Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[NH:20][C:19]=3[C:18](=[O:29])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:30])[N:10]=1.O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[C:18](=[O:29])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:30])[N:10]=1
Reactant: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4ccc(Br)cc4c32)N1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4ccccc4c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-7-bromo-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one TFA salt (13 mg, 0.027 mmol), in MeOH (5 mL) is added sodium acetate trihydrate (24 mg, 0.18 mmol) and 10% Pd/C (4.5 mg). It is stirred at room temperature under a hydrogen atmosphere overnight and then the catalyst is removed by filtration. The solution is concentrated and the residue is purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 5-(2-amino-5-oxo-3.5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one; 1H NMR (DMSO-d6) δ 3.30-3.36 (m, 4H), 7.20 (t, 1H, J=7.6 Hz), 7.33 (t, 1H, J=7.2 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.58 (d, 1H, J=7.2 Hz), 8.36 (t, 1H, J=2.4 Hz), 9.20 (bs, 1H), 10.37 (bs, 1H), 12.45 (s, 1H); m/z [M++1] 296.1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:4][CH2:3]1.N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](CCN2C3C=C(C#N)C=CC=3OCC2=O)CC1.[Si](O[C@@H]1CN(C(OC(C)(C)C)=O)[C@H](C(OCC)=O)CC1)(C(C)(C)C)(C)C.[Si](O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H](C(OCC)=O)CC1)(C(C)(C)C)(C)C.[O:111]1[C:120]2[CH:119]=[C:118]([CH:121]=O)[N:117]=[CH:116][C:115]=2[O:114][CH2:113][CH2:112]1>>[O:111]1[C:120]2[CH:119]=[C:118]([CH2:121][NH:1][C@H:2]3[CH2:7][NH:6][C@H:5]([CH2:15][CH2:16][N:17]4[C:22]5[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=5[O:20][CH2:19][C:18]4=[O:29])[CH2:4][CH2:3]3)[N:117]=[CH:116][C:115]=2[O:114][CH2:113][CH2:112]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: CCOC(=O)[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Product: N#Cc1ccc2c(c1)N(CC[C@@H]1CC[C@@H](NCc3cc4c(cn3)OCCO4)CN1)C(=O)CO2

Procedure:
The product was obtained following the procedure described for Example 105, except, the enantiomer of Intermediate 183, tert-butyl (2S,5R)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (prepared by the exact route as Intermediate 183, but starting from 1-tert-butyl 2-ethyl (2S,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate, the enantiomer of Intermediate 191) was reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde to yield the named compound.
Reaction SMILES: [C:1]([Cl:6])([C:3](Cl)=O)=O.CN(C=O)C.[N:12]1[C:17]2[CH:18]=[CH:19][S:20]C=2C(=O)[NH:14][CH:13]=1>O>[Cl:6][C:1]1[C:3]2[S:20][CH:19]=[CH:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccsc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a stirred solution of (COCl)2 (7.33 mL, 84.11 mmol) in anhydrous (CH2Cl)2 (20 mL) at 0° C. under nitrogen was added DMF (4.47 mL, 57.18 mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19) (4 g, 26.28 mmol) in anhydrous (CH2Cl)2 (5 mL added drop wise to the reaction mixture which was stirred for 20 min at 0° C., warmed to room temperature over another 20 min, heated at 80° C. for 1.5 hours, and cooled to room temperature. Finally, the reaction mixture was poured into water and extracted with DCM. The extract was washed sequentially with water, brine, dried over Na2SO4, filtered and evaporated to afford the title compound 20 (4.36 g, 97% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.02 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>CCOCC>[CH2:15]([C:17]1[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1)[CH3:16]
Reactant: CCc1cc2ccccc2o1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCc1oc2ccccc2c1C(=O)c1ccc(Br)c(S(N)(=O)=O)c1

