Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[I:16]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:6][C:7]1[C:14]([I:16])=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: II
Reactant: Cc1ccc(C#N)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (45 mL, 267 mmol) in THF (400 mL) was cooled to −78° C. under an atmosphere of nitrogen. n-Butyl lithium (2.5 M in hexane, 110 mL, 275 mmol) was added slowly maintaining the temperature below −70° C. After addition, the reaction mixture was warmed to −50° C. and stirred for 30 minutes. The clear solution became turbid indicating the salt formation. The reaction mixture was recooled to −80° C., and a solution of 2-fluoro-4-methylbenzonitrile (32.4 g, 240 mmol) in THF (150 mL) was slowly added maintaining temperature below −70° C. The mixture was then warmed to −50° C. and stirred for 30 minutes. The mixture was recooled to −70° C. and a saturated solution of iodine (67 g, 264 mmol) in THF (150 mL) was added slowly maintaining the temperature at −70° C. After addition, the mixture was warmed to ambient temperature. The reaction mixture was poured into a solution of Na2S2O3 (160 g in 1.5 L of water) and stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. The volatiles were evaporated under reduced pressure. The crude product was subjected to vacuum distillation, and at about 60° C., the excess TMP was removed, at about 100° C., the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of 2-fluoro-3-iodo-4-methylbenzonitrile were removed and, finally at 115° C., pure 2-fluoro-3-iodo-4-methylbenzonitrile was obtained as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 261.9 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C:31]#[C:30][CH2:29][OH:32])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C#CCO)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1-iodo-3,5-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 10 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (2.39 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(NC2CCCCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A cooled (0° C.) solution of methyl 2,4-dichloropyrimidine-6-carboxylate (Apollo, OR2558, 10.00 g; 48.31 mmol) in THF (300 mL) was treated with a solution of cyclohexylamine (Fluka, 5.53 mL; 48.3 mmol) and triethylamine (7.37 mL; 53.1 mmol) in THF (100 mL). The reaction mixture was stirred for 16 hours at RT. Water (50 mL) was poured into the reaction mixture which was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to obtain the crude product, which was purified by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][NH:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=O
Reactant: NC1Cc2ccccc2C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC1CCNC1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[CH:25]=[CH:24][CH:23]=[N:22]1>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[N:21]5[CH:25]=[CH:24][CH:23]=[N:22]5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1ccccc1-n1cccn1
Product: O=C(c1ccccc1-n1cccn1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) mass calcd. for C26H24N6, 436.52; m/z found, 437.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13]Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(CCCCl)c1ccc(Cl)cn1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cn1)C1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
5-Chloro-2-[(3-chloropropyl)sulfonyl]pyridine (732 mg, 3.05 mmol) synthesized in Example (125b) was dissolved in tetrahydrofuran (10 mL) and cooled to −30° C., and subsequently potassium-t-butoxide (582 mg, 5.18 mmol) was added, followed by stirring as it is for 30 minutes. To the reaction solution, a saturated aqueous ammonium chloride solution (40 mL) was added, and extraction was carried out twice with methylene chloride (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-25%) to afford the desired compound (397 mg, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([C:12]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:15]3[C:16]([C:26]([NH:28][CH3:29])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[O:18][C:14]=3[CH:13]=2)[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:44]1[CH:45]=[CH:46][C:47]2[O:60][CH2:59][N:50]3[C:51]4[CH:52]=[CH:53][CH:54]=[C:55]([F:58])[C:56]=4[CH:57]=[C:49]3[C:48]=2[N:61]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]([C:12]2[C:31]([C:44]3[CH:45]=[CH:46][C:47]4[O:60][CH2:59][N:50]5[C:51]6[CH:52]=[CH:53][CH:54]=[C:55]([F:58])[C:56]=6[CH:57]=[C:49]5[C:48]=4[N:61]=3)=[CH:30][C:15]3[C:16]([C:26]([NH:28][CH3:29])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[O:18][C:14]=3[CH:13]=2)[S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(Cc3ccc(Cl)cc3)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C

