Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCC>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.O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](=[O:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CC[C@H](C(=O)c2ccccc2)CC1)OCc1ccccc1

Procedure:
Under argon atmosphere, a mixture comprising 1.0 g trans-4-(benzyloxycarbonylamino)cyclohexanecarbonyl chloride, 1.92 g of tributylphenyltin, 61 mg of dichlorobis(triphenylphosphine)palladium and 10 mL of dioxane was stirred at 110° C. for 12 hours. After cooling, the reaction mixture was concentrated by a centrifugal concentrator, and then, the residue was dissolved in tetrahydrofuran and evaporated to dryness with 5 g of silica gel. The resulting residue was purified by silica gel flash chromatography (solvent: ethyl acetate-hexane (1:2) to (1:1) to obtain 883 mg of N-benzyloxycarbonyl-trans-4-benzoylcylohexylamine.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29].C(N(CC)CC)C.O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([NH:32][NH:31][CH:28]([CH3:30])[CH3:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)NN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(C(=O)NNC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
A mixture of 0.60 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.29 g of isopropylhydrazine hydrochloride, 0.27 g of triethylamine and 6 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(N′-isopropylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]([C:11]1[NH:12][C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][C:29]3[CH:34]=[C:33]([CH:35]([F:37])[F:36])[CH:32]=[C:31]([C:38]#[N:39])[CH:30]=3)[C:22]=2[F:40])=[O:18])=[C:14]([Cl:16])[N:15]=1)=[N+]=[N-].O.CP(C)C>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:11]1[NH:12][C:13]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][C:29]3[CH:34]=[C:33]([CH:35]([F:36])[F:37])[CH:32]=[C:31]([C:38]#[N:39])[CH:30]=3)[C:22]=2[F:40])=[O:18])=[C:14]([Cl:16])[N:15]=1
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)cc(C(F)F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To a solution of 2-azido-4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide trifluoroacetate (39.0 mg, 0.079 mmol) in THF (6 ml) was added water (2.83 μl, 0.157 mmol) followed by trimethyl phosphine (2.0 M solution in THF) (0.039 ml, 0.079 mmol) and the reaction mixture was stirred at RT for 15 minutes. The solvent was removed and the crude material was purified via reverse phase HPLC to give 2-amino-4-chloro-N-[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide trifluoroacetate (28 mg, 0.048 mmol, 61.0% yield). 1H NMR (DMSO-d6) δ ppm 7.76-7.88 (m, 2H) 7.68 (s, 1H) 7.39-7.54 (m, 2H) 7.31 (t, 1H) 6.84-7.20 (m, 1H) 5.97 (br.s., 2H) 4.45 (d, 2H). LC-MS (ES+) m/z 470.05 [M+H].
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]>C1COCC1.CCOCC>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8](=[O:17])[CH:1]=[CH2:2]
Reactant: CON(C)C(=O)Cc1ccccc1C
Reactant: C=C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=O)Cc1ccccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of vinylmagnesium bromide (220 mL, 1.0 M, 220 mmol) in 100 mL THF, was added dropwise under nitrogen atmosphere at 0° C. a solution of 2-(2-methylphenyl)-N-methoxy-N-methylacetamide (Step A, 21 g, 106.6 mmol) in ˜150 mL dry ether. The reaction mixture was stirred at 0° C. for 0.5 hr then poured slowly into an ice/2N aq HCl (300 mL) mixture. The resulting mixture was diluted with ether, transferred to a separation funnel. The organic layer was separated, washed with brine, dried over MgSO4, filtered and the solvent evaporated under vacuum to give 14.2 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.15-7.25 (4H, m), 6.47 (1H, dd, J1=14.2 Hz, J2=11 Hz), 6.35 (1H, d, J=14.2 Hz), 5.86 (1H, d, J=11 Hz), 3.83 (2H, s), 2.28 (3H, s).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[F:11][C:12]1([F:16])[CH2:15][NH:14][CH2:13]1.Br[CH2:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[C:21]#[N:22]>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:19]([CH2:18][N:14]2[CH2:15][C:12]([F:16])([F:11])[CH2:13]2)=[C:20]([CH:23]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(Cl)ccc1CBr
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(Cl)ccc1CN1CC(F)(F)C1
Yield: 55.9 %

