Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]CC4C=CC=CC=4)[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1.C(OC([NH:50][C@H:51]([C:61]([OH:63])=O)[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=O)C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C.[Cl-].[Na+].O.C1COCC1.[Pd]>[NH2:50][C@@H:51]([CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:61]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1)=[O:63]
Reactant: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cc2c(-c3ccc(NC(=O)[C@@H](N)COCc4ccccc4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.1 %

Procedure:
2-(4-Aminophenyl)-6-benzyloxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophene (Preparation 7; 273 mg) and N-benzyloxycarbonyl-O-benzyl-(L)-serine (184 mg) were dissolved in DMF (5.0 mL), treated with DCC (130 mg) and HOAt (88 mg) sequentially, and allowed to stir at ambient temperature under argon for 22 h. The reaction mixture was diluted with brine (30 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:EtOAc (0-3%) afforded the direct coupling product. This product was dissolved in THF (5.0 mL), treated with a solution of ammonium formate (25% in H2O, 2.0 mL) and 10% palladium on carbon (100 mg) sequentially at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 45 h before it was filtered through diatomaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) followed by NH4OH:MeOH:EtOAc (5:10:85) afforded the title compound (124 mg) along with a minor amount of the completely debenzylated product (20 mg) described below in Example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:33])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH:24]=[CH:25][CH:26]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:35][N:36]([CH3:43])[CH2:37]/[CH:38]=[CH:39]/[C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:35][N:36]([CH3:43])[CH2:37]/[CH:38]=[CH:39]/[C:40]([N:31]([C@@H:29]([CH3:30])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]#[C:19][C:12]2[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:10][CH:11]=2)[CH:22]=1)=[O:33])[CH3:32])=[O:41]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#Cc1cccc(NC(=O)[C@H](C)NC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#Cc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CN(C)C)c1
Reaction time: 13 h

Procedure:
To (S)—N-(3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)phenyl)-2-(methylamino)propanamide (G3, 67 mg), 4-dimethylaminocrotonic acid hydrochloride (50 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg), N,N-dimethylformamide (1.5 mL) and N,N-diisopropylethylamine (105 μL) were added at room temperature, and the mixture was stirred at the same temperature for 13 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 100 to 94% ethyl acetate in methanol). The obtained solid matter was washed with water, and then dried under reduced pressure to obtain (S,E)-4-(dimethylamino)-N-(1-((3-((2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)phenyl)amino)-1-oxopropan-2-yl)-N-methyl-2-butenamide (8-1, 50 mg).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1)=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C(N(CC)CC)C>[N+]([O-])([O-])=O.[Ag+].CN(C)C=O>[C:1]([NH:9][C:10]([NH:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1)=[N:12][CH2:13][CH2:14][S:15][CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:23]([NH2:25])=[NH:24])[S:20][CH:21]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]cn1
Reactant: N=C(N)Nc1nc(CSCCNC(=S)NC(=O)c2ccccc2)cs1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(CSCCN=C(NCCc2c[nH]cn2)NC(=O)c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-benzoyl-3-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]thiourea (0.394 g), histamine dihydrochloride (0.276 g), triethylamine (0.20 g), silver nitrate (0.204 g) and dimethyl formamide (20 ml) was stirred at room temperature overnight. After filtration the solution was evaporated to dryness and the residue purified by preparative thin layer chromatography (Merck 60F-254 plates developed with ethyl acetate/ethanol/ammonia (s.g. 0.88) 6:1:1 v/v/v). Isolation of the main band (RF 0.3) gave an oil which crystallized on trituration with acetone to give 1-benzoyl-2-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-3-[2-(imidazol-4-yl)ethyl]guanidine, decomposing at 147°-150° after softening at 115°-117°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.Br[C:57]1[CH:58]=[C:59]2[C:64](=[CH:65][CH:66]=1)[N:63]=[C:62]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH:61]=[CH:60]2.[C:73](=[NH:86])([C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:80]1([C:73]([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)=[N:86][C:57]2[CH:58]=[C:59]3[C:64](=[CH:65][CH:66]=2)[N:63]=[C:62]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:61]=[CH:60]3)[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(C(=Nc2ccc3nc(-c4ccccc4)ccc3c2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
In a 20 mL microwave tube was charged cesium carbonate (0.440 mL, 5.50 mmol), palladium(II)acetate (0.018 g, 0.079 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.068 g, 0.118 mmol) in dioxane (6.0 mL) to give a yellow suspension. The mixture was stirred for 10 minutes and then triethylamine (0.016 mL, 0.118 mmol) was added. The solution was stirred for another 10 minutes; and then 6-bromo-2-phenylquinoline (1.1168 g, 3.93 mmol) and benzophenone imine (0.791 mL, 4.72 mmol) were added as a solution in dioxane (6.0 mL). The mixture was heated at 100° C. overnight. The mixture was cooled to room temperature and dilute with ethyl acetate. The organics were washed 2×100 mL with water, dried over magnesium sulfate, filtered, and concentrated onto silica gel. The reaction was purified by flash chromatography using an Argonaut Flashmaster Solo, 20 g column (10% ethyl acetate:hexanes for 30 min) to afford a yellow oil. (ESI(+)) m/e 385.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:16]2[C:11](=[CH:12][C:13]([F:30])=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][C@@H:9]1[NH:31][C:32](=O)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+].O>O1CCCC1>[CH2:1]([C@H:8]1[C:16]2[C:11](=[CH:12][C:13]([F:30])=[C:14]([O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]3[N:25]=[CH:26][N:27]([CH3:29])[CH:28]=3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][C@H:9]1[NH:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N[C@H]1Cc2cc(F)c(OCCNS(=O)(=O)c3cn(C)cn3)cc2[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@@H]1Cc2cc(F)c(OCCNS(=O)(=O)c3cn(C)cn3)cc2[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
To ethyl cis-1-benzyl-5-fluoro-6-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-2,3-dihydro-1H-inden-2-ylcarbamate (45.3 mg, 0.088 mmol) in tetrahydrofuran (1 ml) was added lithium aluminium hydride 1M in tetrahydrofuran (0.263 ml, 0.263 mmol) and the reaction mixture was refluxed for 2 h. Cooled down to room temperature and added a mixture of 0.5N potassium hydroxide (1 ml) and water (7 ml), filtered over Celite, washed with tetrahydrofuran and the Celite Filter cake was poured into tetrahydrofuran, refluxed for 30 min, and again filtered over Celite. The combined organic layers were evaporated, re-dissolved in dichloromethane, washed with sodium bicarbonate and brine, dried over magnesium sulfate, filtered and evaporated to obtain a pale yellow oil, that was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to obtain cis-N-(2-(3-benzyl-6-fluoro-2-(methylamino)-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a pale yellow oil. m=14.2 mg (35%)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 82.5 %