Procedure:
To a solution of 6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (0.15 g, 0.25 mmol), 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (0.09 g, 0.33 mmol) and K3PO4.3H2O (0.15 g, 0.56 mmol) in dioxane/H2O (6 mL/12 drops) was added Pd2(dba)3 (12 mg, 0.013 mmol) and X-Phos (12 mg, 0.026 mmol) under N2. The mixture was stirred at 100° C. under reflux for 2 hours. Then it was filtered and extracted with EtOAc. The combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ether:EtOAc=2:1) to provide 6-(N-(4-chlorobenzyl)methylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide. 1H-NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.82˜7.86 (m, 2H), 7.39 (s, 2H), 7.04˜7.19 (m, 10H), 6.76˜6.80 (m, 1H), 5.95 (s, 2H), 5.86 (s, 1H), 4.66˜4.78 (m, 2H), 2.89 (d, J=4.0 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 725.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:43])[NH:36][C:37]1([CH2:41]O)[CH2:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:43])[NH:36][C:37]1([CH2:41][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:38][CH2:39][CH2:40]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCC1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCC1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}cyclobutyl)carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and (1-hydroxymethylcyclobutyl)carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([O:39][CH3:40])[CH:33]=2)[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([O:39][CH3:40])[CH:33]=3)[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2ccc(F)c(OC)c2)nc1C(=O)Cl
Product: CCOc1cn(-c2ccc(F)c(OC)c2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5 X9 was prepared from A2 and 4-ethoxy-1-(4-fluoro-3-methoxyphenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d5-DMSO, 300K) δ 1.39 (t, J=7.0 Hz, 3H), 3.94 (s, 6H), 3.96 (s, 3H), 4.10 (q, J=7.0 Hz, 2H), 6.48 (d, J=5.2 Hz, 1H), 7.40 (m, 2H), 7.46 (t, J=9.0 Hz, 1H), 7.52 (m, 2H), 7.70 (m, 2H), 8.03 (dd, J=2.4 Hz, J=13.2 Hz, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.52 (s, 1H), 10.19 (s, 1H). MS (ES) C30H26F2N4O6 requires: 576. Found: 577 (M+H)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[CH2:14][N:15]=[N+:16]=[N-:17].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[C:1]1([C:7]2[N:17]=[N:16][N:15]([CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[C:11]([C:10]([F:9])([F:22])[F:21])[CH:12]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: FC(F)(F)c1cccc(Cn2cc(-c3ccccc3)nn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
Route B: Phenylacetylene (0.409 g, 4 mmol) and 3-(trifluoromethyl)benzyl azide (0.805 g, 4.00 mmol) were dissolved in 4:1 t-BuOH/H2O (25 ml) and then treated sequentially with a 1M aq. solution of CuSO4 (0.200 ml, 0.200 mmol) followed by solid sodium ascorbate (0.079 g, 0.400 mmol). The sample was stirred at r.t. for 4 h. during which time a precipitate formed. The sample was quenched with 10 mL of 10% NH4OH aq. and the solid was isolated by filtration. The solid was washed with water and dried under vacuum, giving 4 (1.112 g, 3.67 mmol, 92% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C1COCC1.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)CNCCCC1(C)OCCO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(CCCC1(C)OCCO1)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 2-4 (24 g, 0.104 mol) in 100 mL THF were added a trace of DMAP, 20 drops of triethylamine, and BOC2O (23.8 g, 0.109 mol). After 4 h, evaporative removal of the solvent gave 2-5 as a colorless oil. TLC Rf =0.38 (silica, 30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 4.22 (m, 3H), 3.93 (m, 4H), 3.27 (m, 2H), 1.63 (m, 4H), 1.51 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.28 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][OH:45].[H-].[Na+].O>CN(C)C=O>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][O:45][CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOCc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 60.5 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 120 (1) was dissolved in 20 mL of dimethylformamide at 0° C., 0.28 mL (2.75 mmol) of 2-dimethylaminoethanol and 220 mg (5.20 mmol) of sodium hydride (60% oil dispersion) were added, and the mixture was stirred at room temperature for 80 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give 477 mg of 7-(2-dimethylaminoethoxymethyl)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 60%).
