Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)c1C

Procedure:
42 mg (50%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (50 mg, 0.170 mmol), 1-(2,3-dimethylphenyl)piperazine (32 mg, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:18])=[O:17]
Reactant: OCC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCOC1
Temperature: 25 °C

Procedure:
To tetrahydro-3-furanmethanol (25 g) in dry DCM (250 mL) at 0° C. under nitrogen was added triethylamine (68 mL) in a single portion. Methanesulphonyl chloride (24.7 mL) was added dropwise over 15 mins. The reaction was warmed to room temperature and was left over a weekend. The mixture was taken up in DCM (50 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organics were dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a brown oil in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:16])[C:11]([C:14]#[CH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.I[C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:16])[C:11]([C:14]#[C:15][C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:32][CH:33]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1N
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3N)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from 5-(4-chlorophenyl)-2-ethynylpyridin-3-ylamine and 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine. Yield: 0.63 (75% of theoretical); C27H28ClN3O (M=445.984); calc.: molpeak (M+H)+: 446/448 (Cl); found: molpeak (M+H)+: 446/448 (Cl); HPLC-MS: 5.05 minutes (method D).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:21]1[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
To a solution of 1H-indole-2,5-dicarboxylic acid 2-ethyl ester (3.08 g, 13 mmol) and tert-butyl 1-homopiperazine-carboxylate (1 eq., 2.657 g) in DMF (50 ml) was added N-hydroxybenzotriazole (0.2 eq., 360 mg). After a five minutes, N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.2 eq., 3.05 g) was added and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as a light-brown solid (5.21 g, 94%). MS (m/z): 416.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:17][CH2:16][C:7]3=[CH:8][C:9]([Br:15])=[CH:10][C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:19]([N:12]1[C:13]2[CH:14]=[C:2]([Br:1])[CH:3]=[C:4]3[CH2:17][CH2:16][C:7]4[C:6]([C:5]=23)=[C:11]1[CH:10]=[C:9]([Br:15])[CH:8]=4)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1cc2c3c(c1)[nH]c1cc(Br)cc(c13)CC2
Reactant: CCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCn1c2cc(Br)cc3c2c2c(cc(Br)cc21)CC3
Yield: 71.2 %

Procedure:
A dried flask fitted with a condenser was charged with 2,6-dibromo-8,9-dihydro-4H-benzo[def]carbazole (1.2) (3.50 g, 9.97 mmol), bromooctane (1.9 cm3, 11.0 mmol), tetrabutylammonium bromide (0.161 g, 0.500 mmol), freshly powdered sodium hydroxide (0.798 g, 19.9 mmol) and acetone (100 cm3). The resulting solution was reflux for 4 hours and then poured into distilled water (100 cm3). The resulting solution was extracted with dichloromethane (3×200 cm3). The combined organic fractions were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane, pre-adsorbed on silica gel, and purified by column chromatography (90:10 petroleum ether:ethyl acetate as eluent) resulting in a off-white solid. (3.29 g, yield 71.2%): NMR (1H, 300 MHz, CDCl3): δ 7.26 (s, 2H); 7.08 (s, 2H); 4.06(t, J=7.1 Hz, 2H); 3.22 (s, 4H); 1.81 (m, 4H); 1.28 (m, 10H); 0.86 (t, J=6.8 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[ClH:17]>>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([Cl:17])=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: Cl
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Product: Nc1cc(C(F)(F)F)c(Cl)nc1C(=O)O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 3D) (100 mg, 0.334 mmol) was dissolved in 5M HCl (2.5 ml) and heated at 150° C., 5.5 bar in the microwave for 1 hour. The reaction mixture was purified by reverse phase chromatography eluting with water/MeCN to afford the title compound. MS m/z 241 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.33 (1H, br hump), 7.79 (1H, s), 7.19 (2H, br s
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=O)C>Br.O>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][CH:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Agent: Br
Solvent: O
Product: c1ccc2sc(NC3CCNCC3)nc2c1
Temperature: -20 °C

Procedure:
A solution of 4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid ethyl ester (3.70 g, 12.0 mmol) in hydrobromic acid 48% in water (20 mL) was heated to reflux. After 18 h hydrobromic acid was removed under reduced pressure and the crude solid dissolved by vigorous stirring in hot methanol (50 mL). The obtained solution was cooled to −20° C. by which a precipitate formed that was removed by filtration. The organic phase was concentrated under reduced pressure, 4 N NaOH (100 mL) added and the solution extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4 to yield after evaporation of the solvent 1.7 g (61%) of the title compound which was used directly in the following step. 1H NMR (300 MHz, DMSO): δ 1.19-1.39 (m, 2H), 1.90-2.00 (m, 2H), 2.92-2.97 (m, 2H), 3.72-3.79 (m, 2H), 6.99 (t, J=8.2 Hz, 1H), 7.20 (t, J=8.2 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H). MS (ISP): 233.9 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C@H:14]([C@H:18]2[CH2:23][CH2:22][C@H:21]([O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:53]([O:57][NH2:58])([CH3:56])([CH3:55])[CH3:54].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:53]([O:57][NH:58][C:15](=[O:17])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]1)([CH3:56])([CH3:55])[CH3:54]
Reactant: CCCO[C@H]1CC[C@H]([C@H](C(=O)O)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCO[C@H]1CC[C@H]([C@H](C(=O)NOC(C)(C)C)N(Cc2ccncc2)S(=O)(=O)c2ccc(OC)cc2)CC1
Reaction time: 8 h

