Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:32])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(CCOc3ccc(OC(C)(C)C(=O)O)cc3)c(C)o2)cc1
Yield: 100.9 %

Procedure:
A solution of 2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.036 g, 0.0819 mmol) in ethanol (5 mL) was treated with 5 N NaOH (0.1 mL) and the reaction heated to reflux for 1 h. The reaction mixture was cooled and the solvent removed in vacuo. The resultant oil was acidified with 1 N HCl and extracted with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.034 g (100%) of 2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, 2H, J=8.60 Hz), 6.94 (d, 2H, J=8.60 Hz), 6.90-6.87 (m, 2H), 6.79-6.77 (m, 2H), 4.17 (t, 2H, J=6.45 Hz), 3.85 (s, 3H), 2.98 (t, 2H, J=6.45 Hz), 2.36 (s, 3H), 1.52 (s, 6H); HRMS (ES+) m/z exact mass calcd for C23H26NO6 412.1760, found 412.1783The following compounds were prepared following the same procedure using ethyl iodide, 2-iodopropane, 1-iodopropane, and 1-iodohexane, respectively:
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([NH2:13])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([CH3:12])=[CH:8]2.[N-:14]([C:17]#[N:18])[C:15]#[N:16].[Na+]>CN(C)C=O>[C:15]([N:14]=[C:17]([NH2:18])[NH:13][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([I:2])[CH:4]=1)[NH:10][C:9]([CH3:12])=[CH:8]2)#[N:16]
Reactant: Cc1cc2cc(N)cc(I)c2[nH]1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(NC(N)=NC#N)cc(I)c2[nH]1
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 42.1 %

Procedure:
A solution of 7-iodo-2-methyl-1H-indol-5-ylamine hydrochloride XVII (1.9 g, 6.158 mmol) in N,N-dimethylformamide (30 mL) at 25° C. was treated with sodium dicyanamide (1.37 g, 15.397 mmol) and then warmed to 45° C. for 4 h. The resulting mixture filtered and concentrated in vacuo and the residue treated with water (20 mL). The resulting mixture was allowed to stand at 25° C. for 2.5 h during which time a solid formed. The solid was collected by filtration and washed with water, resuspended in methanol, filtered and dried to give N″-cyano-N-(7-iodo-2-methyl-1H-indol-5-yl)guanidine XVIII (0.88 g, 42%) as a light grey solid: LRMS for C11H10IN5 (M−H)+ at m/z=338.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:37]([OH:54])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:37]([O:54][CH3:3])[C:36]3=[O:55])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: O=C1C(O)=C(c2ccccc2)C(c2cccc(F)c2F)N1c1ccc2nc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C(c2ccccc2)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2.8 v/v, 34 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-hydroxy-4-phenyl-1H-pyrrol-2(5H)-one (1 g, 2.48 mmol, 1 eq) and MeOH (10 ml); yield: 0.160 g (60%); MS m/z: 418.1 [M+H]+; 1H-NMR: (400 MHz, CDCl3) δ: 7.87 (s, 1H), 7.74 (s, 1H), 7.58-7.50 (m, 3H), 7.36-7.2 (m, 5H), 4.18 (s, 3H); HPLC (METHOD [A]): rt 14.70 min (99.68%)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([I:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(I)ccc1O
Product: Oc1ccc(I)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-iodo-2-hydroxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 611.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([O:36][CH2:37][CH2:38][OH:39])[CH:30]=[CH:29]2.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+].COC1C=C2C(=CC=1)C=C(O)C=C2.C1(=O)OCCO1>CO.C(Cl)(Cl)Cl.CCCCCC>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=1)[CH:21]=[CH:20]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([O:36][CH2:37][CH2:38][OH:39])[CH:30]=[CH:29]2
Reactant: C1CNCCN1
Reactant: COc1ccc2cc(OCCOc3cncc(Cl)n3)ccc2c1
Agent: COc1ccc2cc(O)ccc2c1
Agent: COc1ccc2cc(OCCO)ccc2c1
Agent: O=C([O-])[O-]
Solvent: O=C1OCCO1
