Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:29]2([CH3:30])[C@H:14]([C@H:15]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:18]([CH2:19][C@H:20]([CH2:22][CH2:23]2)[OH:21])=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH3:5].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].O>O1CCCC1.C(OCC)C>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:29]2([CH3:30])[C@H:14]([C@H:15]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:18]([CH2:19][C@@H:20]([O:21][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a stirred 60% suspension of NaH in mineral oil (400 mg; 3 mmol) under nitrogen a solution of cholesterol (387 mg, 1 mmol) in dry tetrahydrofuran (30 ml) and tert-butyl bromoacetate (585 mg; 3 mmol) was slowly added and the mixture was refluxed under stirring for 16 h. After cooling to room temperature, water (50 ml) was carefully added and the product was taken in diethyl ether (2×50 ml). The combined extracts were dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography of the residue on silica gel column (200 ml) in hexane-tert-butyl methyl ether (gradient: 0-30%—tert-butyl methyl ether, 10 ml/min, 160 min) afforded compound tert-Butyl cholest-5-en-3β-yloxyacetate (general formula XII, where n2=1; 131 mg, 26%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.34-5.38 m, 1H (H-6); 4.01 s, 2H (H-1′); 3.24 tt, J=11.23, 4.56 Hz, 1H (H-3); 2.37-2.43 m, 1H (H-4a); 2.22-2.32 m, 1H (H-4b); 1.76-2.07 m, 5H (CH-1, H-12, H-2, H-7, H-16); 1.48 s, 9H (t-butyl); 1.01 s, 3H (CH3-19); 0.92 d, J=6.60 Hz, 3H (CH3-21); 0.88 d, J=1.80 Hz, 3H (CH3-26); 0.86 d, J=1.80 Hz, 3H (CH3-27); 0.83-1.63 m, 42H (cholesterol+tert-butyl) 0.68 s, 3H (CH3-18); 13C NMR (101 MHz, CDCl3) δ (ppm): 170.11 (C-2′) 140.69 (C-5) 121.78 (C-6) 81.33 (CCH3) 79.81 (C-3) 66.11 (C-1′) 56.80 (C-14) 56.20 (C-17) 50.20 (C-9) 42.35 (C-13) 39.81 (C-12) 39.53 (C-24) 38.79 (C-4) 37.17 (C−1) 36.85 (C-10) 36.21 (C-22) 35.78 (C-20) 31.95 (C-7) 31.92 (C-8) 28.22 (C-2) 28.16 (C-16) 28.12 3C (3×CCH3) 28.00 (C-25) 24.29 (C-15) 23.84 (C-23) 22.80 (C-26) 22.55 (C-27) 21.08 (C-11) 19.35 (C-19) 18.72 (C-21) 11.86 (C-18); for C33H56O3 monoisotopic mass: calculated: 500.4. found: MS ESI m/z: 524.0 [M+Na]+. for C33H56O3—Na+ HR-MS calculated: 523.41217. found: 523.41201; IR (CHCl3): 2954, 2869, 1467, 1457, 1370, 1394, 1161, 1032, 843 (tert-butyl); 1744, 1712, 1125 (C═O); 1670 (C═C); 1125 (C—O); 1181, 1370 (C-26, C-27); 1125 (ether); [α]D −33.7° (c 0.338; CHCl3).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1[CH:21]([CH3:40])[C:22]([C:28]1[CH:39]=[CH:38][C:31]2[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=2[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24].C(N(CC)CC)C.C1N2CCN(CC2)C1>CN(C=O)C.O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([O:20][C:18]2[CH:17]=[CH:16][C:15]([CH:21]([CH3:40])[C:22]([C:28]3[CH:39]=[CH:38][C:31]4[N:32]([CH3:37])[C:33](=[O:36])[N:34]([CH3:35])[C:30]=4[CH:29]=3)([OH:27])[C:23]([F:24])([F:25])[F:26])=[C:14]([Cl:13])[CH:19]=2)=[N:11][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)nc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2,6-dichloronicotinate (CAS Reg. No. 65515-28-8, 20 mg) in DMF (0.5 ml) was added 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 40 mg), followed by triethyl amine (0.02 ml). The mixture was stirred for 10 min, then DABCO (2 mg) was added. The mixture was stirred at room temperature over night. Water was added to the mixture and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 1:2 EtOAc/heptane) to give the title compound (55 mg) as white foam. MS (m/e)=585.9 [M+H+].