Procedure:
A solution of N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (120 mg, 0.23 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in tetrahydrofuran/methanol/water (2:2:1; 2.5 mL) was stirred at room temperature for 90 min. The solvent was evaporated, then water was added, followed by 1 M HCl (1.1 mL). The resulting solid was filtered off, washed with water, dried, and purified by HPLC to give N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]-benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (95 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2Cl)=[CH:4][CH:3]=1.[F-:21].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[F:21])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(F)c(-c2ccc(Cl)cc2)c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To 10 ml of dimethylsulfoxide, 0.33 g (1.09 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.05 g (0.86 mmol) of potassium fluoride were dissolved, followed by heating and stirring at 120° C. for 2 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.12 g (yield: 38%) of the desired product. Melting point: 120-122° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)[N:8](S(C3C=CC=CC=3)(=O)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc(N)ccc2F)OC1(C)C
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CC=C(c2cc3c(-c4cc(N)ccc4F)ncnc3[nH]2)CC1
Temperature: 90 °C

Procedure:
To a solution of Example 29A (1.10 g, 2.429 mmol), 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (749 mg, 3.16 mmol), and bis(triphenylphosphine)palladium(II) dichloride (170 mg, 0.243 mmol) in 7/2/3 1,2-dimethyoxyethane/ethanol/water (30 mL) was added sodium carbonate (3.64 mL, 7.29 mmol). The mixture was heated at 90° C. for 1 hour, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in 30 mL dioxane, treated with 6M sodium hydroxide (4.05 mL, 24.29 mmol), heated at 100° C. for 1 hour, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was triturated with ethyl acetate to give the title compound. MS (ESI+) m/z 388.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.N[CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25][CH2:27][C:28]3[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=3[CH3:34])=[O:24])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(COC(=O)c2cc(C3CC3)nc3c2cnn3CCNC(=O)OC(C)(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of DMSO (10 mL) were sequentially added 6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (270 mg, 0.779 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (178 mg, 1.169 mmol), and 1-hydroxy-7-azabenzotriazole (212 mg, 1.559 mmol), and the mixture stirred at room temperature for 10 min. Next was added EDC (299 mg, 1.559 mmol) and N-methylmorpholine (0.343 mL, 3.12 mmol), and reaction mixture was stirred at room temperature for 16 h. The contents were diluted with water (25 mL) and stirred for 10 min. The solid product was filtered off, dried, and collected as 0.290 g (98%). LCMS E-S (M+H)=381.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.15 (m, 4H), 1.30 (s, 9H), 2.13 (s, 3H), 2.18-2.32 (m, 4H), 4.36 (d, J=4.80 Hz, 2H), 4.42 (t, J=5.81 Hz, 2H), 5.90 (s, 1H), 6.85 (t, J=5.56 Hz, 1H), 7.44 (s, 1H), 8.22 (s, 2H), 8.73 (t, J=4.67 Hz, 1H), 11.57 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc([N+](=O)[O-])cc2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 4-nitrobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.15-8.23 (m, 2H) 7.31-7.42 (m, 3H) 6.97-7.05 (m, 1H) 6.71-6.80 (m, 1H) 5.80-6.03 (m, 3H) 5.15-5.44 (m, 1H) 4.16-4.26 (m, 2H) 3.61-3.71 (m, 3H) 2.64-2.76 (m, 2H) 2.07-2.16 (m, 2H) 1.93-2.06 (m, 3H) 0.98-1.19 (m, 9H); LCMS (m/z) ES+=560 (M+1).
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cn2ccccc2n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccccc2n1
