Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]([Cl:31])[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)(=O)C.[Li+].[OH-]>C1COCC1.CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]([Cl:31])[CH:13]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCOc1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(OC(=O)c2ccc(O)cc2)cc1Cl

Procedure:
In ethanol, chlorohydroquinone was reacted with dodecylbromide in ethanol by using 1 equivalent of potassium hydroxide to obtain 3-chloro-4-dodecyloxyphenol. Then, 3.1 g of this 3-chloro-4-dodecyloxyphenol was reacted with 2.0 g of 2,4-acetoxybenzoic acid chloride in pyridine and the reaction mixture was treated by customary procedures to obtain 4 g of 3-chloro-4-dodecyloxyphenyl 4-acetoxybenzoate. This ester was dissolved in a THF/methanol liquid mixture and 1 equivalent of 1N LiOH was added to selectively isolate the acetoxy group, whereby 3-chloro-4-dodecyloxyphenyl 4-hydroxybenzoate was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:19][CH:20]([CH3:24])[C:21](=[O:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[Br:1][C:2]1[C:3]([S:19][CH:20]([CH3:24])[C:21]([OH:23])([CH3:25])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C(C)Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br
Solvent: C1CCOC1
Product: CC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)(C)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
108 mg (0.25 mmol) of 5-[5-bromo-4-(1-methyl-2-oxo-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide is dissolved in tetrahydrofuran p.a. at 4° C. that is mixed in portions with 1 ml (3 mmol) of methylmagnesium bromide (3 M in ether). After 24 hours of stirring at room temperature, it is quenched by adding ammonium chloride solution. After extraction with ethyl acetate, the dried residue is flashed with dichloromethane/methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2[N:12]([CH:13]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][C:33]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:34]=1[CH2:35][N:36]([C:49]1[S:53][N:52]=[CH:51][N:50]=1)[S:37]([C:40]1[CH:45]=[C:44]([F:46])[C:43](F)=[CH:42][C:41]=1[F:48])(=[O:39])=[O:38].C(OCC)(=O)C>CS(C)=O.ClCCl.C(OC)(C)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:43]2[CH:42]=[C:41]([F:48])[C:40]([S:37]([N:36]([CH2:35][C:34]3[CH:54]=[CH:55][C:56]([O:58][CH3:59])=[CH:57][C:33]=3[O:32][CH3:31])[C:49]3[S:53][N:52]=[CH:51][N:50]=3)(=[O:38])=[O:39])=[CH:45][C:44]=2[F:46])=[C:6]([C:8]2[N:12]([CH:13]3[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]3)[N:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Tert-butyl 3-[5-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (Preparation 851, 80.0 g, 0.2287 mol) and potassium carbonate (94.82 g, 0.686 mol) were combined in dimethylsulphoxide (600 mL). To this slurry was added N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide, (Preparation 647, 101.87 g, 0.2287 mol) and stirred at room temperature for 4.5 hours. Ethyl acetate (1600 mL) and water (1000 mL) were added and the layers separated. The ethyl acetate was washed with water (2×800 mL), then saturated aqueous sodium chloride solution (200 mL) and then dried over anhydrous magnesium sulphate. To this suspension, tert-butylmethyl ether (250 mL) was added and the mixture was washed with dilute aqueous sodium chloride solution (1000 mL), the organics were dried over magnesium sulphate, filtered and the solvents removed in-vacuo to give a pale yellow solid. This solid was dissolved in dichloromethane (500 mL) and tert-butylmethyl ether was added gradually whilst evaporating the dichloromethane in vacuo to give a white precipitate which was filtered off and washed with a little tert-butylmethyl ether to give the title compound as a white solid, (145.47 g).
