Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11])[CH:8]=[O:9]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=Cc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
2,6-Dichloro-4-hydroxymethylphenol (3.56 g, 18.4 mmol) was dissolved in dioxane, and DDQ (4.19 g, 18.4 mmol) was added. The reaction mixture was stirred at rt overnight. The solvents were removed under reduced pressure. The residue was diluted with CH2Cl2, and the mixture was filtered. The filtrate was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Crystallization from EtOAc yielded the title compound (0.77 g, 22%). LC-MS: tR=0.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:11]=1)=[O:8]>C(O)(=O)C.[Zn]>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][C:6]=1[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:11]=1)=[O:8]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3N)n2)cc1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide (300 mg, 0.81 mmol, 1.00 equiv) in acetic acid (10 mL), and zinc (527 mg, 8.11 mmol, 9.96 equiv). The resulting solution was stirred for 1 h at 70° C. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 8 with ammonia (2 mol/L). The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 200 mg (73%) of a solid.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[F:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][C:34]=1[OH:35])[CH2:17][N:18]([N:27]1[CH:31]=[N:30][N:29]=[CH:28]1)[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>O.C(OCC)(=O)C.CN(C)C(=O)C>[C:23]([C:22]1[CH:21]=[CH:20][C:19]([N:18]([CH2:17][C:16]2[CH:32]=[CH:33][C:34]([O:35][S:1](=[O:4])(=[O:3])[NH2:2])=[C:14]([F:13])[CH:15]=2)[N:27]2[CH:28]=[N:29][N:30]=[CH:31]2)=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1ccc(N(Cc2ccc(O)c(F)c2)n2cnnc2)cc1
Reactant: NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N(Cc2ccc(OS(N)(=O)=O)c(F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulphamoyl chloride solution in toluene (3 mL, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 mL volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethylacetamide (5 mL) was added. 4-[(3-Fluoro-4-hydroxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03020, 220 mg, 0.71 mmol) was added to the colourless solution and the mixture was stirred for 4 h at room temperature. Ethyl acetate (50 mL) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×25 mL) and brine (25 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in acetone (5 mL) and precipitated by addition of diethyl ether. The precipitate was filtered off and dried under high vacuum. Yield: 228 mg (83%) white powder. 1H-NMR (400 MHz, d6-DMSO) δ=5.11 (s, 2H), 6.71 (d, J=9.0 Hz, 2H), 7.23 (dd, 8.2, 1.2 Hz, 1H), 7.39 (dd, J=8.2, 8.2 Hz, 1H), 7.43 (dd, J=11.1, 2.1 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.28 (s, 2H, —NH2), 8.92 (s, 2H). LRMS (FAB+): 389.1 (100, [M+H]+). HRMS (FAB+): 389.08298 C16H14N6O3SF requires 389.083214.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH3:35])[CH:33]=2)[CH:28]=[CH:27][N:26]=1>>[CH3:35][C:32]1[CH:33]=[C:34]2[C:29]([CH:28]=[CH:27][N:26]=[C:25]2[NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:30][CH:31]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Cc1ccc2ccnc(Cl)c2c1
Agent: Cl
Product: Cc1ccc2ccnc(Nc3cccc(CNc4ncnc5c(C(N)=O)cccc45)c3)c2c1

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 1-Chloro-7-methyl-isoquinoline at 120° C.:
Reaction SMILES: C1CCCCC=1.[C:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]1[O:36][C@:26]2([CH2:37][O:38]CC3C=CC=CC=3)[C@@:27](CC3C=CC=CC=3)([OH:28])[C@H:23]1[O:24][CH2:25]2)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[C:7]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C@@H:22]1[O:36][C@:26]2([CH2:37][OH:38])[C@@H:27]([OH:28])[C@H:23]1[O:24][CH2:25]2)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Oc1ccccc1[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@]2(O)Cc1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: O=C(Oc1ccccc1[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O)c1ccccc1
Yield: 87.6 %

