Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(Oc4ccccc4)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-phenoxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (53 mg, yield 96%).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([O-:25])=[O:24])=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].[Na+]>CN(C)C=O>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH3:26])[C:23]([O:25][CH:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[O:3]2)=[O:24])=[CH:20][CH:21]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(C)C(=O)OC2OC(=O)c3ccccc32)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
To a solution of 10.65 g of 3-bromophthalide in 100 ml of dimethylformamide, 11.5 g of sodium 2-(4-isobutylphenyl)propionate is added under stirring at room temperature. The reaction mixture is stirred 24 hours at room temperature, and it is then poured into 500 ml of ice water. After extraction with chloroform, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, yields 12.3 g of phthalidyl 2-(4-isobutylphenyl)propionate, having the same physico-chemical characteristics of the compounds of Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 19.7 %

Procedure:
At 0° C., a solution of N-methyl-2-(2-nitrophenyl)acetamide (7.00 g, 36.05 mmol) in tetrahydrofuran (410 ml) was added dropwise to a suspension of sodium borohydride (1.63 g, 43.25 mmol) in tetrahydrofuran (110 ml). A solution of iodine (4.57 g, 18.02 mmol) in tetrahydrofuran (150 ml) was added dropwise. The reaction mixture was warmed to reflux for 16 h. It was cooled to 0° C. Methanol (310 ml) was added dropwise. The solvent was removed in vacuo The residue was dissolved in 20% aqueous sodium hydoxide solution (300 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (160 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.28 g of N-methyl-N-(2-(2-nitrophenyl)ethyl)amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH3:18].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][O:11][CH2:16][CH2:17][CH3:18])=[CH:7][C:6]=2[CH:12]=1
Reactant: OCc1cc2cc(Br)ccc2o1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCOCc1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (57 ml) was dissolved 5-bromo-2-(hydroxymethyl)-1-benzofuran (5.7 g), and to the solution was added at 0° C. 60% sodium hydride (1.4 g). The mixture was stirred at room temperature for 1 hour, and to the mixture was added at 0° C. 1-bromopropane (3.1 ml). The mixture was stirred at 65° C. for 16 hours and cooled to room temperature. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-(propoxymethyl)-1-benzofuran (5.0 g).
Reaction SMILES: [C:1]([O:11]CC)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>C(O)C.O1CCOCC1>[C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-ethyl 2-nonenoate in ethanol and 1,4-dioxane was added a 1N aqueous solution of sodium hydroxide. After being stirred at room temperature for 3 hours, the reaction mixture was concentrated and acidified with diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give the object compound.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([O:5][CH:6]2[CH2:9][N:8]([C:10]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=3[C:12]([OH:14])=[O:13])[CH2:7]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(Cl)cc1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(Cl)cc2)C1
Yield: 130 %

Procedure:
The title compound (D123) (125 mg) was prepared according to the experimental procedure described in Description 103A vero starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 4-Chlorophenol (0.033 ml, 0.338 mmol).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][O:19][C:20]1[C:29]([O:30][CH3:31])=[N:28][C:27]2[C:26]([C:32](Cl)=[O:33])=[C:25]([CH3:35])[C:24]([N+:36]([O-:38])=[O:37])=[CH:23][C:22]=2[N:21]=1>O1CCCC1>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:26]1[C:27]2[N:28]=[C:29]([O:30][CH3:31])[C:20]([O:19][CH3:18])=[N:21][C:22]=2[CH:23]=[C:24]([N+:36]([O-:38])=[O:37])[C:25]=1[CH3:35])=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCC(=O)OC(C)(C)C)c2nc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of glycine tert-butyl ester hydrochloride 104 mg (0.67 mmol) and triethylamine in 3 mL anhydrous tetrahydrofuran 0.26 mL (1.69 mmol) under an atmosphere of nitrogen was added dropwise a solution of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) in 7 mL anhydrous tetrahydrofuran at 0° C. After the addition was complete (approximately 5 minutes), the reaction mixture was stirred at room temperature for 24 hours, filtered, and concentrated. The residue was taken up in ethyl acetate and the organic solution was washed with water, saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The crude product was purified by elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes/ethyl acetate) to give a yellow oil which crystallized on standing, 200 mg (77%), mp 125-126° C.; 1H NMR (CDCl3): δ 8.32 (s, 1H, 8-H), 6.32 (br s, 1H, amide NH), 4.14 (d, 2H, J=5.1 Hz), 4.09 (s, 3H), 3.99 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H, tert-butyl protons); MS (APCI): m/z 407 (M+H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[Li+].[Cl-].C1CCN2C(=NCCC2)CC1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])[CH:33]=O)=[CH:28][CH:27]=1>CC#N>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:37]2[C:45]3[C:40](=[C:41]([N:46]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:56])[CH3:57])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:42]=[CH:43][CH:44]=3)[CH:39]=[N:38]2)([CH2:35][CH3:36])/[CH:33]=[CH:3]/[C:1]#[N:2])=[CH:28][CH:27]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCC(C=O)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl cyanomethylphosphonate (20 mg, 0.12 mmol), LiCl (5 mg, 0.12 mmol) and DBU (18 mg, 0.12 mmol) in MeCN (2 mL) was added a solution of N-(1-(2-(4-chlorophenyl)-1-oxobutan-2-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) methane sulfonamide (50 mg, 0.10 mmol) in MeCN (1 mL). The mixture was stirred at room temperature for 2 h and evaporated. The residue was purified by silica gel chromatography (PE/EA=6/1) to afford the title compound as a white solid. LC/MS m/z=545.2 [M+H]+.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[NH2:8][C:9]1[C:10](=O)[NH:11][C:12]([CH3:15])=[CH:13][N:14]=1.[OH-].[Na+]>>[NH2:8][C:9]1[C:7](=[O:6])[N:11]([CH3:10])[C:12]([CH3:15])=[CH:13][N:14]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cnc(N)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(N)c(=O)n1C
Reaction time: 15 h
Yield: 18.8 %