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25][CH2:26][CH2:27][C:28](OC)=[O:29].[OH-].[Na+]>O.O1CCCC1>[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCCCCO
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To 17 ml of dry ether, 550 mg of lithium aluminum hydride was added and 3.3 g of methyl 5-(5-methyl-2-phenyloxazol-4-yl)-1-pentanoate/10 ml of dry ether was added dropwise. After 1-hour-stirring at room temperature, the mixture was cooled with ice-cold water and 12 ml of tetrahydrofuran/0.7 ml of water was added dropwise gradually. Then, 0.7 ml of 1N sodium hydroxide and 2.5 ml of water were added and stirred for 15 minutes. The mixture was filtrated to remove insolubles and the filtrate was concentrated to provide 2.9 g of the objective compound as yellowish crystals. M.p. 40-42° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][O:15][CH3:31])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1c2cc(COc3ccccc3)nn2C[C@@H](CO)N1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
A solution of (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.135 g, 0.36 mmol) in THF (0.5 mL) was added to a suspension of a 60% dispersion of sodium hydride in mineral oils (17 mg, 0.44 mmol) in THF (0.5 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C., then iodomethane (0.046 mL, 0.73 mmol) was added. The reaction was heated at 120° C. for 10 minutes under microwave irradiation. Then the mixture was quenched with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with DIPE to yield (S)-5-(4-fluoro-phenyl)-6-methoxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.26 (s, 3H), 3.36 (t, J=9.2 Hz, 1H), 3.51 (dd, J=9.5, 3.9 Hz, 1H), 4.21 (dtd, J=9.0, 4.5, 4.5, 2.3 Hz, 1H), 4.59 (dd, J=13.3, 4.7 Hz, 1H), 4.74 (dd, J=13.3, 2.2 Hz, 1H), 5.13 (s, 2H), 6.94-7.00 (m, 1H), 7.00-7.04 (m, 3H), 7.10-7.19 (m, 2H), 7.27-7.36 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 60 °C
Reaction time: 144 h
Yield: 40.4 %

Procedure:
1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy-pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[F:21][C:22]([F:36])([F:35])[CH2:23][C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([CH2:23][C:22]([F:36])([F:21])[F:35])[N:25]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)Cc1csc(N2CCNCC2)n1
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(CC(F)(F)F)cs2)CC1)C(F)(F)F
Yield: 29 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[4-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine (Example 56(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 29%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.Cl>C1COCC1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[B:21]([OH:24])[OH:22])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: COB(OC)OC
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: -80 °C
Reaction time: 2 h

Procedure:
In a 500 mL three-neck flask, 7.7 g (30 mmol) of 9-bromoanthracene was placed, and the air in the flask was replaced with nitrogen. Then, 200 mL of THF was added into the flask and the solution was cooled to −80° C. under nitrogen stream. After cooling, 18 mL (30 mmol) of 1.6 M n-butyllithium was dripped into the solution and stirred at the same temperature for 2 hours. After a certain period, 6.8 mL (60 mmol) of trimethyl borate was added into the solution, the temperature of the solution was raised to room temperature, and then, the solution was stirred for 17 hours. After a certain period, 100 mL of 1.0 M hydrochloric acid was added to the solution and stirred for 1 hour. An aqueous layer of the obtained mixture was extracted with ethyl acetate. The resulting extracted solution and the organic layer were combined and washed with saturated saline, and then the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give a solid. The solid was recrystallized with toluene, so that 5.2 g of target white powder was obtained in a yield of 80%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: Cl
