Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:47])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([CH3:46])=[N:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].FC(F)(F)C(O)=O>>[CH3:1][N:2]([CH3:47])[S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[C:23]([CH3:46])=[N:24][NH:25][CH:26]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(S(=O)(=O)N(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(S(=O)(=O)N(C)C)CC3)c2c1
Yield: 69.4 %

Procedure:
37 mg N,N-dimethyl-4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]-1-piperazine sulfonamide obtained in Example 183 and 0.2 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 16 mg of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C@@H:18]1[O:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH3:16][C:17]([CH3:22])([CH3:21])[C@H:18]([OH:20])[CH2:19][N:11]1[CH:12]=[CH:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:8][CH:7]=2)=[N:10]1
Reactant: CC(C)(C)[C@H]1CO1
Reactant: FC(F)(F)c1ccc(-c2cc[nH]n2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H](O)Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 48.2 %

Procedure:
A mixture of 4.11 g (19.4 mmol) of 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole, 2.0 g (19.9 mmol) of (S)-3,3-dimethyl-1,2-epoxybutane, 3.1 mL (22.3 mmol) of triethylamine, and 10 mL of isopropyl alcohol was placed in a sealed tube and heated at 85° C. for 48 h. Solvent was evaporated and the residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (1:7) to give 2.92 g (49%) of (2S)-3,3-dimethyl-1-{3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol as a pale yellow solid and 0.4 g (7%) of its isomer (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol. Data for (2S)-3,3-dimethyl-1-{3-[4-(tifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol: 1H-NMR (DMSO-d6): δ 7.96 (d, J 8 Hz, 2H), 7.75 (s, 1H), 7.69 (d, J=8 Hz, 2H), 6.76 (d, J=2 Hz, 1H), 4.86 (d, J=6 Hz, 1H), 4.26 (dd, J=14 Hz, J=2 Hz, 1H), 3.88 (dd, J=14 Hz, J=10 Hz, 1H), 3.45–3.50 (m, 1H), 0.88 (s, 9H); ES-LCMS m/z 313 (M+H). Data for (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol: 1H-NMR (DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H), 7.52 (d, J=2 Hz, 1H), 6.42 (d, J=2 Hz, 1H), 5.01 (d, J=6 Hz, 1H), 4.10 (dd, J=14 Hz, J=2 Hz, 1H), 3.92 (dd, J=14 Hz, J=10 Hz, 1H), 3.62–3.67 (m, 1H), 0.82 (s, 9H); ES-LCMS m/z 313 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH:18]([NH:20][C:28](=[O:30])[CH3:29])[CH3:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CC(C)N)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(C)NC(C)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 210 (2.07 g, 7.6 mmol) was added triethyl amine (1.6 ml, 11.4 mmol). The solution was cooled to 0° C. and acetic anhydride was added slowly dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at rt for 23 h. Water (30 ml) and DCM (30 ml) were added, the layers separated and the aqueous layer extracted with DCM (3×30 ml). The combined organic phases were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (2.268 g, 95%) as a white powder. mp=139.142° C. 1H NMR (270 MHz; CDCl3) 0.99 (3H, d, J=6.7 Hz, CH3CH), 1.91 (3H, s, CH3CO), 2.57 (1H, dd, J=13.6, 7.2 Hz, CH), 2.70 (1H, dd, J=13.6, 5.7 Hz, CH), 3.85 (3H, s, OCH3), 4.1-4.22 (1H, m, CH), 5.12 (2H, s, CH2Ph), 5.17-5.23 (1H, m, NH), 6.68-6.71 (2H, m, 2×CH), 6.79-6.82 (1H, m, CH), 7.24-7.44 (5H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 19.86 (CH3), 23.62 (CH3), 41.84 (CH2), 46.07 (CH), 56.12 (OCH3), 71.07 (CH2), 111.83 (CH), 115.62 (CH), 122.21 (CH), 127.40 (CH), 127.90 (CH), 128.62 (CH), 130.36 (C), 137.23 (C), 147.91 (C), 148.45 (C), 169.31 (C). LC/MS (APCI−) tr=0.89 min, m/z 312.29 (10%, M−H−), 21 1.95 (82), 120.85 (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:32])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH:24]([NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH3:25])=[CH:6][CH:5]=2.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:1][C:2]1[N:3]([CH3:32])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:43][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Cl:33])(=[O:42])=[O:41])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH:24]([NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH3:25])=[CH:6][CH:5]=2
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(C(=O)O)ccc1Cc1c(Cl)n(C)c2ccc(CC(C)NC(=O)N(C)C)cc12
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1c(Cl)n(C)c2ccc(CC(C)NC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[2-chloro-5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (47%) as a white solid; mp 126°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[CH2:11](O)[CH2:12][CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:14][CH2:13][CH2:12][CH2:11][O:7]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(C2OCCCO2)ccc1Br