Procedure:
8.87 g of dimethyl sulfate are added dropwise to a mixture of 8.13 g of 3-amino-6-methylpyrazin-2-one and 72 ml of 1N sodium hydroxide solution at room temperature. After the mixture has been stirred at 20°-25° C. for 15 hours, the precipitate is filtered off, the filtrate is concentrated to one quarter of the volume and the concentrate is extracted with ethyl acetate. 1.7 g of 3-amino-1,6-dimethylpyrazin-2-one with a melting point of 217°-219° C. are obtained by washing with saturated sodium chloride solution, drying with sodium sulfate and concentrating the organic phase.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][SH:4].[H-].[Na+].CS(O[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C.O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:4][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1
Reactant: FC(F)(F)CS
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CSCC(F)(F)F)CC1
Reaction time: 0.25 h

Procedure:
2,2,2-Trifluoroethane-1-thiol (471 μL, 3.41 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 0.065 g, 1.636 mmol) in dry DMF (10 mL) at 0 C and the mixture was stirred for 15 min. A solution of tert-butyl 4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 181, 1 g, 3.41 mmol) in DMF (5 mL) was added dropwise and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated aq. sodium bicarbonate (25 mL) then brine (25 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a light yellow oil (1.13 g, quant.). Method B HPLC-MS: MH+ requires m/z=314 Found: m/z=258 (MH+-tBu), Rt=2.39 min (98%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[NH2:13][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>CO.C(O)(=O)C>[C:14]1([N:13]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:13][C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH3:11])[N:5]=2)[CH3:2])[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=Nc1cccc2c1CCCC2)c1cccc(C(C)=Nc2cccc3c2CCCC3)n1
Reaction time: 48 h
Yield: 29.6 %

Procedure:
Chemicals 2,6-Diacetylpyridine (1.0 g, 6.1 mmol) and 1-amino-5,6,7,8-tetrahydronaphthalene (3.6 g, 24.5 mmol) were dissolved in a round-bottom flask, to which 50 ml of anhydrous methanol were added. Three drops of glacial acetic acid were added, and the flask was sealed. After stirring the solution for two days, a yellow solid was collected and re-crystallized from methanol to give 760 mg (30%) of the desired ligand for catalyst 3. H NMR (C6D6) δ 8.48 (d, 2), 7.30 (t, 1), 7.10 (m, 2), 6.85 (d, 2), 6.56 (d, 2).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCCC1CCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of phenylmethyl 2-(2-hydroxyethyl)-1-piperidinecarboxylate (1.76 g, 6.70 mmol) in anhydrous dichloromethane (29 mL) was added carbon tetrabromide (4.44 g, 13.39 mmol). The resulting solution was cooled in ice/water. A solution of triphenylphosphine (1.76 g, 6.70 mmol) in 10 ml dry DCM was added dropwise over 30 mins. After complete addition the reaction was allowed to warm slowly to ambient temperature and stirring continued overnight. The reaction solution was reduced in volume to <10 ml (opaque) and this was loaded onto a 100 g silica cartridge and purified by chromatography on a Flashmaster 2 using a gradient of 0-25% ethyl acetate in cyclohexane over 40 minutes. Product fractions were combined and evaporated in vacuo to give the title compound as a colourless oil (1.62 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][C:9](=[CH2:22])[S:8]1)=[O:5])[CH3:2].C[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])[CH3:2]
Reactant: C=C1CN(c2cccc(C(F)(F)F)c2)C(=NC(=O)OCC)S1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (2.0 g) and sodium methoxide (28 % methanolic solution; 1.2 g) in ethanol (50 ml) was refluxed for 30 minutes. After removal of the solvent under reduced pressure, the concentrated residue was extracted with chlorofom (200 ml), washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 1.6 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl) 5-methylthiazoline (Compound No. 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:18][O:28]1)=[O:19])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCCC1CCCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCCC2CCCCCC2)CO1