Yield: 39 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from imidazo[1,2-a]pyridine-2-carboxylic acid (0.853 g, 5.26 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol). The product was purified by flash chromatography and recrystallization from acetonitrile/water, respectively. Yield 39.0%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 4.35 (dd, 1H), 4.43 (dd, 1H), 4.47-4.57 (m, 1H), 6.96-7.01 (m, 1H), 7.02 (d, 1H), 7.34-7.40 (m, 1H), 7.60 (dd, 1H), 7.89 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.32 (d, 1H), 8.55-8.58 (m, 1H), 8.61 (d, 1H).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:40])[N:9]=[C:10](SC)[C:11]([C:25]1[C:26]([F:37])=[C:27]2[C:32](=[C:33]([O:35][CH3:36])[CH:34]=1)[O:31][CH2:30][CH2:29][CH2:28]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C[O:42][C:43]([C:45]1[S:46][CH:47]=[CH:48][C:49]=1[NH:50][NH2:51])=[O:44]>C(N(CC)CC)C>[F:37][C:26]1[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:40])[N:50]([C:49]3[CH:48]=[CH:47][S:46][C:45]=3[C:43]([OH:44])=[O:42])[N:51]=2)=[CH:34][C:33]([O:35][CH3:36])=[C:32]2[C:27]=1[CH2:28][CH2:29][CH2:30][O:31]2
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCC2
Temperature: 85 °C
Reaction time: 12 h

Procedure:
To 1 ml of a DMF solution containing 100 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)), 35 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.028 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 12 hours under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1.5 ml of methanol, 1.5 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours, and 1 ml of a 5 N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature overnight. Acetic acid (0.3 ml) was added to the reaction mixture, and the resulting mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: C(O[C:5]([NH:7][CH2:8][CH:9]([C:18]1[CH2:24][C@H:23]2[N:20]([C:21](=[O:28])[C@@H:22]2[C@H:25]([OH:27])[CH3:26])[C:19]=1[C:29]([O:31]CC=C)=[O:30])[CH2:10][NH:11]C(OCC=C)=O)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C(O)(=O)C>O1CCCC1.C(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(OCC)(=O)C>[OH:27][C@@H:25]([C@H:22]1[C:21](=[O:28])[N:20]2[C@@H:23]1[CH2:24][C:18]([CH:9]1[CH2:10][N:11]=[CH:5][NH:7][CH2:8]1)=[C:19]2[C:29]([OH:31])=[O:30])[CH3:26]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3CN=CNC3)C[C@H]12
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 22.8 %

Procedure:
To a solution of 741 mg of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 9.25 ml of tetrahydrofuran and 3.07 ml of ethanol were added successively 163 mg of triphenylphosphine, 870 mg of dimedone, 0.089 ml of acetic acid and 143 mg of tetrakis(triphenylphosphine)palladium at room temperature under nitrogen. The mixture was stirred at 30° C. for a few minutes, and then stirring was continued at room temperature for 30 minutes. After a pale yellow precipitate was deposited, 2.2 ml of ethyl acetate was added. The precipitate was filtrated and washed with ethyl acetate and dichloromethane under nitrogen, and dissolved in pH 6.86 buffer solution. 399 mg of Benzyl formimidate hydrochloride was added to the solution at 0° C., while the pH was kept at 8.5. After stirring for 1.5 hours at pH 7.0, the reaction mixture was washed five times with 30% tetrahydrofuran in ethyl acetate while the pH was kept at pH 7. Purification was carried out by a column chromatography on "Diaion HP-20" (trademark, made by Mitsubishi Chemical Industries) (eluent: water followed by 2% acetonitrile in water) and silica gel (eluent: 0-30% water in acetonitrile gradiently) successively to give 99 mg of [5R,6S)-6-[(R)-1-hydroxyethyl]-3-[3,4,5,6-tetrahydropyrimidin-5-yl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.