Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:20](=[O:31])[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[N+:12]([C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:30][CH2:29][CH2:28][N:25]3[CH2:24][CH2:23][CH:22]([NH:21][C:20]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:31])[CH2:27][CH2:26]3)=[N:3]2)=[CH:8][CH:7]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ncc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc([N+](=O)[O-])cc5n4)CC3)cc2N1

Procedure:
The title compound is prepared as a yellow lyophilizated powder following Scheme 1 and in analogy to Examples 1 and 12 using 2-chloro-7-nitro-quinoxaline, [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: CN.[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1.Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>CO.O>[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH2:16][NH:24][CH3:23])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 70 °C

Procedure:
A solution of methylamine in MeOH (8M, 1.06 ml, 8.46 mmol) was added to a mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.0 g, 4.23 mmol) and methylamine hydrochloride (0.57 g, 8.46 mmol), in MeOH (20 ml) at room temperature. Sodium cyanoborohydride (1.06 g, 16.93 mmol) was then added and the reaction mixture heated at 70° C. for 2 h. Water was added to the cooled reaction mixture and the volume reduced under vacuum. The remaining predominantly aqueous phase was then extracted with DCM (3×), dried over Na2SO4 and evaporated to give the title compound. (UPLC-MS 7) tR 0.33; ESI-MS 252.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.C1COCC1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>CCN(CC)CC>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=2)=[O:8])[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: C#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Temperature: 55 °C
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.135 g, 0.854 mmol) and THF (5 mL) was added. 3-Ethynyl-phenylamine (0.100 g, 0.854 mmol) was added to the THF solution of the acid chloride followed by NEt3, and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature. The reaction was extracted twice with EtOAc (˜5 mL) and water (˜10 mL) followed by saturated aqueous NaHCO3 (˜10 mL). The combined organic layers were dried over anhydrous Na2SO4 (s) and then concentrated. The crude residue was purified by chromatography (silica gel, gradient elution EtOAc/Hexanes 0 to 60%). The product containing fractions were concentrated to give the title compound as a tan solid (147 mg. 72%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([S:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH:31]1[C:39]2[C:34](=[CH:35][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:38]=2)[CH:33]=[CH:32]1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:36]3[CH:35]=[C:34]4[CH:33]=[CH:32][NH:31][C:39]4=[N:38][CH:37]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[C:11]1[CH:12]=[C:13]([S:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(-c2cccc(S(=O)(=O)C[C@H](C)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Cc1c(-c2cccc(S(=O)(=O)C[C@H](C)O)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
(S)-1-(3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylsulfonyl)propan-2-ol (10 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 38 mg of 415. MS (Q1) 550.0 (M)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][CH2:12][CH2:11]O2)=[CH:5][CH:4]=1)#[N:2].Br[C:15]1C=[CH:19][C:18]([F:21])=[CH:17][C:16]=1COCOC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[B:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[O:13][CH2:12][C:11]=2[CH:19]=1
Reactant: N#Cc1ccc(B2OCCO2)cc1
Reactant: COCOCc1cc(F)ccc1Br
Product: N#Cc1ccc(B2OCc3cc(F)ccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo4-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH3:8])=[CH:4][CH:3]=1.C(C[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(O)=O.[C:28]([O-:31])([O-])=[O:29].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[N:9]1([CH:7]([C:5]2[O:6][C:2]([C:19]3[CH:24]=[CH:23][C:22]([C:28]([OH:31])=[O:29])=[CH:21][CH:20]=3)=[CH:3][CH:4]=2)[CH3:8])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: CC(c1ccc(Br)o1)N1CCOCC1
Reactant: O=C(O)Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(c1ccc(-c2ccc(C(=O)O)cc2)o1)N1CCOCC1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
4-[1-(5-bromo-furan-2-yl)-ethyl]-morpholine (0.54 mmol) was taken up in 7 ml toluene and 4-carboxymethylphenylboronic acid (0.54 mmol) was added as a solution in 0.7 ml of EtOH. 12 mi of 2M aqueous Na2CO3 solution was added, followed by Pd(PPh3)4 (0.054 mmol). Reaction was stirred at 70° C. for 17 h under a nitrogen atmosphere and then cooled to room temperature and extracted with DCM (×2). Combined organic layers were washed with brine, concentrated in vacuo and the residue purified by flash chromatography (silica, 20-50% EtOAc in hexane). This fumished the pure 4-[5-(1-Morpholin-4-yl-ethyl)-furan-2-yl]-benzoic acid methyl ester as a powdery grey solid: m/z in MS ES+=316 [M+H]+, 0.08 mmol, 15% yield.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:14](C1C=C(C=C(C)N=1)C(O)=O)C>>[CH2:13]([C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH3:2])[N:12]=1)[C:6]([NH:8][NH2:9])=[O:7])[CH3:14]
Reactant: CCc1cc(C(=O)O)cc(C)n1
Reactant: Cc1cc(C(=O)NN)cc(C)n1
Agent: Cl
Product: CCc1cc(C(=O)NN)cc(C)n1

