Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[N:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C(F)(F)F)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a mixture of 4-t-butylbenzenesulfonyl chloride (0.067 g, 0.29 mmol) and 1-(quinolin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.011 g, 0.04 mmol) in pyridine (0.5 mL) was heated at 80° C. for 2 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol), and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL). The phases were separated and the aqueous layer was further extracted with dichloromethane (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.006 g, 0.013 mmol, 32%). 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, J=1.6, 4.4 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.63 (s, 1H), 7.55 (t, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.48 (s, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.27-7.24 (m, 1H), 7.09 (d, J=6.0 Hz, 1H), 6.70 (s, 1H), 1.38 (s, 9H); MS: (ES) m/z calculated for C23H22F3N4O2S [M+H]+ 475.2. found 475.3.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH2:30][CH:31]([CH3:33])[CH3:32])C>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Reactant: CCOC(=O)C#CCC(C)C
Solvent: CCO
Product: CC(C)Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2
Temperature: 160 °C
Yield: 35.1 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.600 g, 1.91 mmol) in ethanol (5 mL) was added 0.294 g (2.86 mmol) of 5-methyl-hex-2-ynoic acid ethyl ester. The reaction mixture was heated in a microwave oven at 160° C. for 20 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel eluting with MeOH/CH2Cl2 to afford 0.283 g of the title compound. [α]D25 −11.17 (c 0.537, CHCl3).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCOCC.CCCCC>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)=[CH:3][CH:4]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Cc1ccc(I)cn1
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1ccc(C23CCCN2CCC3)cn1
Temperature: -95 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
5-Iodo-2-methylpyridine (345 mg, 1.39 mmol) was dissolved in Et2O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 1.8 mL, 3.06 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (435 mg, 2.1 mmol) was added, and the reaction mixture was allowed to warm to -10° C. with stirring for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford the title compound as an oil (126 mg, 45%): 1H NMR (CDCl3, 300 MHz) δ1.57-1.71 (m, 2H), 1.77-2.05 (m, 6H), 2.52 (s, 3H), 2.64-2.72 (m, 2H), 3.12-3.19 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.1, 2.6 Hz, 1H), 8.56 (d, J=2.6 Hz, 1H); MS (CI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)glycine (3.0 g, 17.1 mmol) in DMF (75 mL), N,N-diisopropylethylamine (14.9 mL, 85.5 mmol) was added, followed by EDC (3.6 g, 18.8 mmol) and HOBT (2.5 g, 18.8 mmol) at 0° C., under argon. The resulting mixture was stirred for 0.5 h after which time morpholine (3.0 mL, 34.2 mmol) was introduced in a dropwise manner. Upon complete addition, the reaction was warmed to ambient temperature, stirred overnight and concentrated. The resulting residue was diluted with EtOAc and saturated NaHCO3. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated to give 2.3 g (55%) of (2-morpholin-4-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1.C(=O)(O)[O-].[Na+]>>[O:7]([CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][OH:18])[CH2:12]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCCNC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: OCC1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture of 2-bromoethyl phenyl ether (20.1 g), piperidin-3-yl-methanol (11.5 g), sodium bicarbonate (8.4 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was treated with water (50 ml), 2M sodium hydroxide solution (20 ml) and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine and then extracted with 2M hydrochloric acid. The combined acidic extracts were washed with dichloromethane then basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give 1-(2-phenoxyethyl)piperidin-3-ylmethanol as an oil.
Reaction SMILES: [CH2:1]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:29][O:30][C:31](=[O:39])[CH2:32][C@H:33]([CH3:38])[CH2:34][C:35](O)=[O:36].[Cl-].[NH4+]>C1COCC1.C(Cl)Cl.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:39])[CH2:32][CH:33]([CH3:38])[CH2:34][C:35]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:36]
Reactant: COC(=O)C[C@H](C)CC(=O)O
Reactant: CCCCCCc1cc2ccccc2[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCc1cc2ccccc2n1C(=O)CC(C)CC(=O)OC
Reaction time: 0.5 h

Procedure:
In flask A postassium-tert-butoxide solution in THF was added to a solution of 2-hexyl-1H-indole and stirred for 30 minutes. In another flask B trifluoro acetic anhydride was added to a solution of 3(R)-methyl-pentanedioic acid monomethyl ester in methylene chloride and stirred for 20 minutes. The solution in flask A was transferred to solution in flask B and the reaction mixture was stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][CH:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][CH:11]=[N:10][CH:9]=3)[CH:3]=2)=[CH:19][CH:18]=[CH:17][NH:16]1
Reactant: COc1ncccc1B(O)O
Reactant: Brc1cccc(-c2cnco2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC1NC=CC=C1c1cccc(-c2cnco2)c1