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc2cc(OCCOc3cncc(N4CCNCC4)n3)ccc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(6-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [0.94 g, 2.8 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(6-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.00 g, 11.6 mmol) and K2CO3 (0.50 g, 3.6 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.52 g (48%) which was obtained as a beige colored solid. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+ 380.1848, found 380.1845. *Prepared from 6-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(6-methoxy-naphthalen-2-yloxy)ethanol was obtained by recrystallization from MeOH/CHCl3/n-hexane.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[C:10]1[CH3:11]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:13](=[O:14])/[CH:12]=[C:10](/[CH3:11])\[C:9]([OH:16])=[O:15])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: CC1=CC(=O)OC1=O
Solvent: C1CCOC1
Product: C/C(=C/C(=O)Nc1ccc(N)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.0 g (92.5 mmol) of 1,4-phenylenediamine and 250 ml of tetrahydrofuran. A solution prepared by dissolving 10.4 g (92.5 mmol) of citraconic anhydride in 20 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 20 minutes, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the deposited crystal was isolated by filtration, and dried to obtain 15 g of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid. Five grams (5 g) of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid was repulped with 2-propanol and methanol each at 50° C. for 3 hours, then, repulped with chloroform, to obtain 13.1 g of (2Z)-4-[(4-aminophenyl)amino]-2-methyl-4-oxo-2-butenoic acid as a yellow solid. Yield: 64.3%.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:13](=O)[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:13]=[N+:14]([O-:32])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CCc2cccc(Oc3cc4ccccc4[nH]c3=O)c21
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2cccc(Oc3cc4ccccc4[n+]([O-])c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
0.2 g of 3-(1,1-dimethylindan-7-yloxy) quinolone was dissolved in 5 mL of chloroform, and 0.2 g of m-CPBA (70%) was added and stirred overnight at room temperature. After the reaction mixture was diluted with chloroform and washed with saturated sodium bicarbonate water, magnesium sulfate was added to dry the resultant. The solvent was evaporated under reduced pressure to obtain 0.2 g of 3-(1,1-dimethylindan-7-yloxy) quinoline-N-oxide.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[N:41]([C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]([C:53]([NH2:55])=[O:54])[CH:45]=1)=[C:42]=[O:43].O>C1COCC1>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][N:12]1[C:42](=[O:43])[NH:41][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]([C:53](=[O:54])[NH2:55])[CH:45]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)OCc2ccccc2)C1)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)n1cc(NC(=O)N2C[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C[C@H]2C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2S,4S)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-pyrrolidine-2-carboxylic acid benzyl ester (3.03 g, 5.45 mmol) and Et3N (1.1 mL, 8.2 mmol) in dry THF (60 mL) was added a solution of 3-isocyanato-indole-1-carboxylic acid amide (1.1 g, 5.4 mmol, prepared as described in Scheme A1) in dry THF (60 mL). The resulting solution was stirred at RT under nitrogen for 20 min. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under high vacuum (the temperature of the water bath of the rotary evaporator was kept to RT) to give the title compound. Rf (c-hexane/EtOAc 1:3)=0.39; MS (LCMS): 644.2 [M+H]+, 666.2 [M+Na]+; tR (HPLC conditions a): 4.0 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]([C:21](=O)[CH3:22])=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[C:25]([NH2:33])(=[NH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)CCC>[CH3:22][C:21]1[N:33]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:32]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]=1[C:8]([N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCN(C)CC1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-methylpiperazin-1-ylcarbonyl)-1-(3-nitrophenyl)-1-buten-3-one (20 g), benzamidine hydrochloride (9.9 g) and triethylamine (11.4 ml) in n-butanol (200 ml) was refluxed for 2 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (200 ml) and chloroform (200 