Procedure:
DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and 2-bromomethyl-5-chlorobenzonitrile (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=3)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)c1cccnc1
Temperature: 67 °C

Procedure:
A mixture of rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.081 g, 0.33 mmol) (from Example 39b supra), 3-chlorobenzyl bromide (0.080 g, 0.39 mmol) (Aldrich), potassium iodide (0.065 g, 0.39 mmol) and potassium carbonate (0.098 g, 0.72 mmol) in acetone (3 mL) was heated at 67° C. for 2 hours in a capped pressure tube. After cooling, the mixture was diluted with ethyl acetate and extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography to give rac-6-chloro-3-(3-chloro-benzyl)-3-pyridin-3-yl-1,3-dihydro-indol-2-one as an off-white solid. (Yield, 0.05 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:21]=[N+]=[N-])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2>CO>[Cl:1][C:2]1[C:3]([NH2:21])=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2N=[N+]=[N-])OC1C(F)(F)F
Solvent: CO
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2N)OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.8 %

Procedure:
To the suspension of stannous chloride hydrate (5.5 g, 24.1 mmol) in 150 mL of methanol was added at room temperature ethyl 6-chloro-5-azido-2-(trifluoromethyl)-2H-chromene-3-carboxylate (5.6 g, 16.1 mmol) in one portion. The reaction mixture gradually turned yellowish. After stirred at room temperature for about 45 min, the reaction turned a clear yellow solution. The volatiles were then removed. The residue was dissolved in EtOAc, and the resulting organic solution was washed with 5% sodium hydroxide solution (×4), brine, and dried over anhydrous magnesium sulfate. After removing the solvents, the residue was purified on silica gel column with 3:7 EtOAc/hexane, it gave 3.2 g of yellow solid. A small fraction of the product was further purified on reverse phase HPLC, it provided a yellow solid. LC-MS(ES+) 322.2(M+1, 100). 1H NMR (CDCl3/400 MHz) 7.80(s, 1H), 7.16(d, J=8.8 Hz, 1H), 6.35(d, J=8.8 Hz, 1H), 5.65(q, J=7.2 Hz, 1H), 4.31(m, 2H), 1.34(t, J=7.2 Hz, 3H). 19F NMR(CDCl3/400 MHz) −78.55(d, J=7.4 Hz). 13C NMR(CDCl3/300 Mhz) 164.1, 152.8, 141.3, 133.1, 131.7, 123.7(q, J=287.7 Hz), 115.2, 113.4, 107.2, 106.6, 70.3(q, J=33.2 Hz), 61.7, 14.5. MS(ES+) 322.1(M+1, 75%), HRMS(EI+) m/z calc for (C13H11ClF3NO3): 321.0380 (M+), found, 321.0359(M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.[H-].[Na+].Cl[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=2)[N:27]=1>O1CCCC1>[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=3)[N:27]=2)[CH2:5][CH2:6]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCOC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 30.5 %