Procedure:
is obtained as described in Example 1 from 10.9 g 4-bromo-3-sulfamoylbenzoyl chloride and 6 g 2-ethylbenzo[b]furan in the presence of 11.7 g aluminum chloride. Colorless crystals, m.p. 202°-206° C. (ether).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH2:15].C(OCC)(=O)C.O>O1CCCC1>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 5-chloroisatoic anhydride (10.0 g, 51 mmol) in tetrahydrofuran (100 ml) at ambient temperature was added a 40% w/w aqueous solution of methylamine (19.80 g, 255 mmol) dropwise. The mixture was stirred at an ambient temperature for 1 hour. Ethyl acetate (100 ml) and water (100 ml) were added and the phases separated. The aqueous layer was back extracted with ethyl acetate (100 ml) and the combined organics were evaporated under reduced pressure to afford a white solid, which was recrystallised from toluene (60 ml) to afford the title compound as a white solid (8.15 g)
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:32]1([CH2:31][O:1][C:2]2[C:3](=[O:29])[C:4]([C:18]3[N:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:21]=[CH:20][CH:19]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)[CH:7]=2)[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(OCC2CC2)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.1 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), (bromomethyl)cyclopropane (0.048 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 20 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (103 mg, 91% yield) as colorless prisms: mp 72-78° C.; 1H NMR (300 MHz, CDCl3): δ ppm 0.32-0.47 (2H, m), 0.60-0.76 (2H, m), 1.26-1.39 (1H, m), 4.06 (2H, d, J=7.2 Hz), 7.04 (1H, dd, J=2.3, 8.3 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.99 (1H, s). LC-MS (ESI) m/z 453 [M+H]+. Anal. Calcd for C24H19F3N4O2.0.5H2O: C, 62.47; H, 4.37; N, 12.14. Found: C, 62.19; H, 4.41; N, 12.15.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O-])([O-])=O.[Na+].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12].C(Cl)Cl>C(OCC)(=O)C.O>[OH:2][CH2:1][CH2:3][NH:4][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO

Procedure:
Ethanolamine (10 mL, 165 mmol) was dissolved in ethyl acetate (60 mL). Then a solution of Na2CO3 (22.7 g, 214.2 mmol) in water (100 mL) was added. Then, a solution of 2-nitrobenzenesulfonyl chloride (35.0 g, 157.9 mmol) in ethyl acetate (100 mL) was added dropwise under stirring. The resulting solution was stirred at room temperature for 2 h (TLC monitoring, eluent: CH2Cl2). The organic layer was separated, washed with water and a solution of citric acid, dried over Na2SO4, and evaporated. Yield of 54: 29.5 g (73%) as white crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CC(=O)N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1
Reactant: CN
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(C2CCN(C(C)=O)CC2)cc1

Procedure:
Reaction of 4-(1-acetylpiperidin-4-yl)benzenesulphonyl chloride (16.0 g) [the product of Example 2(i)] with an excess of aqueous methylamine (100 ml, 30%) in ethanol (10 ml) according to the method of Example 2(ii) gave the title compound, (15.0 g), used directly in the next stage.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>C(O)C>[CH2:19]([NH:22][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH2:20][CH3:21]
Reactant: CCCN
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCO
Product: CCCNc1cc(=O)[nH]c(-c2ccccc2OCCC)n1

Procedure:
4-Chloro-6-hydroxy-2-(2-propoxyphenyl)-pyrimidine (0.66 g), n-propylamine (1.8 g) and ethanol (20 ml) was heated at 90° C. in a pressure vessel for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which solidified on washing with water. The residue was recrystallized from isopropanol:water to yield the title compound, 0.56 g, m.p. 172°-3° C.
Reaction SMILES: [C:1]([Si:5]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][C:7]1[CH:8]=[C:9]([C:13]2(O)[CH:25]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][C:15]3(OCC(C)(C)C[O:16]3)[CH2:14]2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([Si:5]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:25]([CH2:26][N:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][C:15](=[O:16])[CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC1CCC2(CC1(O)c1cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)OCC(C)(C)CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CCC(=O)C=C1c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 10 h