Procedure:
The title compound is prepared in analogy to 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride starting from 2-ethyl-6-methyl-isonicotinic acid; 1H NMR S 1.46 (t, J=7.6 Hz, 3H), 2.87 (s, 3H), 3.15 (q, J=7.6 Hz, 3H), 8.14 (s, 1H), 8.16 (s, 1H).
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:75]=[CH:74][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([CH3:73])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:75]=[CH:74][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([CH3:73])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(C)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(C)c2)cc1
Yield: 92 %

Procedure:
The compound of example 472 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 471.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[C:16](=O)([O:18]C1C=CC=CC=1)N.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>C(OCC)(=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:38])[F:39])[N:33]([C:16](=[O:18])[NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:10][CH:11]=1)[CH2:32][CH2:31]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: NC(=O)Oc1ccccc1
Reactant: Nc1ccc(OCc2ccncc2)cc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(OCc3ccncc3)cc1)CC2
Yield: 24 %

Procedure:
4-(Pyridin-4-ylmethyloxy)aniline (0.5 g, 2.5 mmol) was converted to the phenyl carbamate and treated with 5-methoxy-6-trifluoromethylindoline (0.54 g, 2.5 mmol) as in the method of Example 52. Chromatography using ethyl acetate as eluant followed by recrystallisation from ethyl acetate/petroleum ether (60-80°) afforded the title compound (0.23 g, 24%) as an off-white crystalline solid m.p. 205-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[C:15]([O:14][C:12]([NH:6][C@H:5]([CH2:10][CH2:9][CH2:8][C:7]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:11])[C:3]([O:2][CH3:1])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.00 g) in THF (120 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether, 42 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was heated from −78° C. to −40° C. over 1.5 hours while stirring, and then quenched with a saturated ammonium chloride solution at −40° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g). A solution of 4 N hydrochloric acid in ethyl acetate (90 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g) in ethyl acetate (90 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Sodium cyanoborohydride (3.29 g) and then acetic acid (4.27 mL) were added to a solution of the residue in methanol (150 mL) at 0° C., and the reaction solution was stirred at 0° C. for one hour and at room temperature for one hour. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with a heptane-diisopropyl ether system to obtain 2.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([N:27]([C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47](C=O)=[CH:46][CH:45]=2)[CH:41]=[CH:42][CH:43]=1)[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH3:26].[C:52]1(C)C=CC=CC=1>>[CH2:25]([N:27]([C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47](/[CH:52]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:46][CH:45]=2)[CH:41]=[CH:42][CH:43]=1)[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH3:26]
Reactant: Cc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(C=O)cc2)c1
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2)c1
Temperature: 90 °C
Yield: 91 %

Procedure:
1.0 g (3 mmol, 1.5 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 740 mg (2.02 mmol, 1 eq) of 1-ethyl-1-(4′-formylbiphenyl-3-yl)-3-heptylurea in 8 ml of toluene. The reaction mixture is heated at 90° C. for 1 hour. The solvent is evaporated off and the residual oil is then chromatographed on silica gel (8/2 heptane/ethyl acetate). 775 mg of methyl (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylate are obtained in the form of an off-white solid. Yield=91%
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=[CH:12][C:4]=2[O:3]1.[C:22](OC(OC(OC(C)(C)C)=O)=O)(C)([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl>[CH3:1][C@@H:2]1[O:3][C:4]2[CH:12]=[C:11]3[C:10](=[CH:9][C:5]=2[NH:6][C:7]1=[O:8])[C@H:13]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:24][CH2:22][CH2:23]3
Reactant: C[C@H]1Oc2ccc(CNCCCC(F)(F)F)cc2NC1=O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1Oc2cc3c(cc2NC1=O)[C@H](NCCCC(F)(F)F)CCC3
Yield: 105.5 %