ml). The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. To this solution was added activated manganese dioxide (120 g) and the mixture was refluxed for 1 hour with stirring vigorously. After cooling to a room temperature, manganese dioxide was filtered off. The filtrate was evaporated in vacuo, and the residue was subjected to column chromatography on alumina (200 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The crystals were recrystallized from diethyl ether to give 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[C:23]([O:25][CH3:26])=[O:24])[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][C:43]([CH3:45])=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH:43]([CH3:45])[CH3:42])[CH2:19][CH:18]2[C:23]([O:25][CH3:26])=[O:24])[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C1CN(C(C)C)CCC1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
(3R,4S)-Methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate (1.00 g, 2.66 mmol, 1 eq.), sodium triacetoxyborohydride (0.85 g, 4.00 mmol, 1.5 eq.) and acetone (0.59 mL, 7.99 mmol, 3 eq.) were mixed in methylene chloride (15 mL) and stirred for 20 hours at room temperature. Worked up by adding 20 mL of 1.000 N NaOH. Stirred 10 minutes then extracted 3 times with methylene chloride. The organic layers were combined, dried over sodium sulfate and stripped to give methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-1-isopropyl-piperidine-3-carboxylate (1.10 g) of a white glass. Yield=99%. LCMS detects (M+H)+=418.41.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[O:14][CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:17](=[O:19])[CH3:18])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: COC(=O)COc1ccc(CO)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(COC(C)=O)cc1OC
Temperature: 0 °C
Yield: 64 %

Procedure:
A solution of (4-Hydroxymethyl-2-methoxy-phenoxy)-acetic acid methyl ester 72 (40 grams, 177 mmol), Acetic anhydride (80 mL) and pyridine (4 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (200 mL) and crude 73 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 73 (30 grams, 64%) as a color less liquid, Bp15 210° C. The structure was confirmed with IR and NMR. IHNMR (CDCl3) δ 2.08 (s, 3H,O═C—CH3), 3.78(s, 3H,ester), 3.90(s, 3H, OCH3), 4.65(s, 2H,OCH2), 5.00 (s, 2H, CH2), 6.76(d,1H,Ar), 6.80 (d, 2H,Ar), 6.85 (dd,1H,Ar).
Reaction SMILES: [OH:1][NH:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1)=[NH:4].[C:38](O)(=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)CCl>[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:28]=1[CH2:27][O:26][CH:14]1[CH:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:3]3[N:4]=[C:38]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:1][N:2]=3)=[CH:8][CH:9]=2)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCC(=N)NO)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCc3noc(-c4ccccc4)n3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 38, by condensing tert-butyl (3RS,4RS)-4-{4-[2-(N-hydroxy-carbamimidoyl)-ethyl]-phenyl}-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoic acid in the presence of EDC and subsequent cyclization there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-ethyl]-phenyl]-piperidine-1-carboxylate; MS: 590 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.[ClH:28].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH:51]([NH:54][C:55](=[O:63])[CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([CH3:53])[CH3:52]>>[ClH:28].[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:60]3[CH2:59][CH2:58][N:57]([CH2:56][C:55](=[O:63])[NH:54][CH:51]([CH3:52])[CH3:53])[CH2:62][CH2:61]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)NC(=O)CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)NC(=O)CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 37.3 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.757 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.166 mL, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg, 1.06 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.984 mmol) and N-isopropyl-2-(piperazin-1-yl)acetamide (210 mg, 1.14 mmol) in a similar manner to Step 7 of Example 1, was purified by silica gel column chromatography (chloroform/methanol=80/20), followed by treating with 4 mol/L hydrogen chloride-ethyl acetate solution (0.665 mL) to obtain Compound 135 (99.7 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][CH:69]([CH3:76])[C@:70]([C:73]([OH:75])=[O:74])([CH3:72])[NH2:71].