Procedure:
The procedure is as in Example 22, but starting with 1-(2-hydroxyethyl)-4-acetylpiperazine (7.75 g) in anhydrous tetrahydrofuran (250 cc), an oily suspension (50% by weight; 2.3 g) of sodium hydride and 3-chloro-2(-7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). After crystallization successively in 2-propanol and then in ethanol, 3-[2-(4-acetyl-1-piperazinyl)ethoxy]-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4.3 g), m.p. 172° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([Si:33]([CH3:34])([CH3:36])[CH3:35])=[CH:31][CH:32]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Product: C[Si](C)(C)c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(3,4-dichloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 547.2/549.3/551.3 (96/100/37) (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:7]2)([O-])=O>CO.[Ni]>[C:13]1([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in MeOH (30 mL) was added Raney Ni (510 mg) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was filtered through a Celite pad and the filtrate was evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5/1) to give 2-phenyl-1H-indol-5-amine (1.6 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.64 (d, J=1.6 Hz, 1H), 6.60 (d, J=1.2 Hz, 1H), 6.48 (dd, J=2.0, 8.4 Hz, 1H), 4.48 (brs, 2H); MS (ESI) m/e (M+H+) 209.0.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C[O-].[Na+].[NH2:26][NH:27][C:28](=O)[CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>C(O)C.CO>[CH2:31]([N:30]([CH2:33][CH3:34])[CH2:29][C:28]1[NH:27][N:26]=[C:5]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)[CH3:32]
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CCN(CC)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCN(CC)Cc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Temperature: 0 °C
Yield: 11 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.400 g, 1.25 mmol) in 4 mL of anhydrous ethanol was prepared and cooled to 0° C. An excess of a commercial solution of sodium methoxide in methanol (0.858 mL, 4.37 M)) was added followed by 3 equivalents of N-amino-2-(diethylamino)acetamide (0.545 g, 3.75 mmol) as a solid. The reaction mixture was heated to reflux temperature in a sealed tube for 2 days. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The residue was purified by preparative HPLC (0.052 g, 11% yield): 1H NMR (CD3OD) δ 8.70 (s, 1H), 8.11–8.02 (m, 3H), 7.67 (d, 1H), 7.29 (td, 2H), 3.8 (s, 1H), 2.68 (q, 4H), 1.15 (t, 3H); ES-MS (m/z) 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.Cl.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30]([Cl:32])=[O:31])[CH2:23]2>CN(C=O)C>[ClH:32].[N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:30]([CH:24]3[CH:25]4[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]4)[CH2:23]3)=[O:31])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)C1CN2CCC1CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2ncccc2c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
172 mg (1.19 mmol) of 6-aminoquinoline are mixed with 461 mg (3.57 mmol) of N,N-diisopropylethylamine in 3 ml of DMF under argon at 0° C. 250 mg (2.57 mmol) of 3-quinuclidinecarbonyl chloride hydrochloride are dissolved in a little dry DMF and added dropwise to the reaction mixture at 0° C. It is then stirred at room temperature overnight. It is worked up by concentrating and taking up in dichloromethane. The crude product is chromatographed on silica gel 60 (mobile phase: dichloromethane/ethyl acetate 10:1, then dichloromethane/methanol 10:1, 3:1). The product fractions are combined and finally purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water, gradient 1:99→30:70).
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@@H:27]([CH3:29])[C@H:25]([OH:26])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:1]([N:19]([CH:20]1[O:28][C@@H:27]([CH3:29])[C@H:25]([OH:26])[C@@H:23]([OH:24])[C@H:21]1[OH:22])[C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
7 g of the compound from Example 21 were acylated with oleoyl chloride as described in Example 6. Column separation in CH2Cl2 /CH3OH=13/1.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:25])[C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[CH3:25][C:19]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:16]([NH:15][C:12](=[O:14])[CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[S:17][CH:18]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: COC(=O)c1c(C)csc1N
Product: COC(=O)c1c(C)csc1NC(=O)Cc1cccc2ccccc12

Procedure:
The title compound was prepared from 2-(naphthalen-1-yl)acetic acid (10 g, 54 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (9.2 g, 54 mmol) according to protocol A (15.4 g, 85%) as a white solid. 1H NMR (CDCl3) δ11.0 (s, 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (m, 4H), 6.36 (s, 1H), 4.29 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3) δ168.3, 165.6, 149.3, 135.0, 134.0, 132.1, 129.8, 128.9, 128.6, 127.0, 126.2, 125.7, 123.7, 112.9, 112.2, 51.1, 41.9, 17.7; MH+ 340.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 0.33 h