Procedure:
In a stream of nitrogen, 20% palladium hydroxide-carbon (53 mg) and cyclohexene (0.52 ml, 5.1 mmols) were added to an anhydrous ethanol (2 ml) solution of the compound (25) (54 mg, 0.10 mmol), and the mixture was heated under reflux for 2 hours. After filtration, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=80:3) to obtain a white powder (26) (30 mg, 85%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]CC2C=CC=CC=2)[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]>CO.Cl.[Pd]>[CH3:1][C:2]([CH3:22])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)Cc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)Cc1cccc(O)c1
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of methyl 2,2-dimethyl-3-(3-benzyloxyphenyl)propionate (208 mg, 0.7 mmole) in 10 mL of MeOH and 1 mL of 1N HCl was treated with 10% Pd/C (100 mg) and hydrogenated on a Parr shaker with 50 psi H2 pressure for 1 hour. The catalyst was filtered, and the filtrate was concentrated, diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed, and gave the titled product, 140 mg (97% yield). MS (ESI) 209 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>>[OH:42][C:25]([CH3:41])([CH3:24])[CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([N:15]5[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]5=[O:22])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:29]=[N:28]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(N4C(=O)NCC4(C)C)nc2-3)cn1
Yield: 12 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 429. Yield 12%. MS (ESI+): 454.1. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=8.2, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.35 (dd, J=8.2, 1.8, 1H), 7.21 (d, J=1.7, 1H), 4.71 (s, 1H), 4.31 (t, J=5.0, 2H), 4.03 (d, J=5.6, 2H), 3.18 (dd, J=9.3, 5.1, 3H), 1.72 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[NH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[NH:3][C:4]=3[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)[nH]c2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 14 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 14% of theory; LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=348 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([N:6]1[CH2:16][CH2:15][C:9]2([C:13](=[O:14])[NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[O:5].CC(C)(C)CC(N1CCC2(C(=O)N(C3C=CC(C(O)C(F)(F)F)=CC=3)CC2)CC1)=O.Br[C:50]1[CH:55]=[CH:54][C:53]([CH:56]([OH:61])[C:57]([F:60])([F:59])[CH3:58])=[CH:52][CH:51]=1>>[F:59][C:57]([F:60])([CH3:58])[CH:56]([C:53]1[CH:52]=[CH:51][C:50]([N:12]2[CH2:11][CH2:10][C:9]3([CH2:15][CH2:16][N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:18])([CH3:17])[CH3:1])[CH2:7][CH2:8]3)[C:13]2=[O:14])=[CH:55][CH:54]=1)[OH:61]
Reactant: CC(C)(C)CC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC(F)(F)C(O)c1ccc(Br)cc1
Agent: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(F)(F)F)cc1)C2=O
Product: CC(C)(C)CC(=O)N1CCC2(CC1)CCN(c1ccc(C(O)C(C)(F)F)cc1)C2=O

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(3,3-dimethyl-butyryl)-2,8-diaza-spiro[4.5]decan-1-one, product of example 165 A) and 1-(4-bromo-phenyl)-2,2-difluoro-propan-1-ol (synthesis: R. Mogi, et al, Journal of Fluorine Chemistry; 10; 2007; p 1098). White solid. MS (ESI): 423.24 (MH+).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:5]([CH2:6][CH2:7][Cl:8])[CH2:4][CH2:3][Cl:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCN(CCCl)Cc1ccccc1