[BH4-].[Na+]>CN(C=O)C.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:71][C@@:70]([C:73]([OH:75])=[O:74])([CH3:72])[CH:69]([CH3:76])[CH3:68])=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)[C@](C)(N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)[C@](C)(NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1 h

Procedure:
N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.035 g, 0.065 mmol) was dissolved in DMF (2 ml) at 30° C. N-Methyl morpholine (0.026 g, 0.259 mmol) and TBTU (0.027 g, 0.084 mmol) were added. After 1 h, 3-methyl-D-isovaline (0.013 g, 0.097 mmol) was added. The mixture was stirred for 2 h and water (1 ml) was added. After 10 minutes, MeOH (2 ml) and NaBH4 (0.037 g, 0.971 mmol) were added. Full conversion to the corresponding alcohol was obtained after 5 minutes and 0.1M NH4OAc buffer (2 ml) was added. The mixture was purified by preparative HPLC (eluent 0-50% CH3CN in 0.1M NH4OAc buffer). Freeze-drying of the pure fractions afforded the title compound (0.020 g, 47%) as a colourless solid. M/z: 654.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.79 (d, 3H), 0.87 (d, 3H), 1.29 (s, 3H), 2.00-2.07 (m, 1H), 2.84-2.94 (m, 2H), 3.73 (d, 2H), 4.25-4.28 (m, 1H), 4.51 (s, 2H), 4.69-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 (m, 12H), 7.82 (s, 1H), 8.24 (t, 1H).
Reaction SMILES: [CH3:1][C@@:2]1([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1>CO.[Pd]>[CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1
Reactant: C[C@@]1(C=Cc2ccco2)COC(=O)N1
Agent: [Pd]
Solvent: CO
Product: C[C@@]1(CCc2ccco2)COC(=O)N1
Yield: 78.3 %

Procedure:
To a suspension of 10% palladium-charcoal (50% wet with water) (1.00 g) in methanol (20 ml) was added a solution of (4R)-4-methyl-4-[2-(furan-2-yl)ethenyl]-1,3-oxazolidin-2-one (10.04 g, 52.0 mmol) obtained in Reference example 3 in methanol (180 ml) with stirring, and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 40 minutes. After stirring, the palladium-charcoal in the reaction mixture was filtered off using celite, and the filtrate was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2-1:1) as the eluent to afford the title compound (7.95 g, yield: 78%).
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[F:6][C:7]([F:19])([F:18])[C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]([C:7]([F:6])([F:18])[F:19])=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C(F)(F)F
Reactant: NNC1CC1
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 5,5,5-trifluoro-2,4-dioxopentanoate at 100° C. for 2 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 9:1). tR: 1.23 min (LC-MS 2); ESI-MS: 249.2 [M+H]+ (LC-MS 2); Rf=0.34 (hexane/EtOAc 9:1).
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:9][C:8]=1[N+:23]([O-])=O.[OH-].[K+]>C(O)C.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:9][C:8]=1[NH2:23]
Reactant: COc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Temperature: 70 °C

Procedure:
Add tin (II) chloride dihydrate (1.41 g, 6.26 mmol) to a suspension of 3-(4-fluoro-3-nitrophenylethynyl)-5-methoxypyridine, (prepared as described in EXAMPLE 116), (190 mg, 0.69 mmol) in ethanol (20 mL) and tetrahydrofuran (17 mL) under nitrogen and heat at 70° C. for 2 h. Cool the reaction mixture, add a 50% aqueous solution of potassium hydroxide (100 mL), and extract with diethyl ether (2×100 mL). Wash the combined organic phases with an aqueous saturated solution of sodium chloride (100 mL), dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with ethyl acetate to give the title compound as a yellow solid. Further purify the title compound by silica gel chromatography, eluting with 100% dichloromethane to 20:80 ethyl acetate:dichloromethane, to give the title compound as a white solid (143 mg, 86%).