Procedure:
2(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-(trans-4-propoxycyclohexyl) acetic acid hydrochloride (2.65 g, 4.82 mmol), 1-hydroxybenzotriazole (0.65 g, 4.81 mmol), 4-methylmorpholine (2.93 mL, 26.5 mmol), and O-t-butylhydroxylamine hydrochloride (1.81 g, 14.4 mmol) are dissolved in methylene chloride (100 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (1.1 g, 5.8 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (5% methanoilmethylene chloride) to give N-(t-butyloxy)-2(R)-[(4-methoxybenzenesulfonyl)-(4-picolyl)amino]-2-(trans-4-propoxy-cyclohexyl)-acetamide.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[OH:7][C:8]1[CH:16]=[CH:15]C(C(O)=O)=[CH:10][CH:9]=1.C([O-])(=O)C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[OH:7][C:8]1[CH:16]=[CH:15][C:2]([C:1]([O:4][CH:5]=[CH2:6])=[O:3])=[CH:10][CH:9]=1
Reactant: C=COC(C)=O
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=COC(=O)c1ccc(O)cc1
Yield: 10 %

Procedure:
2000 g of dichloromethane, 24.9 g of vinyl acetate, 40.0 g of 4-hydroxybenzoic acid, 0.79 g of palladium acetate and 3.5 g of potassium acetate were charged into a separable flask of the same type as used in Reference Example 3 and subjected to reaction at 50° C. for 6 hours, while replacing the flask inside atomosphere with a nitrogen gas. After completion of the reaction, the reaction mixture was washed successively with an aqueous 0.5N sodium carbonate solution and water, and then treated in th same manner as in Reference Example 3, whereby 4.8 g of vinyl 4-hydroxybenzoate having the following chemical formula was obtained (yield: 10%): ##STR5##
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23].O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32]>CN(C)C=O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([O:24][N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32])=[O:23]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccccn1
Reaction time: 8 h