Reaction SMILES: C(O[C@@H:5]([C-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:6])(=O)C.[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17].[CH3:18][NH:19][CH3:20]>CO>[CH3:18][N:19]([CH3:20])[C@@H:5]([C-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:6].[CH-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Fe+2:17]
Reactant: CNC
Reactant: CC(=O)O[C@H](C)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CO
Product: C[C@H]([c-]1cccc1)N(C)C
Reaction time: 48 h

Procedure:
In a 10 l flask, 812 g of crude (R)-1-acetoxy-ethylferrocene from Example 2 was admixed under argon at 25° C. while stirring with 1.0 l of 50% strength aqueous dimethylamine solution and 1.0 l of methanol, with the temperature rising to 40° C. The reaction mixture was subsequently allowed to stand for 2 days at 25° C. The mixture was then evaporated at 50° C. in a waterpump vacuum to 1.1 kg and the residue was added to 2.0 l of 20% strength sodium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: COCCN
Solvent: CN(C)C=O
Product: COCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 82.1 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3.5 g) in anhydrous dimethylformamide (80 cc), N,N'-carbonyldiimidazole (1.6 g) and 2-methoxyethylamine (0.65 g). After recrystallization in ethanol, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(2-methoxyethyl)acetamide (3 g), m.p. 172° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:19]C)C(OC)=CC=C(CO)C2)=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.[Mg].COC1C=CC(C=O)=CC=1[N+]([O-])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=2)[OH:19])=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: COC1=CC=C(CO)CC1(OC)c1ccc(OC)c([N+](=O)[O-])c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Mg]
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Yield: 60 %

Procedure:
(4-Methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was prepared analogously to 3-(4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using 3,5-dimethoxy-bromobenzene (5.0 g, 23.0 mmol), magnesium turning (0.6 g, 23.0 mmol) and 4-methoxy-3-nitro-benzaldehyde (3.5 g, 19.2 mmol). The crude product was purified by flash chromatography (silica gel, Hexane:EtOAc 1:1) to afford (4-methoxy-3-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.7 g, 60%) as an oil: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.54-7.50 (dd, J=2, 8 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 6.38 (d, J=1 Hz, 1H), 5.72 (d, J=3 Hz, 1H), 3.93 (s, 3H), 3.76 (s, 6H), 2.45 (d, 2 Hz, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[Si:26]([O:33][CH:34]1[CH2:45][C:44](=[O:46])[O:43][C@H:42](/[C:47](/[CH3:51])=[CH:48]/[CH2:49][OH:50])[C@@H:41]([CH3:52])[CH:40]=[CH:39][C@@H:38]2[O:53][C@H:54]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:55][C@:37]2([CH3:62])[CH2:36][CH2:35]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CCOCC>[Si:26]([O:33][CH:34]1[CH2:45][C:44](=[O:46])[O:43][C@H:42](/[C:47](/[CH3:51])=[CH:48]/[CH:49]=[O:50])[C@@H:41]([CH3:52])[CH:40]=[CH:39][C@@H:38]2[O:53][C@H:54]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:55][C@:37]2([CH3:62])[CH2:36][CH2:35]1)([C:29]([CH3:30])([CH3:31])[CH3:32])([CH3:28])[CH3:27]
Reactant: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Agent: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: C/C(=C\CO)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2/C=C/[C@@H]1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: C/C(=C\C=O)[C@H]1OC(=O)CC(O[Si](C)(C)C(C)(C)C)CC[C@@]2(C)O[C@@H](c3ccccc3)O[C@H]2C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dess-Martin reagent (565 mg, 1.33 mmol) was added to a dichloromethane (12.0 ml) solution of (2S,3aS,4E,6S,7S,13aR)-11-{[tert-butyl(dimethyl)silyl]oxy}-7-{(1E)-3-hydroxy-1-methylprop-1-en-1-yl}-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f]oxacyclododecin-9-one (587 mg, 1.11 mmol). The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ether and washed with a saturated sodium hydrogen carbonate aqueous solution containing sodium sulfite, water and brine sequentially and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=10:1→8:1→6:1) to obtain the title compound (587 mg) as a white solid. This was obtained as a colorless crystal by recrystallization (hexane:ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (76 mg, 0.24 mmol) and TBTU (86 mg, 0.27 mmol) in DMF (1.2 mL) was added DIPEA (209 μL, 1.22 mmol). Then 4-aminotetrahydropyran (27 mg, 0.27 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (67 mg, 70%) as a white solid after recrystallisation from methanol/water. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)(=[O:25])=[O:24])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 2-thiophenesulphonylchloride (29 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant residue was purified by semi-preparative HPLC to yield the title compound as a white solid (10 mg, 0.03 mmol, 16%). LCMS: [M+H]+=373, Rt=1.63 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:36][O:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1>CO.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([C:13]1[CH:14]=[C:2]([C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([O:37][CH3:36])[CH:43]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Br)cc12