Procedure:
7.5 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate; thin layer chromatography on silica gel with petroleum ether/ethyl acetate 8:2: Rf =0.55), are obtained by the procedure described in Example (1a) from 13.1 g of 7-cycloheptyl-2-methyleneheptanoic acid ethyl ester and 12.0 g of m-chloroperbenzoic acid in 200 ml of methylene chloride.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 105 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 79 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1COCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCO
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCOc1ccccn1
Yield: 42.8 %

Procedure:
3-Aminopropan-1-ol (0.28 ml, 3.64 mmol) was added to a mixture of NaH 60% dispersion in mineral oil (16 mg, 4.11 mmol) in dry THF (8 ml) at rt. The resulting mixture was heated at reflux for 35 mins and cooled to rt before 2-bromopyridine (0.50 g, 3.16 mmol) was added. The mixture was then refluxed for 2 h 20 mins and stirred at rt for another 17 h before more NaH (127 mg, 3.16 mmol) was added and the mixture heated at reflux for 3 h. The mixture was evaporated to dryness, water was added, and the mixture was acidified to pH5 with 1N HCl and washed with DCM. The aqueous phase was then basified to pH4 and extracted again with DCM. The organic extracts were combined and evaporated to give the title compound (0.206 g, 43%) as an oil. 1H NMR (500 MHz CDCl3): 8.17-8.12 (m, 1H), 7.58-7.53 (m, 1H), 6.67-6.63 (m, 1H), 6.72 (d, 1H), 4.39 (t, 2H), 2.88 (t, 2H), 1.93 (quintet, 2H). 13C NMR (125 MHz CDCl3): 164.1, 147.1, 138.7, 116.8, 111.3, 63.8, 39.5, 33.3.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]>>[C:10]([C:15](=[CH:21][NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(CO)cc1
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC

Procedure:
4-Aminobenzylalcohol (25 g) and ethyl 2-butyryl-3-ethoxyacrylate (61 g) were heated together on a rotary evaporator (bath temp 100°) for 30 minutes. Ethyl 2-butyryl-3-(4-(hydroxymethyl)phenylamino)acrylate (49.5 g, 84%) crystallized on standing, was filtered off, washed with a little petroleum ether and vacuum dried, m.p. 44°-6°
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:37])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH2:22][S:23]([N:26]2[CH2:35][CH2:34][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:16]([CH3:36])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7].Br[CH2:39][CH2:40][Cl:41].[Cl-].[NH4+]>C1COCC1>[C:6]([O:10][C:11](=[O:37])[N:12]([C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([S:23]([N:26]2[CH2:27][CH2:28][C:29]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:34][CH2:35]2)(=[O:24])=[O:25])[CH2:39][CH2:40][Cl:41])=[C:16]([CH3:36])[CH:15]=1)[CH3:13])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)OCCO2
Reactant: ClCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1CC(CCCl)S(=O)(=O)N1CCC2(CC1)OCCO2
Reaction time: 0.33 h
Yield: 60 %

Procedure:
n-Butyllithium (1.6 M solution in hexane, 0.58 ml, 0.93 mmol) was added to a solution of {4-[2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-ethyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (195.7 mg, 0.4176 mmol) in THF (4.2 ml) at −78° C. over six minutes, and the mixture was stirred at the same temperature for 20 minutes. 1-Bromo-2-chloro-ethane (105 μl, 1.26 mmol) was added to the reaction solution at −78° C. within 10 minutes. The mixture was then stirred while warming from −78° C. to 0° C. over one hour, and further stirred at room temperature for one hour. A 50% saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/2) to give {4-[4-chloro-2-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-butyl]-3,5-dimethyl-phenyl}-methyl-carbamic acid tert-butyl ester (133 mg, 60%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:33])[CH:25]=2)=[O:23])[CH2:11]1)=[O:7])(C)(C)C.[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38](C(O)=O)=[C:37]([O:45][CH3:46])[CH:36]=1>>[NH2:34][C:35]1[C:43]([Cl:44])=[CH:42][C:38]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH3:33])[CH:25]=3)=[O:23])[CH2:11]2)=[O:7])=[C:37]([O:45][CH3:46])[CH:36]=1
Reactant: Cn1cc(C(=O)NCCCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(6-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-hexyl)-1-methyl-1 H-indole-3-carboxamide (0.62 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.28 g) to give N-(6-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)hexyl)-1-methyl-1 H-indole-3-carboxamide.