Procedure:
The N-picolinoyloxysuccinimide is prepared by adding 8.4 g of N,N'-dicyclohexylcarbodiimide to a solution of 5.0 g of picolinic acid and 4.7 g of N-hydroxysuccinimide in 50 ml of dimethylformamide. The mixture is stirred overnight, triturated with ether and recrystallized from ethyl acetate, methylene chloride (1:1). The solid is collected and dried; mp. 174°-175°.
Reaction SMILES: S(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:33])(C)(=O)=O.[C:45]1([SH:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N+:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:11][C@H:7]2[CH2:6][S:51][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:33])=[CH:41][CH:40]=1)([O-:44])=[O:43]
Reactant: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CSc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a solution of (2S,4S)-2-mesyloxymethyl-N-(p-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (9.6 g, 15.2 mmol) in THF (190 ml), thiophenol (2.34 ml, 22.8 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (3.4 ml, 22.8 mmol) were successively added dropwise in a nitrogen stream under cooling with ice. The reaction solution was stirred at room temperature for 15 minutes and the solvent was distilled off. To the residue, ethyl acetate was added. The organic layer was washed with 1N aqueous potassium hydrogensulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residue was subjected to silica gel column chromatography (Wakogel™ C-300 heptane-ethyl acetate 3:1) to give (2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-phenylthiomethyl-4-tritylthiopyrrolidine (9.24 mg, yield: 94%) as a yellow oily substance.
Reaction SMILES: [OH:1][C@@:2]1([C:34]([F:37])([F:36])[F:35])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH:11]=[C:10]([C:23]3[CH:24]=[N:25][N:26]([C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30])[CH:27]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Cl-].[NH4+].C([N:43](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C)C=O.O>[OH:1][C@@:2]1([C:34]([F:37])([F:35])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH:11]=[C:10]([C:23]3[CH:24]=[N:25][N:26]([C:28]([CH3:32])([CH3:33])[C:29]([NH2:43])=[O:30])[CH:27]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(O)CCCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CCCOc1cc(-c2cnn(C(C)(C)C(N)=O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 2-{4-[(9R)-9-hydroxy-2-(4-hydroxy-4-methylpentyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionic acid (89 mg) was dissolved in N,N-dimethylformamide (1 ml), ammonium chloride (28 mg), N,N-diisopropylethylamine (148 μl) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate (HATU) (99 mg) were added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate (twice). The obtained organic layer was washed successively with diluted brine (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel thin layer chromatography (a mixture of chloroform and methanol at a mixing ratio 9:1 (chloroform:methanol) was used as an elution solvent) to give the title compound (48 mg, optical purity 96.9% e.e.). The optical purity was determined under the HPLC analysis condition 2. Retention time of (R) form 13.0 min, retention time of (S) form 14.4 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]2=[O:23].[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)[N:10]=2)[C:5](=[O:23])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)[CH3:27]
Reactant: CCOC(=O)c1c[nH]c2nc(-c3ccncc3)c(F)cc2c1=O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2nc(-c3ccncc3)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A mixture containing 2.63 g of ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate, 0.42 g of 50% sodium hydride (dispersed in mineral oil) and 30 ml of dimethylformamide was heated at 50°-60° C. for 10 minutes. To the stirred mixture was added 1.31 g of ethyl iodide, and heating was continued for 1.5 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo and the residue was taken up in a mixture of chloroform and water. The chloroform layer was separated and the chloroform was evaporated in vacuo to give crystals which were recrystallized from ethyl acetate to yield ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate (2.1 g, m.p. 185°-186° C.). This compound was heated at 90°-100° C. with 25 ml of 2N sodium hydroxide for 5 minutes. The reaction mixture was treated with decolorizing charcoal and filtered. The filtrate was adjusted to pH 6-7 with acetic acid and chilled. The resulting solid was collected by filtration and recrystallized from ethanol to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylic acid (Compound 1) (1.5 g, m.p. 286°-288° C.).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[CH:21]=O)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=[O:38])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1CCCCC1.C(Cl)Cl.CCOC(C)=O.CC(O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.CCOCC.C(Cl)Cl>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20](/[CH:21]=[C:36](\[C:33]4[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:28])=[O:29])=[CH:35][CH:34]=4)/[C:37]([OH:39])=[O:38])[CH:23]=[CH:24][CH:25]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:1]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CC(C)(c1cc(-c2cccc(C=O)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(c1cc(-c2cccc(/C=C(/C(=O)O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A mixture of 3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}benzaldehyde from step 4 of Example 18 (2.33 g, 6.60 mmol), 4-(methylsulfonyl)phenyl acetic acid (1.71 g, 7.98 mmol) and piperidine (0.20 ml, 1.98 mmol) in 10 mL of toluene was refluxed for 2 days. The mixture was cooled to r.t., diluted with CH2Cl2, subjected to flash chromatography (CH2Cl2/EtOAc/AcOH, 50/50/1) and finally stirred with (Et2O/CH2Cl2) and isolated to give (E)-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid (single isomer) as a white solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.C([Li])(CC)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1>C1COCC1>[F:33][CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: BrC=C1c2ccccc2COc2ccccc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: FC=C1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 11-Bromomethylene-6,11-dihydro-dibenzo[b,e]oxepine (1 eq.) in dry THF (0.1 M). Cool the solution to −78 C in a dry ice/acetone bath. Slowly add s-butyl lithium (1.2 eq., 1.3 M in cyclohexane) to the above solution. Stir the dark brown solution at −78 C. for two hours. Add a solution of N-fluorobenzene sulfonimide (1.2 eq.) in dry THF (0.4 M) over 2 minutes. Remove the cold bath and allow the reaction mixture to warm to ambient temperature. Stir the reaction mixture at room temperature for 1 hour. Quench the reaction with water. Wash the resulting mixture with saturated aqueous NaHCO3.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:26][CH:27]=[CH2:28])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:5])C>CC(O)=O.O.[Pd]>[NH2:22][C@@:10]1([C:12]([OH:14])=[O:13])[C@H:9]([O:25][CH2:26][CH2:27][CH3:28])[CH2:8][C@@H:7]2[C@H:11]1[C@H:6]2[C:4]([OH:5])=[O:3]
Reactant: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CCCO[C@@H]1C[C@H]2[C@H](C(=O)O)[C@H]2[C@]1(N)C(=O)O
Temperature: 23 °C
Yield: 73.2 %

Procedure:
A solution of (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (28 mg, 0.073 mmol) in HOAc (0.75 mL) and H2O (0.25 mL) was hydrogenated in the presence of Pd/C (3 mg, 10% Pd/C) at 23° C. for 18 h. The catalyst was removed by filtration, the filter cake washed with 50% aqueous ethanol. After removal of the solvent in vacuum, the beige residue was refluxed in 10% HCl (1.25 mL) for 4 h. The solution was cooled to 23° C. and evaporated to dryness. The remaining pale yellow solid was dissolved in EtOH (1 mL) and propylene oxide (0.5 mL) and refluxed for 10 min, whereupon the amino acid precipiated. After cooling to 23° C., the product was filtered off, washed with ether and dried to give (1S,2R,3R,5R,6S)-2-amino-3-propoxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid (I-8) (13 mg, 72%) as a white solid. 1H-NMR (250 MHz, D2O) □0.81 (1H, t, J=7.5 Hz), 1.48 (2H, m), 1.84 (1H, m), 2.16 (3H, m), 2.26 (1H, dd,J=12,7 Hz), 3.43 (2H, m), 3.73 (1H,bt,J=8Hz); MS[ISN] 242 [(M-H)- ]; mp >2500 C; □D20 3.72° (c=0.19, H2O).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:7]([OH:9])=[O:8])([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:22](=[O:25])(=[O:24])[NH2:23])[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c(C)c1
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: Cc1ccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)c(C)c1

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(2,4-dimethylanilino)-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained with a melting point of 241°-241.5° C after recrystallization from ethanol.