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3cccc(OC)c3)cc12
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a suspension of ethyl 6-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (3.5 g, 6.85 mmol, Example 58C), tetrakis(triphenylphosphine)palladium (0)(0.317 g, 0.274 mmol), toluene (30 mL), and 2 M aqueous sodium carbonate (6.85 mL, 13.70 mmol) under nitrogen were added a solution of 3-methoxyphenylboronic acid (1.457 g, 9.59 mmol) in MeOH (4 mL). The resulting reaction mixture was heated at reflux for 5 h. After cooling to room temperature, it was diluted with a mixture of water (250 mL) and ethyl acetate (250 mL) and the two phases were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), and the combined organic phases were washed with water (2×200 mL), 5% aqueous NH4OH solution (120 mL), and brine (100 mL). The organic phase was dried over Na2SO4 and the solvent removed. The crude material was suspended in a mixture of DCM and ethyl acetate. The solid was collected by filtration, washed with DCM, and air dried to afford 1.31 g product 82A. The filtrate was mixtured with silica gel and the solvent removed. This was loaded onto a silica gel column and eluted with hexane containing 10 to 50% ethyl acetate to afford additional 1.01 g of product for a total of 2.32 g of crude. MS (ESI) m/z 389.2 (M+H). 1H NMR (DMSO-d6) δ ppm 11.73 (1H, s), 8.78 (1H, s), 8.30-8.51 (4H, m), 7.83 (1H, d, J=8.24 Hz), 7.55-7.67 (1H, m), 7.37-7.54 (3H, m), 6.96 (1H, d, J=8.24 Hz), 4.38 (2H, q, J=6.92 Hz), 3.90 (3H, s), 1.39 (3H, t, J=7.02 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:33]2[C:28](=[CH:29][C:30]([F:53])=[C:31](OS(C3C(C(C)C)=CC(C(C)C)=CC=3C(C)C)(=O)=O)[N:32]=2)[C:27](=[O:54])[C:26]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:25]1.O>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:31]2[N:32]=[C:33]3[C:28]([C:27](=[O:54])[C:26]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:25][N:24]3[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[F:16])=[CH:29][C:30]=2[F:53])[CH2:5]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OS(=O)(=O)c3c(C(C)C)cc(C(C)C)cc3C(C)C)c(F)cc2c1=O
Reactant: NC1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 96.3 %

Procedure:
In 5 ml of ethanol was suspended 150 mg of 3-aminopyrrolidine dihydrochloride, and 310 mg of triethylamine was added thereto to form a solution. Subsequently, 500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-triisopropylbenzenesulfonyloxy)-1,8-naphthyridine-3-carboxylate was added thereto, and the resulting mixture was subjected to reaction at room temperature for 2 hours. Subsequently, 6 ml of water was added to the reaction mixture, and the crystals thus deposited were collected by filtration, and washed with 5 ml of water to obtain 330 mg (yield 96.3%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 200°-202° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].I[CH3:27].[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH3:27])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.44 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere and the solution was cooled on ice. 0.27 ml of iodomethane and 63 mg of sodium hydride (60% oil dispersion) were added, the mixture was stirred at the same temperature for 1 hour and the temperature was raised to room temperature to stir for additional 2 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off and the tan residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to give 2-[4-(N-acetyl-N-methylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([B:28]([OH:33])[OH:29])[C:24]([F:27])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(OCc2ccccc2)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OB(O)c1cc(OCc2ccccc2)cnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of diisopropylamine (Aldrich) (0.33 mL, 2.16 mmol) in THF (5 mL) was cooled to 0° C. and treated with n-butyllithium (Aldrich) (0.94 mL, 2.36 mmol). The resulting mixture