Procedure:
Bis-(2-chloro-ethyl)-amine hydrochloride was suspended in 150 mL acetonitrile. Added were 34.8 g K2CO3 (3 equiv.) and 10.0 mL benzylbromide (1 equiv.). The mixture was refluxed overnight, Concentration on silica and purification with flash column chromatography (eluents PA:ether=95:5) yielded 4.11 g of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 2.93 (t, J=7 Hz, 4H), 3.50 (t, J=7 Hz, 4H), 3.74 (s, 2H), 7.22-7.37 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([C:19]2[NH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:16]=[C:15]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:14]=1)[C:5]([O:7]C)=[O:6].O.O.[OH-].[Li+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([C:19]2[NH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:16]=[C:15]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Methyl 3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate (611 mg, 1.42 mmol) synthesized in Example 43 was dissolved in methanol (18 mL), and water (3 mL) and lithium hydroxide monohydrate (298 mg, 7.10 mmol) were added, followed by stirring at 60° C. for 4 hours under nitrogen atmosphere. To the reaction solution, water (50 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL), followed by drying over sodium 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=30%-75%) to afford the desired compound (519 mg, yield 88%) as a white solid.
Reaction SMILES: [Sb](F)(F)F.FC([SiH](F)[CH:9]([SiH:11]([CH:13]([F:15])[F:14])F)[CH3:10])F>O>[F:14][CH:13]([SiH2:11][CH2:10][CH2:9][SiH2:11][CH:13]([F:14])[F:15])[F:15]
Reactant: CC([SiH](F)C(F)F)[SiH](F)C(F)F
Agent: F[Sb](F)F
Solvent: O
Product: FC(F)[SiH2]CC[SiH2]C(F)F
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A glass reactor equipped with a thermometer, a stirrer, and a condenser was charged with 76.8 g (0.43 mol) of antimony trifluoride, and, while cooling with water to 0° to 10° C., 76.8 g (0.3 mol) of 2-bis(dichloromethylsilyl)ethane was added thereto dropwise. The 2-bis(dichloromethylsilyl)ethane used here had a purity of 99.5% and contained 0.1% of 1,1-bis(difluoromethylfluorosilyl)ethane. After the dropwise addition, the mixture was stirred at 30° C. for 2 hours to complete the reaction. The reaction solution was distilled twice to yield 40.2 g of 1,2-bis(difluoromethylsilyl)ethane (designated compound A1) free from 1,1-bis(difluoromethylsilyl)ethane. The 1,2-bis(difluoromethylsilyl)ethane thus obtained is a compound of general formula (1) in which R1 and R2 are both methyl.
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O>CN(C=O)C>[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=[C:5]1[C:6](=[O:14])[NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:4]1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1COc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0,01 mol) and pyrrole-2-carboxaldehyde (1.58 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 48 h, then cooled at room temperature and poured into crushed ice and left overnight at 4° C. The precipitated solid was collected by filtration, washed with water and dried. The precipitate was boiled with ethanol (150 ml) and filtered while hot to remove impurities. The filtrate was evaporated to dryness under reduced pressure, and the residue was chromatographed on a silica gel column using (95:5) toluene:ethyl acetate as the mobile phase.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]([C:12]1[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:6]2.C(O)C>[Pd].O1CCCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[O:13][C:12]([C:10]([N:5]3[CH2:6][CH:7]4[N:2]([CH3:1])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[O:11])=[CH:16][CH:15]=2)=[CH:18][CH:19]=1
Reactant: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc([N+](=O)[O-])cc3)o1)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C2CCC1CN(C(=O)c1ccc(-c3ccc(N)cc3)o1)C2

Procedure:
A mixture of (8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-[5-(4-nitro-phenyl)-furan-2-yl]-methanone free base, palladium on carbon (5%, 0.60 g), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred under hydrogen (530 ml). The crude mixture was purified by chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound as a solid. Mp. 189.7-191.3° C. Yield 1.68 (65%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.N#[O+:18]>C(#N)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:18])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: N#Cc1ccc(C(=O)O)cc1
Yield: 94.2 %

Procedure:
Acetonitrile (20 ml) and p-cyanobenzamide (2.92 g) were placed in a 100-ml three-neck flask disposed in an ice bath. After the solution was cooled, a solution of nitrosonium tetrafluoroborate (2.57 g) in acetonitrile (20 ml) was added dropwise to the solution over five minutes with stirring. When the addition was completed, the solution was further stirred until generation of gas was terminated. The solvent was removed through distillation under reduced pressure, and water (10 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.77 g of p-cyanobenzoic acid (yield 95%). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:11]>CO.[Pt]=O>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([OH:11])=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=[Pt]
Solvent: CO
Product: Nc1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:7]([CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:6]2.[CH3:34][C:35]1[CH:48]=[CH:47][C:38]([CH2:39][C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=1.Cl>C1(C)C=C(C)C=C(C)C=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH:7]([CH2:22][N:43]1[CH2:42][CH2:41][C:40]([CH2:39][C:38]3[CH:37]=[CH:36][C:35]([CH3:34])=[CH:48][CH:47]=3)([OH:46])[CH2:45][CH2:44]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)N2S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Agent: Cl
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc2c(c1)CC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)N2S(=O)(=O)c1ccc(C)cc1
Yield: 73.2 %