Procedure:
4-Bromo-3-fluorobenzaldehyde (100.00 g, 492.6 mmol) was added to toluene (1 L). Propane-1,3-diol (42.72 mL, 591.1 mmol), and p-toluenesulfonic acid monohydrate (4.685 g, 24.63 mmol) were added to above and the reaction mixture was brought to reflux. The solvent (500 mL) was azeotroped off using a dean stark trap. The reaction mixture was cooled and extracted with sat. aqueous sodium bicarbonate (500 mL). The organics were dried over magnesium sulfate and concentrated in vacuo to give 2-(4-bromo-3-fluorophenyl)-1,3-dioxane as a white solid. MS (ESI) m/z: Calculated: 260.0/262.0; Observed: 260.9 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].O[CH:16]([CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH3:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[CH3:17][CH:16]([O:5][C:4](=[O:6])[C:3]1[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1])[CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: COc1cc(O)c(C(=O)O)c(OC)c1
Reactant: C=CCCCC(=O)CCC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C=CCCCC(=O)CCC(C)OC(=O)c1c(O)cc(OC)cc1OC
Yield: 65.2 %

Procedure:
A solution of 2-hydroxy-4,6-dimethoxy-benzoic acid (0.36 g, 0.18 mmol), 2-hydroxy-dec-9-en-5-one (0.024 g, 0.14 mmol), PPh3 (0.042 g, 0.16 mmol), diethyl azodicarboxylate (25 μL, 0.15 mmol) in diethyl ether (1.5 mL) was stirred at room temperature for 7 hours. Concentration under vacuum and chromatography afforded 2-hydroxy-4,6-dimethoxy-benzoic acid 1-methyl-4-oxo-non-8-enyl ester as a light yellow oil (32 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([CH2:21][O:22][NH2:23])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22]/[N:23]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=2)\[CH3:9])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1cc(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 55.3 %

Procedure:
4′-Hydroxy-3′-methoxyacetophenone (25) (150 mg, 0.903 mmol) was condensed with compound 19 (0.203 g, 0.992 mmol) according to the general procedure II-A defined above. After being heated for 3 h the reaction mixture was cooled and the solvent removed under reduced pressure. The ensuing residue was dissolved in CH2Cl2 (20 mL), washed with H2O (2×15 mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography (1:9 v/v ethyl acetate/hexane elution) to afford the title compound CP30261 (158 mg, 55%) as a yellow solid, m.p. 118.4-121.1° C., Rf 0.5 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:10](O)(=O)CC=CCCC.C(O)(=O)CCC=CCC.C(O)(=O)CCCCC=C.C(O)(=O)C=CCCC>>[C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:10]
Reactant: CCCC=CCC(=O)O
Reactant: CCCCC=CC(=O)O
Agent: C=CCCCCC(=O)O
Agent: CCC=CCCC(=O)O
Agent: CCCC=CC(=O)O
Product: C=CCCCCCC(=O)O

Procedure:
2-heptenoic acid; 3-heptenoic acid; 4-heptenoic acid; 5-hetpenoic acid; 6-heptenoic acid; 2-hexenoic acid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]=[C:12]([CH3:24])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[F:26][C:27]([F:31])([F:30])[CH2:28]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:26][C:27]([F:31])([F:30])[CH2:28][N:10]1[C:9](=[O:25])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:12]([CH3:24])=[N:11]1
Reactant: FC(F)(F)CI
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC(F)(F)F)c(=O)c(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 48.7 %

Procedure:
The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1,1,1-trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60° C. for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%). 1HNMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.10 (s, 3H), 4.85 (q, J=9 Hz, 2H), 6.90 (m, 2H), 7.10 (d, J=6 Hz, J=9 Hz, 2H), 7.25 (m, 2H), 7.95 (d, J=9 Hz, 2H),. MS (DCI/NH3) 458 (M+NH4)+. Anal. calc. for C20H16N2F4SO3: C, 54.54; H, 3.66; N, 6.36. Found: C, 54.41; H, 3.56; N, 6.35.
Reaction SMILES: C(O)C.[CH3:4][N:5]([CH2:7][C:8]1[S:12][C:11]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21])=[CH:10][C:9]=1[CH3:25])[CH3:6].[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:36])[CH2:34][NH2:35])[CH:30]=[CH:31][CH:32]=1.C(O)(C)C>C(OCC)C>[Br:26][C:27]1[CH:28]=[C:29]([CH:33]([OH:36])[CH2:34][NH:35][C:18]([NH:17][CH2:16][CH2:15][S:14][CH2:13][C:11]2[S:12][C:8]([CH2:7][N:5]([CH3:4])[CH3:6])=[C:9]([CH3:25])[CH:10]=2)=[CH:19][N+:20]([O-:22])=[O:21])[CH:30]=[CH:31][CH:32]=1
Reactant: NCC(O)c1cccc(Br)c1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1cc(C)c(CN(C)C)s1
Solvent: CCOCC
Solvent: CCO
Solvent: CC(C)O
Product: Cc1cc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2cccc(Br)c2)sc1CN(C)C
Yield: 65 %

