC)CCCC
Reaction time: 0.5 h
Yield: 121.9 %

Procedure:
A solution of (S)-2-bromo-1,5-difluoro-3-(pent-4-en-2-yloxy)benzene (0.28 g, 1.01 mmol, 1 equiv) in THF (5 mL) was cooled to −78° C. (IPA/dry ice). nBuLi (0.76 mL of a 1.6 M solution in hexane, 1.21 mmol, 1.2 equiv) was added slowly. Orange color observed. After 30 min, tributyltin chloride (0.33 mL, 1.21 mmol, 1.2 equiv) was added. The reaction was stirred 30 min. The reaction was remove from the cold bath, diluted with ether, and washed with saturated aqueous NaHCO3. The ether layer was dried (MgSO4) and concentrated in vacuo to provide the crude stannane (0.60 g, 100%) as a yellow oil. Contaminated with tin byproducts, used as is. 1H NMR (400 MHz, CDCl3) δ 6.44-6.25 (m, 2H), 5.95-5.62 (m, 1H), 5.21-5.06 (m, 2H), 4.52-4.28 (m, 1H), 2.62-2.43 (m, 1H), 2.31 (dd, J=13.9, 6.7 Hz, 1H), 1.70-0.74 (m, 27H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1.[Cl-].[NH4+]>O1CCCC1.CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:35]3[N:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Fc1cnc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(OCCOc3ncc(F)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 12.4 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2, 126 mg) in tetrahydrofuran (5 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 34 mg) and the reaction mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 2-chloro-5-fluoropyrimidine (50 mg) in dimethyl acetamide (1 ml) and the reaction was stirred for a further 16 hours. The reaction was poured cautiously into a stirred mixture of saturated aqueous ammonium chloride solution (10 ml) and ethyl acetate (10 ml). The organic fraction was separated, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC on a 5μ ODS Phenomenex Magellen™ column with gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the title compound as a white solid (19 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][Si](C(C)C)(C(C)C)C(C)C)[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Si:30]([CH3:33])([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[Si:30]([CH3:33])([CH3:31])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Oc1ccc2ccc([Si](C)(C)C)c(NC(=O)OC(C)(C)C)c2c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c([Si](C)(C)C)ccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(tert-butoxycarbonylamino)-7-(triisopropylsilyloxy)-2-(trimethylsilyl)naphthalene, as described above in Step B, (9.72 g, 19.9 mmol) in THF (200 mL) at 0° C. was added TBAF (1.0 M in THF, 20.9 mL, 20.9 mmol). The resulting mixture was stirred at 0° C. for 15 min then poured into dilute aqueous NH4Cl (250 mL) and extracted with CH2Cl2 (500 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with CH2Cl2—10% EtOAc to yield the desired product.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 79.7 %

Procedure:
479 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(methylsulfonyl)phenethyl]piperidine obtained in Example 1 and 2 ml of thionyl chloride were dissolved in 50 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate), to give 368 mg of the title compound as white crystals.