Procedure:
(RS)-Toluene-4-sulfonic acid 5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-2-ylmethyl ester (200 mg, 0.41 mmol) and 4-(4-methylbenzyl)-piperidin-4-ol (337 mg, 1.64 mmol) were heated in mesitylene (10 ml) for 20 hr at 140° C. After cooling 4N HCl was added to pHl and the mixture extracted with EtOAc (3×25 ml), the extracts dried (Na2SO4), filtered and evaporated. Purification of the crude material over SiO2 (Merck 230-400 mesh) eluting with EtOAc-cyclohexane-Et3N (9:10:1) afforded the title compound as a yellow oil (155.9 mg, 0.3 mmol, 73%), MS: m/e=521.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([CH:12]2[CH2:17][CH2:16][S:15](=[O:32])[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(C(=O)C1CCSCC1)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=O)C1CCS(=O)CC1)c1ccc(OC)cc1

Procedure:
A chloroform solution of ethyl [(4-methoxyphenyl)-(tetrahydrothiopyran-4-carbonyl)amino]acetate was stirred by adding 3-chloroperbenzoic acid (>65%; MCPBA). Sodium bicarbonate aqueous solution was added to the reaction mixture, the organic layer was separated, washed and dried, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by SCG, ethyl [(4-methoxyphenyl)-(1-oxo-tetrahydrothiopyran-4-carbonyl)amino]acetate (pale brown foam) was obtained.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([NH:1][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18]([O:20][CH3:28])=[O:19])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of Boc-L-Lys(Z)OH (2.00 g, 5.2 mmol) in dry DMF (50 mL) was added Cs2CO3 (1.71 g, 5.2 mmol). The mixture was stirred at rt for 2 h. To the reaction mixture was then added dropwise methyl iodide (392 μL, 6.3 mmol) and the mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (2% MeOH/DCM) to give the subject compound (2.00 g, yield 97%). Intermediate 31 was characterized by the following spectroscopic data: 1H NMR (DMSO-d6, 300 MHz) δ (ppm) 7.34 (m, 5H), 7.23 (t, 1H), 4.99 (s, 2H), 3.91 (m, 1H), 3.60 (s, 3H), 3.34 (s, 2H), 2.96 (m, 2H), 1.56 (m, 2H), 1.37 (m, 11H), 1.32 (m, 2H).
Reaction SMILES: C[C@]12[C@@H]3CC[C@@]4([O:19][C@@H:20]5[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([OH:29])[C@H:21]5[O:30][C@@H:31]5[O:36][C@H:35]([CH2:37][OH:38])[C@@H:34]([OH:39])[C@H:33]([O:40][C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H:32]5[OH:52])C(C[C@@]3(C4)CC[C@@H]1[C@@](C(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)=O)(C)CCC2)=C.C[C@@H]([C@@H]1[C@@]2(C)C[C@@H](O)[C@@]3(C)[C@@H]4CC[C@H](O[C@@H]5O[C@H](CO[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@@H](O)[C@H](O)[C@H]5O)C(C)(C)C4=CC[C@H]3[C@]2(C)CC1)CC[C@@H](O[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C(O)(C)C>O>[CH2:37]([OH:38])[C@H:35]1[O:36][C@H:31]([O:30][C@:21]2([CH2:20][OH:19])[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@@H:22]2[OH:29])[C@H:32]([OH:52])[C@@H:33]([OH:40])[C@@H:34]1[OH:39]
Reactant: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@@H]2CC[C@]1(O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H]1O)C3
Agent: C[C@H](CC[C@@H](O[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)C(C)(C)O)[C@H]1CC[C@@]2(C)[C@@H]3CC=C4[C@@H](CC[C@H](O[C@@H]5O[C@H](CO[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@@H](O)[C@H](O)[C@H]5O)C4(C)C)[C@]3(C)[C@H](O)C[C@]12C
Solvent: O
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Yield: 5 %

Procedure:
Rebaudioside A and mogroside V were mixed in the same manner as in Example 1 with the compounding ratio (weight ratio) shown in Table 3. Water was added to the mixture so as to obtain a degree of sweetness (intensity of sweetness) similar to that of a 5% aqueous sucrose solution, and eight types of aqueous solutions containing rebaudioside A and/or mogroside V were prepared. Among these aqueous test solutions, thaumatin was added to each aqueous solution, except for an aqueous solution consisting of 100 parts by mass of rebaudioside A (Control, rebaudioside A:mogroside V=100:0), so that its concentration became 1 ppm. The pH of each aqueous solution was adjusted to 3 and 4.5 using citric acid and trisodium citrate, and to 7 using sodium bicarbonate.