Procedure:
With 7.5 ml of ethanol were mixed 4.5 g of 1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroethene and 3.5 g of DL-[2-(3-bromophenyl)-2-hydroxyethyl]amine, and the resulting mixture was subjected to reaction at room temperature for 30 hours. Thereto were added 5 ml of isopropanol and 30 ml of diethyl ether, and the mixture thus obtained was stirred, after which the crystals formed were collected by filtration. The crystals were recrystallized from 40 ml of isopropanol to obtain 4.3 g (yield 65%) of N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine having a melting point of 104°-106° C.
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9](=[O:45])[CH2:10][CH:11]([NH:19][C:20]([C:22]1([NH:37]C(=O)OC(C)(C)C)[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1>C(Cl)Cl>[NH2:37][C:22]1([C:20]([NH:19][CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][C:9]([NH2:8])=[O:45])=[O:21])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 11.3 %

Procedure:
HCl in 1,4-dioxane (4M) (0.228 mL, 0.91 mmol) was added to tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 108) (99 mg, 0.18 mmol) in DCM (4 mL) at 20° C. The resulting solution was stirred at 20° C. for 3 hours. The reaction mixture was filtered through a PTFE cup and the collected solid was purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(3-amino-1-(4-chlorophenyl)-3-oxopropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (9.00 mg, 11.1%) as a cream solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(COc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(COc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenoxymethyl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)phenoxymethyl)benzoic acid.
Reaction SMILES: [C:1]([C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:15]([O:14][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1c(O)ccc2occc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1c(OCc2ccccc2)ccc2occc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
4-tert-butyl-5-hydroxybenzofuran [J. Org. Chem., 53, 4135 (1988); 40 g, 0.21 mol], benzyl bromide (43 g, 0.25 mol) and potassium carbonate (28.8 g, 0.21 mol) were dissolved in N,N-dimethylformamide (200 ml) and the solution was stirred at room temperature for 24 h. After distilling off the N,N-dimethylformamide under vacuum, water was added to the residue and the mixture was subjected to extraction with ethyl acetate. The extracted layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 5-benzyloxy-4-tert-butylbenzofuran [49.1 g (yield, 83%)].
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].Cl.[C:13](=[NH:18])(OCC)[CH3:14]>>[ClH:1].[NH:18]=[C:13]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])[CH3:14]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCOC(C)=N
Agent: Cl
Product: CC(=N)NCCCC[C@H](N)C(=O)O