Product: CCOC(=O)N1CCC(c2cn(CCN3CCOCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B), starting with 11 g (40 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 9 g (48 mmol) of 4-(2-chloro-ethyl)-morpholine hydrochloride. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up and purification, 13.5 g (88% of yield) of 4-[1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[NH:24][CH:25]=[C:26]([C:28](F)(F)F)[N:27]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.[NH2:32]O>CC#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[NH:24][CH:25]=[C:26]([C:28]#[N:32])[N:27]=3)[CH2:20][CH2:21]2)=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(c1ccc(-c2ccccc2F)cc1)N1CCC(Cc2nc(C(F)(F)F)c[nH]2)CC1
Reactant: NO
Solvent: CC#N
Product: N#Cc1c[nH]c(CC2CCN(C(=O)c3ccc(-c4ccccc4F)cc3)CC2)n1
Temperature: 60 °C
Yield: 12 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Matthews et al, J. Org. Chem., 1986, 51, 3228. To a stirred solution of (2′-fluorobiphenyl-4-yl)(4-{[4-(trifluoromethyl)-1H-imidazol-2-yl]methyl}piperidin-1-yl)methanone (0.114 g, 0.27 mmol) in MeCN (10 mL) is added hydroxylamine (5% aqueous solution, 40 mL). The reaction is heated at 60° C. for 4 h then allowed to cool to room temperature. The mixture is extracted with DCM and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography (silica, eluent: DCM, 0-4% MeOH) gives 12.8 mg (12%) of 2-({1-[(2′-fluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}methyl)-1H-imidazole-4-carbonitrile.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[CH:18]=[O:19]>CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=[CH:6][N:5]=1
Reactant: CN(C)C=O
Reactant: Brc1ccnc(Br)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 2,4-dibromo-pyridine (1.90 g, 8.02 mmol) in dry Et2O (40 mL) was treated with n-BuLi (3.36 mL of a 2.5M solution in hexanes, 8.42 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethyl-formamide (0.78 mL, 10.03 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h and stirred at this temperature for 20 min. The reaction was quenched by the addition of sat. aq. NH4Cl (30 mL). The layers were separated and the aq. layer extracted with Et2O (3×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a white solid. TLC: rf (1:1 hept-EA)=0.44.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([OH:13])=[O:12])[CH:4]=1)[CH3:25]
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxyisophthalic acid (10.0 g) in ethanol (100 mL) was added conc. sulfuric acid (3.0 mL), and the mixture was heated for 4 hours under reflux. The reaction solution was allowed to stand for cooling to room temperature, and poured into ice-water. Sodium bicarbonate was added thereto while stirring until the pH reached 10 to 11. The resulting precipitated solid was filtered off. To the filtrate was added conc. hydrochloric acid until the pH reached 2 to 3, and the precipitated solid was filtered off. The filtered solid was recrystallized from methanol and water (2:1, v/v) to give the title compound (4.53 g).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH:22](O)[C:23]([F:41])([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:29]=3)C(O)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH:22]=[C:23]([F:41])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:29]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: O=C(O)C(F)(Cc1cccc(Oc2ccccc2)c1)C(O)C1(c2ccc(Cl)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1cccc(Oc2ccccc2)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
p-Toluenesulfonyl chloride (19.07 mg, 0.10 mmol) is added to a solution of 1-(p-chlorophenyl)-α-fluoro-β-hydroxy-α-(m-phenoxybenzyl)cyclopropanepropionic acid having a 9:1 [R,S and S,R] to [R,R and S,S] ratio (20 mg, 0.05 mmol) in pyridine (2 mL). The reaction mixture is heated to 60° C. and poured into water. The aqueous mixture is extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2 N hydrochloric acid, water, 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless oil (18 mg, 100%) which is found to have a 9:1 Z to E ratio by NMR spectral analyses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=O>C(O)C.N1CCCCC1>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]3[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(C=O)cc12