was stirred at 0° C. for 30 min and then cooled to −78° C. 5-(Benzyloxy)-2-fluoropyridine (Aldrich) (0.200 g, 0.982 mmol) in THF (3 mL) was added dropwise and the solution was stirred at −78° C. for 40 min before being treated with triisopropyl borate (Aldrich) (0.50 mL, 2.16 mmol) in THF (2 mL). After the addition, the cooling bath was removed and the reaction mixture slowly warmed up to rt and and was stirred for 1 h. The reaction mixture was quenched with 5% NaOH (10 mL). The aqueous layer was separated and acidified to pH 5 using 5 N HCl. The resulting mixture was extracted with EtOAc (2×15 mL). The combined organic extracts were dried over MgSO4 and concentrated to give the crude product as yellow solid (0.210 g). m/z (ESI, +ve ion) 248.0 (M+H)+. 1H NMR (300 MHz, d4-MeOH) δ 6.60 (br. s., 1H); 6.36 (br. s., 1H); 6.00-6.24 (m, 5H); 3.87 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[C:20]([Cl:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1cc(Cl)cc(Cl)c1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1cc(Cl)cc(Cl)c1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Step BF (3): To a solution of (S)-methyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)propanoate (20.60 g, 53.94 mmol) in THF was added 2M LiOH (250 mL). After the reaction was stirred at rt for 18 h, the THF was removed in vacuo. The pH was adjusted to below two by 6M HCl. The mixture was extracted three times into EtOAc, and the combined organic layers were dried with MgSO4. Concentration in vacuo afforded pure (S)-2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)propanoic acid. This material was taken up in methylene chloride (250 mL), and p-nitrophenol (7.50 g, 53.94 mmol) was added. EDC was added portionwise (12.43 g, 64.73 mmol), followed by Hunig's base (11.3 mL, 64.73 mmol). The reaction was allowed to stir at rt for 80 h. The reaction was extracted 3 times with 1M HCl, then with brine. The reaction was next extracted with 0.5M NaOH (yellow color formed), and again with brine. The organic layer was dried with MgSO4, and concentrated to a yellow gum. Silica gel chromatography (EtOAc/hexane gradient) afforded (S)-4-nitrophenyl 2-(benzyloxycarbonylamino)-3-(3,5-dichlorophenyl)propanoate (26.37 g, 58% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([CH:7]=[N:8]O)[C:5]([OH:11])=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[C:7]([C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11])#[N:8]
Reactant: ON=Cc1cc(F)ccc1O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1cc(F)ccc1O
Temperature: 80 °C
Yield: 87.5 %

Procedure:
5-Fluorosalicylaldehyde oxime (20.2 g, 0.13 mol) was dissolved in acetic anhydride (100 ml) and refluxed for 5 hours. After completion of the reaction, acetic anhydride was distilled off under reduced pressure, followed by adding to the remaining oily substance, a solution of KOH (20 g) dissolved in water (100 ml) and ethanol (100 ml), warming the mixture at 80° C. for 2 hours, allowing it to cool down to room temperature, adding 6N hydrochloric acid (50 ml) and water (200 ml) to deposit crystals, which were then filtered off and recrystallized from methanol (30 ml) to obtain needle crystals (15.6 g) having a melting point of 121°-122° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH:6]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:4].[ClH:30]>C(O)C.C(OCC)(=O)C>[ClH:30].[ClH:30].[OH:1][CH2:2][CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(CO)N1CCNCC1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CO)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
1-(1-Hydroxy-2-propyl)-2-triphenylmethylpiperazine (1.69 g) obtained in step 2 was dissolved in ethanol (20 ml), and a 4 mol/l hydrogen chloride solution in ethyl acetate (10 ml) was dropwise added thereto. The mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure, the residue was suspended in ethyl ether, and the precipitated crystals were collected by filtration to give Compound L (840 mg, 89%).
Reaction SMILES: O1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][C:2]1=[O:3].[C:12](O)(=O)C>>[C:6]1([CH2:5][CH2:4][C:2](=[O:3])[CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=1
Reactant: O=C1CCC2CCCCC2O1
Reactant: CC(=O)O
Product: CC(=O)CCC1=CCCCC1
Yield: 47.1 %

Procedure:
Using the same procedure as described under A) but starting with a solution consisting of octahydrocoumarine (22 g, 145 mmoles) into 58 g of acetic acid and a supported catalyst obtained according to procedure a), there were obtained (after bulb to bulb distillation at 42 mbar, oven=175°) 10.4 g of 4-(1-cyclohexen-1-yl)-2-butanone (purity: 71%; yield: 33%).