Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:31]1[CH2:32][CH2:33][CH2:34][C@H:30]1[C:29]([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:35])=[O:19])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a suspension of N-Boc-L-phenylalanine (1.000 g, 3.77 mmol) in acetonitrile (25 ml) at room temperature was added L-proline benzyl ester HCl (1.002 g, 4.15 mmol), PyBOP (2.060 g, 3.96 mmol) followed by DIPEA (1.382 ml, 7.92 mmol). The reaction turned to clear and was stirred at room temperature for 1 hour. The reaction was quenched by brine and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 30 to 50% EtOAc/HEP) and gave the title compound: 1.6 g (yield: 97%). LCMS (condition B): 453.4 (M+1); retention time=1.44 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 116.1 %

Procedure:
To a suspension of solution of (S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (18.3 g, 45 mmol) and potassium carbonate (8.2 g; 59 mmol) in DMF (150 ml) cooled to 0° C. under N2, was added dropwise a solution of iodomethane (7.36 ml; 118 mmol). The reaction mixture was left to stir at room temperature for 18 h. It was diluted with ethyl acetate, washed with water and brine. The organic was dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid (18 g; 95%). 1H NMR (CDCl3) 1.46-1.50 (18H, d), 1.65 (3H, s), 2.80-2.90 (1H, m), 3.10-3.40 (2H, m), 3.75-4.10 (2H, m), 4.60-4.70 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH3:47])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CP(=O)(O)CCCN
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)O[C@H](OC(=O)NCCCP(C)(=O)O)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet is added (25) (100 mmol), 3-aminopropylmethylphosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension is stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture becomes homogeneous. The THF is removed in vacuo and the reaction mixture is diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase is separated and concentrated in vacuo to leave a white solid. The solid is purified by flash chromatography to afford the title compound (119) as a white solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[CH2:36][C:35]1([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]1[CH3:46])[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][C:35]3([C:43](=[O:44])[NH:42][C:41](=[O:45])[N:40]3[CH3:46])[CH2:34]4)=[O:20])[CH2:17][C:6]=2[CH:5]=1
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)cc1C2
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1ccc(NC(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(Cc4ccncc4)C3=O)cc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-[4-chloro-8-oxo-9-(pyridine-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]acetic acid dihydrochloride (105 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (65 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1.[H-].[Na+].[CH:18](Br)=[CH:19][C:20](=[CH2:22])[CH3:21].O>O1CCCC1>[CH:18]([O:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1)=[CH:19][C:20](=[CH2:21])[CH3:22]
Reactant: OCC1CCn2c(nc3ccccc32)S1
Reactant: C=C(C)C=CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C=COCC1CCn2c(nc3ccccc32)S1
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of one gram of 3,4-dihydro-2-hydroxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in dry tetrahydrofuran (20 ml) was treated with 0.5 g of 50% sodium hydride containing mineral oil at 0° C. under stirring. The mixture was stirred for 1 hr, then one gram of isoprenylbromide was added, and the stirring was continued for three hours at room temperature. The reaction mixture was condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.42 g (yield: 30%) of the intended product, m.p. 56°-60° C.;
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[N:12]=[N:13][C:14]([N:17](C)[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[CH:15][CH:16]=1)[C:6]#[N:7].Cl.N1C=CC=CC=1>CO.CS(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[N:12]=[N:13][C:14]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[CH:15][CH:16]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC1(C)CC(Nc2ccc(-c3ccc(C#N)cc3O)nn2)CC(C)(C)N1
Temperature: 150 °C