Procedure:
Triethylamine (149 μL, 1.07 mmol, 10.00 equiv) and pivaloyl chloride (26 μL, 0.214 mmol, 2.00 equiv) were added sequentially to a solution of 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, 0.107 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated and the residue purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)-2-phenyl-2,5-dihydro-1H-pyrrole (10-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, 1H, J=8.8, 5.2 Hz), 7.33 (m, 4H), 7.26 (m, 1H), 7.05 (dd, 1H, J=9.2, 3.1 Hz), 6.99 (m, 1H), 6.20 (m, 1H), 5.98 (m, 1H), 5.00 (m, 2H), 1.28 (s, 9H). LRMS m/z (M+H) 358.0 found, 358.1 required.
Reaction SMILES: [O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28](S(C)(=O)=O)[N:27]=1.O>CN(C)C=O.C(O)(=O)C>[O:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH:9]([O:14][C:28]1[N:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:26]([O:25][CH3:24])[N:27]=1)[C:10]([O:12][CH3:13])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
4.4 g (15.4 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (compound 1.1) are dissolved in 40 ml of dimethylformamide, and 0.46 g (18.4 mmol) of sodium hydride are added. Stirring is carried out for 1 hour, after which 3.4 g (15.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added. After stirring has been carried out for 24 hours at room temperature, hydrolysis is effected carefully with 10 ml of water, the pH is brought to 5 with acetic acid and the solvent is distilled off under greatly reduced pressure. The residue is taken up in 100 ml of ethyl acetate, washed with water and dried over sodium sulfate and the solvent is distilled off. 10 ml of methyl tert-butyl ether are added to the residue and the precipitate formed is filtered off with suction. After drying, 1.6 g of a white powder remains.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15].[OH2:16]>>[C:1]([O:7][CH2:8][C:9]([F:14])([F:13])[S:10]([O-:16])(=[O:12])=[O:11])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Na+:15]
Reactant: CCCCC(=O)OCC(F)(F)S(=O)[O-]
Reactant: O
Agent: [Na+]
Product: CCCCC(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A 100 mL reactor was charged with 6.6 g (28% purity, 7.3 millimoles) of sodium 2-valeryloxy-1,1-difluoroethanesulfinate, 60 mL of water, 0.0047 g (0.014 millimole/0.0019 equivalent) of disodium tungstate dihydrate and 1.9 g (16.4 millimoles/2.25 equivalents) of 30% oxygenate, followed by stirring at room temperature for 1.5 hours. A reaction solution was heated under a reduced pressure to evaporate a volatile component to dryness, thereby obtaining 6.6 g of the target sodium 2-valeryloxy-1,1-difluoroethane sulfonate. In this case, purity was 26% and yield was 88%.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1.[CH2:36]([C:42]1[S:43][C:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52](O)[CH:53]=3)[CH:48]=2)=[N:45][N:46]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[CH2:36]([C:42]1[S:43][C:44]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:8][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:53]=3)[CH:48]=2)=[N:45][N:46]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Reactant: CCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCC(=O)Oc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 51.5 %

Procedure:
In a 30 ml-round-bottomed flask, 0.60 g (1.92 mM) of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole, 0.25 g (1.92 mM) of heptanoic acid were dissolved in 10 ml of dichloromethane. Under stirring, 0.39 g (1.89 mM) of N,N'-dicyclohexylcarbodiimide and 0.02 g of 4-pyrrolidinopyridine were successively added the above solution at room temperature, followed by stirring for 8 hours at room temperature. After the reaction, precipitated N,N'-dicyclohexylurea was filtered off and the filtrate was dried off under reduced pressure to obtain a solid. The solid was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=3/1) and recrystallized from a mixture solvent (ethanol-ethyl acetate) to obtain 0.42 g of 2-hexyl-5-(6-heptanoyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 81.5 %). ##STR139##