Procedure:
197 g 8-[3-(tert-Butyl-diphenyl-silanyloxy)-phenyl]-9-dimethylaminomethyl-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-8-ol were dissolved in tetrahydrofuran and the solution was cooled to 5° C. A mixture of 300 ml concentrated hydrochloric acid and 300 ml water was added dropwise at this temperature. The mixture was then stirred at room temperature for 10 hours. 400 ml ethyl acetate were then added, while cooling with ice, and the pH was then brought to 12 with 32% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted three times with 400 ml ethyl acetate each time. The combined organic phases were washed twice with 100 ml saturated sodium chloride solution each time and dried over magnesium sulfate and the solvent was then evaporated in vacuo. The residue was purified on silica gel with ethyl acetate/methanol=1/1. 68 g (42% of theory) of the title compound were obtained in this way.
Reaction SMILES: CC(OO)=[O:3].[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([CH2:11][C:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:9][CH:8]=1>C(O)(=O)C.ClC(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]23[O:3][C:13]2([C:19]([O:21][CH3:22])=[O:20])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16]3)=[CH:23][CH:24]=1
Reactant: COC(=O)C1=C(Cc2ccc(Cl)cc2)CCC1(C)C
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C12OC1(Cc1ccc(Cl)cc1)CCC2(C)C

Procedure:
23.5 g (3 equivalents) "PROXITANE 4002" (Trade Mark: 36-40% (w/w) peracetic acid in acetic acid) were added to 9.8 g (35.1 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-methoxycarbonylcyclopent-1-ene prepared as described in Example 1 (f) in 90 ml trichloromethane. The resulting mixture was refluxed for 3 hours and then extracted twice with 50 ml aliquots of trichloromethane, backwashed once with 50 ml dilute aqueous sodium bicarbonate solution and twice with 50 ml aliquots of saturated aqueous sodium metabisulphite solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and flashed to give 12 g of a pale yellow oil which crystallised on cooling. Trituration in 30/40 petroleum gave 5.8 g 1-(4-chlorobenzyl)-1,2-epoxy-3,3-dimethyl-2-methoxy-carbonylcyclopentane as a white crystalline solid, m.pt. 86°-87° C. Yield 56%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31]>C1COCC1.CCOCC>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]\[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH2:29][C:30](=[O:31])[NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:6]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(/C=C\C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 50 °C

Procedure:
To a stirred solution of (Z)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)benzoic acid (200 mg, 0.41 mmol) in anhydrous THF (5.0 mL) was added DCI (82 mg, 0.51 mmol). The mixture was heated in a 50° C. oil bath for 1.5 h, treated with 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (109 mg, 0.057 mmol) and the resulting mixture heated to reflux for 8 h. After cooling to ambient temperature, the mixture was taken up in Et2O and washed twice with aq. 5% NaHSO4 (2×) and once with sat. NaCl (1×). After dying over MgSO4, concentration in vacuo and purification by medium pressure chromatography on silica with EtOAc/Hexanes as the eluents, the title compound was obtained as a white foam (160 mg, 41%) mp 48-61° C.: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.9 Hz, 1H), 7.44-7.29 (m, 3H), 7.14 (dd, J=7.9, 1.6 Hz, 1H), 6.86 (d, J=11.4 Hz, 1H), 6.76 (t, J=5.9 Hz, 1H), 6.59 (br s, 1H), 6.21-6.04 (m, 1H), 4.23 (d, J=5.5 Hz, 1H), 3.98 (qd, J=9.0, 6.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −69.31, −72.3; EIMS m/z 626.9 ([M+1]+).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.C[CH2:9][O:10]CC.[Si:13]([O:20][C:21]1[CH:48]=[CH:47][C:24]([CH2:25][C:26]2[C:27](=[O:46])[O:28][C:29](=[O:45])[C:30]=2[C@H:31]2[CH2:36][CH2:35][C@@H:34]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:33][CH2:32]2)=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CO>[Si:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25]/[C:26](=[C:30](\[C@H:31]2[CH2:32][CH2:33][C@@H:34]([O:37][Si:38]([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:40])[CH3:39])[CH2:35][CH2:36]2)/[C:29]([O:10][CH3:9])=[O:45])/[C:27]([O:28][CH3:1])=[O:46])=[CH:47][CH:48]=1)([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15]
Reactant: CCOCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC2=C([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C(=O)OC2=O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)/C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 2.0 M trimethylsilyldiazomethane solution in ether (0.43 ml, 0.85 mmol) was added to a solution of 3-(4-((tert-butyldimethylsilyl)oxy)benzyl)-4-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)furan-2,5-dione (60 mg, 0.11 mmol) in methanol (1.5 ml) at room temperature. The mixture was stirred at room temperature for 5 hr, and the solvent was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=93:7) to give the title compound as a yellow oil (55 mg, yield 85%).
Reaction SMILES: [CH3:1][CH:2]1[CH:13]=[C:12]([CH3:14])[CH2:11][CH2:10][C:3]21[CH:8]([OH:9])[O:7][CH2:6][CH2:5][CH2:4]2.[CH3:15]C1C=CC(S(O)(=O)=O)=CC=1>CO.CC(OC)(C)C>[CH3:15][O:9][CH:8]1[C:3]2([CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH:2]2[CH3:1])[CH2:4][CH2:5][CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=CC(C)C2(CCCOC2O)CC1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC1OCCCC12CCC(C)=CC2C
Yield: 7041.6 %