Procedure:
To a microwave vial was added 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile (Example 5-1, Step 1, 100 mg, 0.264 mmol) and pyridine hydrochloride (610 mg, 5.27 mmol), and the mixture was heated at 150° C. for 90 minutes in the microwave. The reaction mixture is dissolved in MeOH/DMSO, and purified by preparative HPLC (Waters Sunfire 30 mm ID×50 mm, 0.1% TFA, 15-40% ACN/H2O) to provide the title compound as a minor product (3 mg, 0.008 mmol). LCMS Rt=0.47 min (Method Q); MS (M+1)=352.2. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J=9.54 Hz, 1H), 7.65 (d, J=8.03 Hz, 1H), 7.34 (d, J=1.51 Hz, 1H), 7.18 (dd, J=1.76, 8.28 Hz, 1H), 6.87 (d, J=9.54 Hz, 1H), 4.83 (br. s., 1H), 4.40 (d, J=7.53 Hz, 1H), 2.11 (dd, J=3.64, 12.67 Hz, 2H), 1.59 (td, J=7.72, 15.18 Hz, 1H), 1.33-1.43 (m, 7H), 1.25 (br. s., 6H).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([CH3:22])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.O>ClCCl>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:13]([C:12]2[O:23][CH2:7][C:8]([CH3:9])([CH3:10])[N:11]=2)[CH3:22])=[CH:20][CH:19]=1
Reactant: CC(Cc1ccc(Br)cc1)C(=O)NC(C)(C)CO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(Cc1ccc(Br)cc1)C1=NC(C)(C)CO1
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
A solution of methanesulphonyl chloride (11.4 g) in dichloromethane (50 ml) was added dropwise over 1 hour to a stirred mixture of N-(1-hydroxy-2-methylpropan-2-yl)-3-(4-bromophenyl)-2-methylpropionamide (31.4 g) and triethylamine (20.2 g) in dichloromethane (400 ml). The mixture was stirred for 2.5 hours and then water (300 ml) was added. The organic phase was separated, washed with water (200 ml) and saturated sodium chloride solution (200 ml) and dried (MgSO4). Volatile material was removed by evaporation to give 2-[1-(4-bromophenyl)propan-2-yl]-4,4-dimethyloxazoline(26.4 g) as a syrup; 1H NMR (CDCl3): 1.15 (d, 3 H), 1.2 (s, 3 H), 1.25 (s, 3 H), 2.25-2.35 (m, 2 H), 2.95-3.0 (m, 1 H), 3.85 (s, 2 H), 7.05 (d, 2 H), 7.4 (d, 2 H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37](CCC3C=C(C=CC=3)N)[CH2:36][CH2:35]2)[N:25]=1.[N:49]1([C:54]2[CH:55]=[C:56]([CH2:60][C:61]([OH:63])=O)[CH:57]=[CH:58][CH:59]=2)[CH:53]=[CH:52][CH:51]=[N:50]1>CN(C)C=O>[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[N:34]2[CH2:39][CH2:38][N:37]([C:61](=[O:63])[CH2:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([N:49]4[CH:53]=[CH:52][CH:51]=[N:50]4)[CH:55]=3)[CH2:36][CH2:35]2)[N:25]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)Cc1cccc(-n2cccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)Cc4cccc(-n5cccn5)c4)CC3)cccc2n1
Yield: 74 %

Procedure:
EDC.HCl (1.5 eq), HOBt (2 eq) and 2-methyl-5-(1-piperazinyl)quinoline (D3)(1 eq) were added sequentially to a stirred solution of [3-(1H-pyrazol-1-yl)phenyl]acetic acid (D19)(1.1 eq) in dimethylformamide at room temperature under an inert atmosphere. The solvent was removed by means of an SCX cartridge. The crude material was purified on SPE cartridge (Silica) eluting with a gradient from dichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2 affording the title compound in 74% yield.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C.O.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:32])=[CH:34][CH:35]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
TEA was added to a mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.0 g, 3.1 mmol) and 4-(t-butyl)benzoyl chloride (0.61 g, 3.1 mmol) in acetonitrile (35 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL), and the organic phase separated and concentrated. The residue was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting 1.1 g of the product at 80-90% ethyl acetate, in 80% yield as a white solid; mp 164-166° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.26 (99.57%); 1H NMR (DMSO-d6) δ 1.30 (s, 9H), 2.01-2.09 (m, 1H), 2.46-2.63 (m, 2H), 2.84-2.96 (m, 1H), 4.65 (d, J=6.0 Hz, 2H), 5.15 (dd, J=12.9 Hz, J=5.4 Hz, 1H), 7.49-7.52 (m, 2H), 7.79-7.91 (m, 5H), 9.16 (t, J=6.0 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 34.6, 42.5, 49.0, 121.9, 123.5, 125.1, 127.1, 129.7, 131.1, 131.6, 133.3, 147.8, 154.3, 166.3, 167.0, 167.1, 169.8, 172.7; Anal. Calcd for C25H25N3O5.25H2O: C, 66.43; H, 5.69; N, 9.30. Found: C, 66.49; H, 5.62; N, 8.96.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25](C)(C)[CH2:24][C:23](C)(C)[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=O)=CC=2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1COCC1.O>CCOCC.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>[C:9]1(=[C:8]([C:21]2[CH:22]=[CH:23][C:24]([C:32]3[O:31][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:26]=2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:15][CH2:16][CH2:17]1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
The round-bottom flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), 2-furanylboronic acid (0.063 g, 0.56 mmol), aqueous 2 M Na2CO3, (0.06 g, 0.56 mmol), and THF/H2O mixture (4:1, 5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 10 h. Reaction mixture was cooled to room temperature, diluted with Et2O (10 mL) and filtered. The filtrate was diluted with EtOAc (30 mL), washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.0.42 g (44%) of compound 202 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 69.28 (s, 1H), 7.70 (br s, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.12 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.66 (d, J=6.3 Hz, 1H), 6.55 (br s, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]3\[CH2:14][N:15]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:17][C:18]\3=[O:19])=[N:8]2)[N:3]=[CH:2]1.[BH4-].[Na+].O.C(OCC)(=O)C>CO>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH:11]=[CH:10][C:9](/[CH:12]=[C:13]3\[CH2:14][N:15]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:17][CH:18]\3[OH:19])=[N:8]2)[N:3]=[CH:2]1
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2cscn2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(Cc2cscn2)n1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of (E)-3-({1-[(1,3-thiazol-4-yl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-one (2.48 g) in methanol (25 ml) was added sodium borohydride (0.09 g) at room temperature. After being stirred at the same temperature for 0.5 hour, water and ethyl acetate were added and the product was extracted. The separated organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave (E)-3-({1-[(1,3-thiazol-4-yl)methyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (ca. 2.5 g) as a crude pale yellow amorphous solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10](O)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].CI>CC(CC)=O.O>[F:7][C:8]1[CH:9]=[C:10]([O:4][CH3:1])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 96.7 %