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1n[nH]c2ccc(/C=C3/C(=O)Nc4ccccc43)cc12
Temperature: 80 °C

Procedure:
To a solution of oxindole (13 mg, 0.01 mmol) and tert-butyl 5-formyl-1H-indazol-3-ylcarbamate (25 mg, 0.01 mmol) in ethanol (1 mL) was added piperidine (1 drop). The mixture was heated to 80° C. for 2 h and cooled to rt. The solution was loaded onto a silica gel column and the title compound was eluted with EtOAc/Hex 4:1 as a red solid (14 mg, 37%). 1H NMR (400 MHz, CD3OD) δ 8.14-8.02 (m, 2H), 7.90-7.83 (m, 2H), 7.63 (s, 1H), 7.24 (bs, 1H), 7.00-6.91 (m, 2H), 1.71 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][C:3]=1[F:15].[OH-].[Na+].O>>[Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[C:6]=2[CH:7]=1
Reactant: O=C(O)CCCCc1ccc(Br)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CCCCc2cc(F)c(Br)cc21
Temperature: 147.5 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A mixture of 5-(4-bromo-3-fluorophenyl)pentanoic acid from step L2 (5.1 g, 18.54 mmol) in polyphosphoric acid (75 g, 18.5 mmol) was stirred at 145-150° C. for 3 h. After cooling to rt, the mixture was poured into ice, neutralized with 50% NaOH/water, and extracted with EtOAc/diethyl ether. The organic layer was dried over sodium sulfate and concentrated. The residue was purified via silica gel column chromatography (hexanes-8% EtOAc) to give 3-bromo-2-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2.7 g, 10.5 mmol, 57% yield). LCMS (M+H)+=257.0. 1H NMR (500 HMz, chloroform-d) δ 7.98 (d, J=7.3 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 2.93-2.89 (m, 2H), 2.77-2.73 (m, 2H), 1.95-1.88 (m, 2H), 1.87-1.81 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([NH2:42])[CH:39]([CH3:41])[CH3:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:38][CH:39]([CH3:41])[CH3:40])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(C)CN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC(C)CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and isobutylamine according to conditions described in general procedure C. Mp: 96-97° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.60-0.80 (m, 6 H), 1.80 (m, 1 H), 2.89 (s, 2 H), 3.26 (t, J=4.8 Hz, 4 H), 3.77 (t, J=5.2 Hz, 4 H), 6.20-6.40 (bd, 1 H), 7.03-7.07 (m, 1 H), 7.22 (s, 1 H), 7.27 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.62 (m, 3 H), 7.81-7.83 (m, 1H), 8.00 (d, J=8.4 Hz, 1 H), 8.21 (s, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (30 mg, 0.079 mmol) and benzoyl chloride (16.4 mg, 0.119 mmol) in tetrahydrofuran (3 mL) was added triethylamine (16 mg, 0.158 mmol) at 0° C. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-benzoylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (27.4 mg, 72%) as a white solid. MS cald. for C24H26N4O5S 482, obsd. (ESI+) [(M+H)+] 483.
Reaction SMILES: CN(C)C=[C:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6].[CH3:23][C:24]([NH:34][NH:35][C:36](OC(C)(C)C)=O)([CH3:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>C(O)(=O)C.C(OCC)C>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([C:4]2[CH:36]=[N:35][N:34]([C:24]([CH3:23])([CH3:33])[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[C:5]=2[OH:6])=[CH:15][CH:14]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Reactant: CCCCCCc1ccc(C(=CN(C)C)C(=O)OCC)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCc1ccc(-c2cnn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Ethyl 3-(dimethylamino)-2-(4-hexylphenyl)acrylate and 0.50 g (1.8 mmol) of tert-butyl 2-(2-methyl-1-(p-tolyl)propan-2-yl)hydrazinecarboxylate were dissolved in 2 mL of acetic acid and stirred at 90° C. for 24 hours. After the stirring, the reaction mixture was mixed with 0.5 mL of acetic acid and stirred for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with distilled water, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=0:100 to 35:65). The resulting solid was washed with isopropyl ether to give 164 mg of the desired product as a white solid.