Procedure:
A solution of 7,9-dimethyl-2-oxaspiro[5.5]undec-8-en-1-ol (5.0 g, 26 mmol) and p-TsOH (50 mg) in methanol (20 ml) was stirred at reflux temperature for 0.5 hours. The mixture was diluted with MTBE, washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled bulb-to-bulb to yield a colorless oil (4.3 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[NH:15][N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(O[CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:32]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#Cc2nn(C3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in Step 1, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70° C. for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (36.2 mg). Physical properties: m/z [M+H]+ 465.1
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[Br:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCBr)c(OC)c1
Temperature: 82.5 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
In a 100 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 10.2 g (54.9 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 12.4 g (60.4 mmol) of 1,3-dibromopropane, 8.3 g (60.4 mmol) of potassium carbonate (purity: 98 wt. %), and 30 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. in an argon gas atmosphere for 8 hours. After the reaction was complete, the reaction mixture was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (gel: Wako gel C-200, eluent: n-hexane), to give 15.1 g (isolated yield: 88.8%, purity: 98% in terms of area percentage by high performance liquid chromatography) of methyl 4-(3-bromopropoxy)-3-methoxybenzoate as a white crystalline product.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1Cl)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>C(O)C>[C:1]([N:4]([C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:19])[C:17]=1[N:31]1[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)N(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CC(=O)N(C(C)=O)C1=C(N2CCN(c3ccc(F)cc3)CC2)C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1.66 g of 2-[N,N-diacetylamino]-3-chloro-1,4-naphthoquinone and 1.441 g of 1-(4-fluorophenyl)-piperazine in 50 ml of ethanol was refluxed overnight, then evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through silica gel and eluted with chloroform:methanol (100:2). The eluent was evaporated and the residue crystallized from dichloromethane/-hexane, giving 800 ml of the desired product, mp 149°-150° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[OH:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:16]=2)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1ccc(F)cc1F
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Oc2ccc(F)cc2F)c1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 19.3 %

Procedure:
To a solution of 3-chloro-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (54.4 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-difluorophenol (19.5 mg, 0.15 mmol) and cesium carbonate (146.6 mg, 0.45 mmol) and the reaction was stirred at 100° C. for 25 minutes. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (5) (13.2 mg, 19%). ESI-MS m/z calc. 456.07, found 457.3 (M+1)+; Retention time: 1.76 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.47-8.37 (m, 1H), 8.27-8.15 (m, 1H), 7.97-7.75 (m, 4H), 7.69-7.50 (m, 4H), 7.45 (s, 2H), 7.30-7.17 (m, 1H) ppm.