Procedure:
608 mg (2.014 mmol) of (2R)-methyl-3-oxo-6-(4,4,4-trifluorobutylamino-methyl)-3,4-dihydro-2H-1,4-benzoxazine is stirred with 439.9 mg (2.014 mmol) of di-tert-butyldicarbonate and 303 mg (2.995 mmol) of triethylamine in 15 ml of dichloromethane for four hours at room temperature. The batch is spun in until a dry state is reached, and the residue is put on a column on silica gel (mobile solvent: ethyl acetate/hexane). 727.6 mg (99%) of the desired compound is isolated.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([CH:15]1[CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:8]([CH:15]1[CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][NH:17][C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)C(=O)C1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC1CNC(=O)C1Cc1ccccc1
Reaction time: 14 h
Yield: 99.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl 3-benzyl-2-oxo-4-propyl-1-pyrrolidinecarboxylate (1.22 g, 3.84 mmol) in methylene chloride (10 ml) while cooling on ice and the mixture was stirred for 14 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield a crude product of the title compound (0.83 g) as white crystals. 1H-NMR (CDCl3) δ(ppm) 0.79 (3H, t, J=7.2 Hz), 1.08-1.36 (4H, m), 2.04-2.21 (1H, m), 2.28-2.40 (1H, m), 2.81-2.96 (2H, m), 3.09 (1H, dd, J=14.0 Hz, 4.8 Hz), 3.29 (1H, dd, J=8.4 Hz, 8.4 Hz), 5.73 (1H, brs), 7.15-7.36 (5H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[CH2:63][C:64](O)=[O:65]>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[N:17]=[C:16]([NH:18][C:64](=[O:65])[CH2:63][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][N:57]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Cc1ccccn1)Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To a dichloromethane (5 ml) solution of 6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-ylamine (74 mg, 0.187 mmol) were added N-methylmorpholine (90 μl, 0.818 mmol), 1-hydroxybenzotriazole (11 mg, 0.313 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.312 mmol) and 2-pyridylacetic acid hydrochloride (54 mg, 0.312 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane. The diluted solution was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (48 mg, 0.0934 mmol, 50%) as a white amorphous substance.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33]([O:35][CH2:36][C:37](O)=[O:38])[CH3:34].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:38])[CH3:34]
Reactant: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCOCC(=O)O
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOCC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 35.5 %

Procedure:
To a solution of 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (889 mg) and ethoxyacetic acid (250 mg) in pyridine (25 ml) is added N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1527 mg) under ice-cooling, and the mixture is stirred at room temperature for 19 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is stirred. The organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), and thereto is added triethylamine (202 mg). The mixture is stirred at 50° C. for 40 minutes, and evaporated to remove the solvent. The residue is dissolved in ethyl acetate, and the mixture is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 2'-(6-O-ethoxyacetyl-β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (377 mg).
Reaction SMILES: N[C@H](C(O)=O)C.[C:7]([C@@H:10]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])[CH2:11][CH2:12][CH3:13])(=[O:9])[NH2:8].Cl.[CH2:21]([O:29][C:30]([C@@H:32]1[CH:37]2[CH2:38][CH2:39][CH:34]([CH2:35][CH2:36]2)[NH:33]1)=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:21]([O:29][C:30]([C@@H:32]1[CH:37]2[CH2:38][CH2:39][CH:34]([CH2:35][CH2:36]2)[N:33]1[C:17](=[O:19])[C@@H:15]([NH:14][C@H:10]([C:7](=[O:9])[NH2:8])[CH2:11][CH2:12][CH3:13])[CH3:16])=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCOC(=O)[C@H]1NC2CCC1CC2
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(N)=O
Agent: C[C@H](N)C(=O)O
Agent: Cl
Product: CCCCCCCCOC(=O)[C@@H]1C2CCC(CC2)N1C(=O)[C@H](C)N[C@@H](CCC)C(N)=O
Yield: 21 %

Procedure:
Using the procedure described in Example 1, but replacing (S)-N-(S)-1-(ethoxycarbonyl)butyl]alanine by (S)-N-[(S)-1-carbamoylbutyl]alanine described in stage A of Example 3, and (3S)-3-carbamoyl-2-azobicyclo[2.2.2]-octane by (3S)-2-azabicyclo[2.2.2]octane-3-carboxylic acid n-octyl ester hydrochloride obtained in stage A (neutralized beforehand with triethylamine), the expected product is obtained from the product being purified by chromatography on silica gel (elution solvent: dichloromethane/ethanol, 95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C(N(CC)CC)C.[C]=O.C[CH2:21][O:22][C:23](C)=[O:24]>CO>[CH3:9][C:5]1[CH:4]=[C:3]([F:10])[C:2]([C:23]([O:22][CH3:21])=[O:24])=[CH:7][C:6]=1[Cl:8]
Reactant: Cc1cc(F)c(Br)cc1Cl
Reactant: CCOC(C)=O
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C)cc1F
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (10 g, 44.7 mmol) in 200 mL of methanol were added 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine)-dichloropalladium (1:1) (358 mg, 0.447 mmol) and N,N-diethylethanamine (8.11 mL, 58.2 mmol). The resulting reaction mixture was placed in a bomb, pressurised to 80 psi of carbon monoxide and heated at 80° C. for 18 hours. The reaction mixture was concentrated in vacuo to yield a semi-solid which was dissolved in EtOAc (300 mL) and washed with water (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 20% EtOAc in heptane to afford the title compound as a white crystalline solid (8.47 g, 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].CCN(CC)CC.CN1CCCC1=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)CCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 67.1 %

Procedure:
459 mg of 4-fluoronitrobenzene, 500 mg of β-alanine ethyl ester and 1.15 ml of Et3N were added to a solution of 10 ml of N-methylpyrrolidinone (NMP). The reaction medium was heated at 70° C. for 8 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, re-slurried in water and then dried over P2O5. 520 mg of ethyl 3-(4-nitrophenylamino)propionate (6) were obtained.