Procedure:
A mixture of 5-(3-bromo-phenyl)-oxazole VI-a (1.33 g, 5.94 mmol), 2-methoxy-3-pyridinylboronic acid (1.00 g, 6.53 mmol), Pd(PPh3)4 and K2CO3 (1.81 g, 13.1 mmol) in THF (20 mL) and water (10 mL) was heated to reflux for 4 h. The mixture was cooled, then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and the residue purified by column chromatography (SiO2; eluting with 30% EtOAc in cyclohexane) to afford the desired product VI-b as brown oil which crystallized on standing (1.37 g, 91%). 1H NMR (300 MHz, CDCl3) δ 8.18 (dd, J=1.8, 5.0 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.64 (d, J=6.9 Hz, 2H), 7.53-7.44 (m, 2H), 7.37 (s, 1H), 6.99 (dd, J=5.0, 7.2 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[CH:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:20]=4)=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH:29]=[C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:14]3[CH:13]=[CH:12][C:10]4[CH:11]=[C:3]5[C:2](=[O:1])[NH:8][CH2:7][CH2:6][CH2:5][N:4]5[C:9]=4[N:15]=3)=[O:17])[CH:24]=[CH:23][CH:22]=2)[N:26]=[CH:27]1
Reactant: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2cc3n(c2n1)CCCNC3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2c[nH]cn2)c1)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a solution of 6-oxo-N-[3-(1-trityl-1H-imidazol-4-yl)phenyl]-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxamide (86 mg, 0.14 mmol) in CH2Cl2 (1 mL) is added TFA (0.5 mL). The mixture is stirred at room temperature for 16 hr then is concentrated under reduced pressure. The residue is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/H2O with 0.1% TFA to afford the title compound (25 mg, 47%). LCMS: 387.86 (M+H+). (System T-med polar) Table 3 below, lists the mass spectral data and the HPLC retention times for Examples 1 to 105.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C@@H:9]1[CH2:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C@@H:9]1[CH2:23][F:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)N(Cc2ccccc2)CC12CC2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CF)N(Cc2ccccc2)CC12CC2
Reaction time: 20 h
Yield: 90 %

Procedure:
A dichloromethane (8 ml) solution of the compound (360 mg, 1.08 mmol) obtained in Step 6 above was cooled to −78° C. Subsequently, bis(2-methoxyethyl)aminosulfur trifluoride (0.26 ml, 1.41 mmol) was added dropwise and the resulting mixture was gradually heated and stirred for 20 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the drying agent was removed by filtration and the solvent was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography [ethyl acetate:n-hexane=1:10 (v/v)] to give the title compound (325 mg, 90%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][C:14]#[N:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([C:14]#[N:15])[C:22]([O:23][CH2:24][CH3:25])=[O:26])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
The 4-benzyloxybenzyl cyanide from step (450a)(3.2 g, 14.33 mmol), sodium ethoxide (1.07 g, 15.7 mmol), and diethyl carbonate (2.23 g, 18.9 mmol) were combined in toluene (100 mL), heated to reflux for 3 h, cooled to rt, and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude was purified by chromatography on silica gel eluting hexane: ethyl acetate (80:20, v:v) to give ethyl 2-(4-benzyloxyphenyl)cyanoacetate (4.2 g, 99%) as an oil. MS (M+NH4)+ =313.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)[CH2:9][CH2:10][CH3:11]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:12][C:13]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][NH:15][CH2:14]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOC1(c2ccccc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution containing 500 mg (1.64 mmol) of 3-butoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 3 hours and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 400 mg in the form of a pale yellow powder are obtained with a yield of 76%.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:9][C:10](=[O:13])[CH2:11]Br)([CH3:8])([CH3:7])[CH3:6]>ClCCl>[C:5]([O:9][C:10](=[O:13])[CH2:11][NH:4][CH2:1][CH:2]=[CH2:3])([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Product: C=CCNCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Allylamine (10 mL, 0.13 mol) was cooled to 0° C., a solution of bromoacetic acid tert-butyl ester (1.0 mL, 6.7 mmol) in dichloromethane (10 ml) was slowly added. After stirring at 0° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The obtained solution was concentrated under reduced pressure to give the title compound as a yellow liquid (1.15 g, 6.7 mmol, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(O)[CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:12]1([O:1][C:2]2[CH:3]=[C:4]([O:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: OC1CCC1
Reactant: CC(=O)Oc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(OC2CCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
Acetic acid 3-hydroxy-phenyl ester (1 ml, 9 mmol) was mixed with cyclobutanol (0.58 g, 8 mmol), triphenylphosphine (2.1 g, 8 mmol) and diisopropyl azodicarboxylate (1.57 ml, 8 mmol) in tetrahydrofuran (20 ml) at 0° C. under a nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated in-vacuo the residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (gradient from 0:100 to 15:85) to give acetic acid 3-cyclobutoxy-phenyl ester (340 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].O=O.[C:7]([OH:10])(=[O:9])[CH3:8]>>[C:7]([O:10][C:1]([O:10][C:7](=[O:9])[CH3:8])=[CH:2][CH2:3][CH3:4])(=[O:9])[CH3:8]
Reactant: CC(=O)O
Reactant: C=CC=C
Agent: O=O
Product: CCC=C(OC(C)=O)OC(C)=O
Temperature: 80 °C