Procedure:
Potassium carbonate (79.0 g, 0.57 mol) was added to a stirred solution of 3-fluoro-4-nitrophenol (45.0 g, 0.29 mol) and methyl iodide (50.0 mL, 0.81 mol) in methylethyl ketone (450 mL) at room temperature. The suspension was stirred at 40° C. for 15 hours and then allowed to cool. The mixture was diluted with water (200 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The organic extracts were combined, dried over MgSO4 and evaporated under reduced pressure to give the title compound (48.0 g, 97% yield) as a light yellow solid.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[NH4+:10]>O1CCOCC1.O.C(O)(=O)C>[CH:5]1[C:6]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[O:7][C:1]=2[CH:2]=[CH:3][C:4]=1[NH2:10]
Reactant: O=C1CCCCC1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C

Procedure:
Following method B, dimethylsulfamoyl chloride (60 mL, 550 mmol) was added to a gently refluxing solution of 4-aminophenol (55 g, 500 mmol) and triethylamine (56 g, 550 mmol) in tetrahydrofuran (350 mL). The reaction mixture was refluxed for 2 h and then cooled to room temperature and then filtered to remove the solids. The filtrate was diluted with ethyl acetate and washed with 2 N HCl and brine, dried (Na2SO4) and concentrated to give crude N′-(4-hydroxy-phenyl)-N,N-dimethyl-sulfamide (108 g). The crude N′-(4-hydroxy-phenyl)-N,N-dimethyl-sulfamide (108 g, 500 mmol) was dissolved in dichloromethane (750 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (130 g, 550 mmol) was added. The reaction mixture was stirred for 35 minutes and then filtered. The solids were washed with dichloromethane and the filtrate was concentrated. The crude material was purified by column chromatography to provide the benzoquinoneimine (85 g). Potassium t-butoxide (0.30 g, 2.5 mmol) was added to a cooled (2° C.) solution of 2-cyclohexanonecarboxylic acid ethyl ester (4.2 mL, 25 mmol) in tetrahydrofuran (60 mL). The reaction mixture was stirred at 2° C. for 10 min and then a solution of benzoquinoneimine (5.4 g, 25 mmol) in tetrahydrofuran (45 mL) was added. After 1 hour, the mixture was quenched with glacial acetic acid (0.14 mL) and stirred at 2° C. for 40 min, and then concentrated. The crude material was dissolved in ethyl acetate and washed with brine, dried (Na2SO4), and concentrated. The material was purified by flash column chromatography (elution with 30% ethyl acetate-hexane) to provide the desired phenolic cyclohexanone (6.8 g). The phenolic cyclohexanone (0.96 g, 2.5 mmol) was dissolved in dioxane (10 mL) and 6 N hydrochloric acid (10 mL) was added and the mixture was heated to reflux for 2.5 hours. The reaction mixture was diluted with water and made basic with concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. Analytical analysis indicated complete furan formation, but incomplete sulfonyl urea hydrolysis. The crude mixture was dissolved in acetic acid (10 mL) and 6 N HCl (10 mL) was added. The mixture was refluxed for 12 hours. After cooling to room temperature, the reaction mixture was cooled to 0° C. and concentrated ammonium hydroxide was added until basic. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with 20% aqueous ammonium hydroxide and brine, dried (Na2SO4) and concentrated. Column chromatography purification provided 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (74 mg).
Reaction SMILES: FC(F)(C(F)(F)C(F)(F)C(F)F)COC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F.FC(F)(C(F)(F)C(F)(F)C(F)F)C[NH:34][C:35](=[O:62])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][O:45][C:46](=[O:61])[NH:47]CC(F)(F)C(F)(F)C(F)(F)C(F)F)[CH:39]=1>>[C:46](=[O:61])([O:45][CH2:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][O:36][C:35](=[O:62])[NH2:34])[CH:39]=1)[NH2:47]
Reactant: O=C(NCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCc1cccc(COC(=O)NCC(F)(F)C(F)(F)C(F)(F)C(F)F)c1
Agent: O=C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: NC(=O)OCc1cccc(COC(N)=O)c1
Yield: 98.5 %

Procedure:
The reaction was carried out in the same manner as Example 3 except for using 80.5 g (0.1642 mol) of bis(2,2,3,3,4,4,5,5-octafluoropentyl)carbonate (to be referred to as “BOFC” hereinafter) synthesized in the above Synthesis Example 4 in place of BTFC, and it was confirmed that m-xylylene bis(2,2,3,3,4,4,5,5-octafluoropentyl carbamate) (to be referred to as XDC-4 hereinafter) was generated as the main product (XDA base yield 98.5%). Structural assignment of the product XDC-4 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of XDC-4, 1H-NMR and 19F-NMR were shown in the following.