Reaction SMILES: Br[CH2:2][C:3](=[O:21])[CH2:4][S:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:21]=[C:3]1[CH2:2][N:9]2[C:8](=[O:10])[C@@H:7]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:6]2[S:5][CH2:4]1
Reactant: O=C(CBr)CS[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1
Yield: 12.8 %

Procedure:
A solution of (3R,4R)-4-(3'-bromoacetonylthio)-3-phenylacetamidoazetidin-2-one (1 g., 2.7 mmole) in acetone (50 ml.) with potassium carbonate (2 g., 14.5 mmole) was stirred at 4° for 16 hours and at 22° for 4 hours. The mixture was filtered and evaporated under reduced pressure. The resulting gum was chromatographed on silica gel (10 × 4 cm.) with Analar chloroform as solvent to give a pale-yellow foam. Crystallisation from ethyl acetate gave (6R,7R)-3-keto-7-phenylacetamidocepham (0.1 g., 12.5%). M.p. I.R. and NMR in agreement with standard obtained from material prepared in Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:30]/[C:28]4[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Solvent: CC(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-ethyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9c, 357 mg, 87%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([OH:32])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:24][CH:25]=2)[O:17][C:18]=1[CH3:19])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:32][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[O:17][C:18]=2[CH3:19])=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1cc(O)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-butyl-4-[2-(5-methyl-2-biphenyl-3-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-3-butylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.22 (d, J=1.5 Hz, 1H), 7.95 (dd, J=7.8, 1.5 Hz, 1H), 7.67-7.62 (m, 3H), 7.51-7.44 (m, 3H), 7.37 (t, J=6.8 Hz, 1H), 6.72-6.69 (m, 2H), 6.64 (dd, J=8.8, 2.9 Hz, 1H), 4.25-4.19 (m, 4H), 2.97 (t, J=6.6 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.52 (s, 6H), 1.51-1.43 (m, 2H), 1.33-1.23 (m, 5H), 0.85 (t, J=7 Hz, 3H); Rf=0.24 (2% ethyl acetate/dichloromethane).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cccnc23)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4cccnc34)cc2=O)n1
Yield: 25 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 55) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionamide as an off-white solid (0.34 g, 25%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2558. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.27-1.76 (m, 8H), 1.91 (m, 1H), 2.23 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.44 (dd, J=4.5, J=10.9 Hz, 1H), 5.50 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.65 (dd, Jo=8.3, 4.2 Hz, 1H), 7.72 (t, Jo=7.9 Hz, 1H), 7.76 (dd, Jo=7.5 Hz, Jm=1.5 Hz, 1H), 8.03 (dd, Jo=8.1 Hz, Jm=1.5 Hz, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.52 (dd, Jo=8.3 Hz, Jm=1.7 Hz, 1H), 8.92 (dd, Jo=4.2 Hz, Jm=1.7 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[C:25]([CH3:26])=[CH:24][C:15]3[O:16][CH:17]([C:19]([O:21]CC)=[O:20])[O:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[C:25]([CH3:26])=[CH:24][C:15]3[O:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:14]=3[CH:13]=2)(=[O:10])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)C1Oc2cc(C)c(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2O1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(cc1S(=O)(=O)c1cc(Cl)cc(Cl)c1)OC(C(=O)O)O2

Procedure:
8.38 g (0.02 mole) of ethyl 5-(3,5-dichlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylate are covered with 30 ml of 2-n sodium hydroxide solution and the batch is heated for 1 hour in a boiling water bath, cooled and acidified, affording 5-(3,5-dichlorophenylsulfonyl)-6-methyl-1,3-benzodioxole-2-carboxylic acid. Melting point 210°-214° C. (crystallisation from ethyl acetate/toluene).