Procedure:
Essentially by the methods of Example 1 L-lysine hydrochloride (7.3 g, 4 mmol) was converted to the copper complex which was reacted with ethyl acetimidate hydrochloride (7.5 g, 60 mmol). The title compound, isolated as described in Example 1, was obtained as a hygroscopic amorphous powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
(R)-1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid (922.3 mg, 4.285 mmol) was dissolved in dichloromethane (42.8 mL, 0.1M) at room temperature under nitrogen and was treated with N,O-dimethylhydroxylamine hydrochloride (501.6 mg, 5.142 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea (1955 mg, 5.142 mmol), and N,N-diisopropylethylamine (1493 μL, 8.570 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was then diluted to 100 mL with dichloromethane and washed with water (100 mL). The water layer was back extracted with 4/1 dichloromethane/isopropanol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated to an oil. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 10% to 70% acetone in hexanes. Product containing fractions (ninhydrin visualization) were pooled and concentrated to afford (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate as an oil (1.1 gram, 100% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19]1(=[O:26])[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]1>C1COCC1>[OH:25][C:22]1([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:19](=[O:26])[CH:20]=[CH:21]1
Reactant: C#Cc1ccccc1
Reactant: O=C1C=CC(=O)C=C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A suspension of potassium bis(trimethylsilyl)amide (1.95 g, 0.0098 mole) in 20 mL of dry THF was treated with phenylacetylene (0.92 g, 0.009 mole). A flocculant white precipitate formed immediately. Benzoquinone (0.97 g, 0.009 mole) was dissolved in dry THF (10 mL) and cooled to -78° C. The potassium phenylacetylide generated above was added dropwise over a period of about 10 min. The reaction was stirred an additional 10 min, quenched by adding saturated ammonium chloride solution (20 mL) and allowed to warm to RT. The mixture was diluted with saturated ammonium chloride solution, extracted with ether and filtered to remove a flocculant dark brown precipitate. The phases were separated and the aqueous phase extracted with additional ether. The combined ether extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flask chromatography on silica gel using 4:1 hexane/EtOAc as the eluent and the fractions containing the title product were combined and concentrated in vacuo to yield 0.27 g (14%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C@H:12]([OH:21])[CH2:13]/[CH:14]=[CH:15]\[CH2:16][Si](C)(C)C.C([O:26]O)(C)(C)C.COP(OC)OC>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C@H:12]([OH:21])[CH2:13][C@H:14]([OH:26])[CH:15]=[CH2:16]
Reactant: CC(C)(C)OO
Reactant: C[Si](C)(C)C/C=C\C[C@@H](O)CC#CCOC1CCCCO1
Agent: COP(OC)OC
Solvent: Cc1ccccc1
Product: C=C[C@@H](O)C[C@@H](O)CC#CCOC1CCCCO1
Reaction time: 1.5 h

Procedure:
17.83 g (57.4 mmol) of (Z)-(5R)-9-(tetrahydro-pyran-2-yloxy)-1-trimethylsilanyl-non-2-en-7-yn-5-ol was dissolved in 210 ml of abs. toluene. At -15°, 30.6 ml t-butyl-hydroperoxide (3 M, toluene) was added, followed by 761 mg (5 mol %) of vanadium-oxyacetylacetonate. The temperature was then rised within 16 h to 22°. TLC indicated the disappearance of starting olefin. While cooling in an ice bath, 13.5 ml (115 mmol) of trimethylphosphite was added in order to destroy the excess of hydroperoxide. 90 minutes later, a solution of 39.8 g of dry TBAF in 125 ml of THF was added and the reaction mixture kept for 90 minutes at RT. The homogeneous solution was then poured onto crushed ice, extracted with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=6/4) yielded 10.40 g of (3S,5S)-9-(tetrahydro-pyran-2-yloxy)-non-1-en-7-yne-3,5-diol as slightly yellow oil (1:1 epimeric mixture).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N:32]12[CH2:39][CH2:38][CH:35]([CH2:36][CH2:37]1)[CH:34]([OH:40])[CH2:33]2.[I:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1.[OH-].[Na+]>O1CCOCC1>[I:41][C:42]1[CH:47]=[CH:46][C:45]([O:40][CH:34]2[CH:35]3[CH2:38][CH2:39][N:32]([CH2:37][CH2:36]3)[CH2:33]2)=[CH:44][CH:43]=1
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 10 °C
Reaction time: 15 h

Procedure:
Triphenylphosphine (37.1 g; 141.5 mmol) solved in dioxane (200 ml) was cooled to 10° C. Diethylazodicarboxylate (24.65 g; 141.5 mmol) was added to the mixture while the temperature was kept below 15° C. (±)3-Quinuclidinol (15.0 g; 117.93 mmol) and 4-iodophenol (28.5 g; 129.7 mmol) was added to the mixture The mixture was stirred at room temperature for 15 hours. Aqueous sodium hydroxide (200 ml; 1 M) was added and the dioxane was evaporated. The mixture was extracted with dichlorometane (2×200 ml), the organic phase was dried and evaporated. Diethylether (150 ml) was added and triphenylphosphine oxide was filtered off. The ether phase was washed with water (100 ml). The organic phase was dried and evaporated followed by column chromatography using a mixture of dichloromethane: methanol (9:1) and aqueous ammonia (1%). The title compound was isolated 8.76 g (23%).
Reaction SMILES: [C:1]([O:11]C)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][NH2:14]>CO>[C:4]1([CH2:3][CH2:2][C:1]([NH:13][NH2:14])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)/C=C/c1ccccc1
Solvent: CO
Product: NNC(=O)CCc1ccccc1

Procedure:
Methyl trans-cinnamate (1.0 g) and hydrazine (1.2 mL) were heated in methanol (25 mL) at 60° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=95/5)to obtain a mixture of the entitled compound and an olefin-unreduced compound (2/1) (499 mg).