Procedure:
A reaction tube having an inner diameter of about 12 mm (sectional area, 1.005 cm2) was packed with 4 g of a catalyst and maintained at 6 MPa and 80° C. Butadiene, acetic acid, and nitrogen gas containing 6 mol % oxygen were continuously introduced upward into the reaction tube from its bottom at rates of 0.15 mol/hr, 2.5 mol/hr, and 100 NL/hr, respectively, to yield diacetoxybutene. A reaction liquid obtained in the period from 4 hours after initiation of the reaction to 5 hours after the initiation and a reaction liquid obtained in the period from 6 hours after the initiation to 7 hours after the initiation were analyzed by gas chromatography. The rate of consumption (mmol/hr) of the butadiene per kg of the catalyst was calculated from the average of those found values and taken as catalytic activity. The results obtained are shown in Table 1.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:10][C:11]([N:13]([CH2:28][C:29]([O:31]C)=O)[C@H:14]([CH2:23][O:24][CH2:25][O:26][CH3:27])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[CH:8]=[CH2:9].Cl.[Cl-].[Na+].C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[OH:31][CH:29]1[CH2:28][N:13]([C:11]([O:10][CH2:7][CH:8]=[CH2:9])=[O:12])[C@H:14]([CH2:23][O:24][CH2:25][O:26][CH3:27])[CH:15]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C=CCOC(=O)N(CC(=O)OC)[C@H](COCOC)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)N1CC(O)C(C(=O)OC(C)(C)C)[C@H]1COCOC
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 30.4 %

Procedure:
To a suspension of potassium tert-butoxide (3.14 g, 28 mmol) in THF (130 ml) heated at 60° C. was added tert-butyl (3S)-3-[[(allyloxy)carbonyl](2-methoxy-2-oxoethyl)amino]-4-(methoxymethoxy)butanoate (5.24 g, 14 mmol) in THF (50 ml) and the mixture was stirred for 5 minutes. After cooled to 0° C. the reaction mixture was poured into diluted hydrochloric acid (after confirming that pH was about 3), a saturated aqueous sodium chloride solution was added thereto and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water, then a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo. To a solution of the residue (4.17 g) in methanol (100 ml) were added acetic acid (1.45 ml, 25 mmol) and sodium cyanoborohydride (1.06 g, 17 mmol) and the mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was purified with silica gel (60 g) chromatography (hexane/ethyl acetate=2/1→1/1) to give 1-allyl 3-tert-butyl (2S)-4-hydroxy-2-[(methoxymethoxy)methyl]-1,3-pyrrolidinedicarboxylate (1.47 g, 30%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:42]=1[CH2:43][N:44]1[C:48]([CH3:49])=[C:47](B2OC(C)(C)C(C)(C)O2)[C:46]([CH3:59])=[N:45]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:40][C:41]1[CH:63]=[CH:62][C:61]([F:64])=[CH:60][C:42]=1[CH2:43][N:44]1[C:48]([CH3:49])=[C:47]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[C:46]([CH3:59])=[N:45]1
Reactant: Cc1nn(Cc2cc(F)ccc2F)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cc(F)ccc4F)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 125.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (160 mg, 0.243 mmol) was coupled with 1-(2,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 25) (85 mg, 0.243 mmol) in sodium carbonate (77 mg, 0.729 mmol), Pd(PPh3)2Cl2 (17 mg, 0.0243 mmol), Toluene/ethanol/water (15/7.5/1 ml) to give 230 mg of titled compound. MS: m/z=753.1 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:1][CH2:2][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(CCBr)cc1

Procedure:
According to the method of Doyle and coworkers in C. T. West, et al., J. Org. Chem. 38, 2675 (1973), a stirred mixture of 4'-(2-bromoacetyl)methanesulfonanilide as prepared in Preparation 4 (6.0 g, 0.021 mol), trifluoroacetic acid (32.7 g, 0.287 mol) and triethylsilane (10.5 g, 0.0902 mol), under N2, is refluxed for 2.5 days and concentrated in vacuo. The residue is mixed with toluene, concentrated, dissolved in 1N NaOH and washed with Et2O. The aqueous layer is acidified with HCl to pH 2 and extracted well with Et2O. The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel (300 g) with 1.5% MeOH:CH2Cl2 and N-[4-(2-bromoethyl)phenyl]methanesulfonamide is crystallized from EtOAc:SSB, mp: 92°-94° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:20])([O-])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O-:28])=[CH:24][CH:23]=1.[Na+].Cl>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:11]2[CH:12]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]3=[O:20])=[CH:24][CH:23]=1
Reactant: [O-]c1ccc(F)cc1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cccc(Oc3ccc(F)cc3)c2C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
5-Nitro-2-phenylisoindole-1,3-dione (5.9 g, 22 mmol) was dissolved in DMF (40 ml) and sodium 4-fluorophenolate (3.1 g, 23.1 mmol) was added. The resulting mixture was stirred at 100° C. for 2 hours under an argon atmosphere. The mixture was allowed to cool to RT then poured into 4% aqueous HCl. The yellow precipitate which formed was filtered off, washed with water and recrystallised (DCM/TBME) to yield (4-fluorophenoxy)-2-phenylisoindol-1,3-dione (2.4 g, 41%);