Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=O.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:42]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: On1nnc2cccnc21
Solvent: C1CCNCC1
Solvent: CN1CCCC1=O
Product: C=CCOC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 150 mL cylidrical glass vessel equipped with a coarse glass frit was charged with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 5 g) and 25% piperidine in N-methylpyrrolidinone (50 mL). The mixture was agitated at room temperature for 30 min. The resin was filtered and treated again with fresh 25% piperidine in N-methylpyrrolidinone (50 mL) at room temperature for 30 min. After filtration, the resin was washed with dichloromethane and methanol. To the resin was added a solution prepared from 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 2.5 g, 8.2 mmol), HOAT (3.7 g, 27.2 mmol) and DICI (4.3 mL, 27.5 mmol) in N-methylpyrrolidinone (50 mL). The reaction mixture was agitated at room temperature for 1 h, and then filtered. The resin was washed with dichloromethane and methanol, and dried under vacuum to afford resin-bound N-[2-chloro-4-[[[(3-hydroxyphenyl) methyl]amino]carbonyl]benzoyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([F:32])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:27]=[C:28]([C:7]2[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: CON(C)C(=O)c1ccc2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1ccc2cccnc2c1-c1cc(F)cc(F)c1
Temperature: 100 °C
Yield: 81.7 %

Procedure:
To a mixture of 7- {[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.15 g, 0.41 mmol) and (3,5-difluorophenyl)boronic acid (0.078 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0-80% EtOAc in Hexane) to give the desired product (110 mg, 81.4%). LCMS calculated for C18H15F2N2O2(M+H)+: m/z=329.1; found: 329.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][CH:5]=1.Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[NH:23][CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=2)[CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(F)nc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)nc1

Procedure:
A mixture of 6-fluoronicotinic acid methyl ester (1.0 g, 6.4 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester HCl (1.6 g, 6.4 mmol), and potassium carbonate (1.78 g, 12.9 mmol) were stirred in DMSO (10 mL) at 120° C. for 2 h, cooled, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[C:3]([NH:6][C:7]([NH2:9])=[S:8])([CH3:5])[CH3:4].[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=O>C(O)C>[BrH:11].[OH:1][CH:2]([CH3:10])[C:3]([NH:6][C:7]1[S:8][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[N:9]=1)([CH3:5])[CH3:4]
Reactant: CC(O)C(C)(C)NC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: Br
Product: CC(O)C(C)(C)Nc1nc(-c2ccc(C#N)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of N-(2-hydroxy-1,1-dimethylpropyl)thiourea (720 mg, 4.4 mmol), prepared in the previous step, and 2-bromo-4′-cyano-acetophenone (980 mg, 4.4 mmol) in 20 mL of ethanol was heated under nitrogen to dissolve all of the solids. The reaction was allowed to come to room temperature and then stirred at room temperature overnight. The solid was collected by filtration and dried under reduced pressure to give 4-{2-[(2-hydroxy-1,1-dimethylpropyl)amino]-1,3-thiazol-4-yl}benzonitrile hydrobromide (1.3157 g, 81%) as a white solid, mp 208-210° C.; MS (ES) m/z 286.0 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20]Br)[CH2:16][CH2:15]1)=[O:13]>CO.[OH-].[K+]>[CH:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][S:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:16][CH2:15]1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: O=CN1CCC(CBr)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCC1CCN(C=O)CC1
Reaction time: 20 h

Procedure:
To a solution of (A) (5.3 g, 0.03 mole) in methanol (10 ml), 5 N potassium hydroxide in methanol (5 ml) was added, followed by N-formyl-4-bromomethylpiperidine (5.2 g, 0.025 mole). The mixture was left at room temperature for 20 hours. After removal of the solvent in vacuo, the residue was diluted with ether (50 ml) and filtered. The filtrate was washed with two 5 ml portions of 2 N sodium hydroxide, followed by water and dried. The solvent was stripped in vacuo, and the residue was chromatographed on silica gel (100 g), eluting with ether to give (B) as a colourless oil.
Reaction SMILES: [CH3:1]C(C)CCCCCCC(OCCC1C=CC(O)=C(OC)C=1)=O.[C:24]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1)(=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C>>[CH3:1][CH:31]([CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([O:35][CH2:36][C:37]1[CH:45]=[CH:44][C:42]([OH:43])=[C:39]([O:40][CH3:41])[CH:38]=1)=[O:34]
Reactant: CCCCCCCCCC(=O)OCc1ccc(O)c(OC)c1
Reactant: COc1cc(CCOC(=O)CCCCCCC(C)C)ccc1O
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O

Procedure:
Using vanillyl alcohol (1.70 g, 11.0 mmol) instead of homovanillyl alcohol, and n-decanoic acid (1.72 g, 10 mmol) instead of 8-methylnonanoic acid in Example 1, similar reaction was performed. The residue was purified by PTLC to find that the yield of the obtained vanillyl decanoate was 1.33 g (4.31 mmol, 43.1%), and vanillyl decanoate was decomposed (i.e., unstabilized) by the contact with silica gel. In contrast, the isolation yield of homovanillyl 8-methylnonanoate obtained by similar operation was 93.2% as mentioned above, suggesting that homovanillyl 8-methylnonanoate is far stabler than vanillyl decanoate even upon contact with silica gel. In addition, since good isolation yields were obtained in Examples 2 to 23 where isolation and purification were similarly performed by PTLC, it is clear that the compound of the present invention is superior to capsinoids in the stability.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=O)[C:6](=O)[CH3:7])[CH3:2].Cl.[NH2:19][NH2:20].Cl.C([O-])(O)=O.[Na+]>C(O)C.O.O1CCOCC1>[CH2:1]([O:3][C:4]([C:5]1[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:19][NH:20][C:6]=1[CH3:7])=[O:17])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1ccncc1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 3-oxo-2-(pyridine-4-carbonyl)-butyric acid ethyl ester (1 g, 4.25 mmol) in 10 ml ethanol, were added a solution of hydrazine hydrochloride (291 mg, 4.25 mmol) in 4 ml water and, then 0.1 ml of 4M HCl in dioxane. The yellow solution was stirred 1 h at room temperature, poured on a saturated solution of NaHCO3 and extracted twice with EtOAc. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford the title compound as light yellow solid (815 mg, 83%). MS: 232.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH:28]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1OC

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3,4,5-trimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3,4,5-trimethoxybenzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 240-245° C. HPLC: TRet (Grad5-40)=22.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:20]([NH:19][N:16]1[C:17](=[O:18])[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:28])[N:3]=2)=[C:13]([OH:27])[C:14]2[S:26][CH:25]=[CH:24][C:15]1=2)[CH2:21][CH2:23][CH3:29]
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.075 g, 0.18 mmol) in tetrahydrofuran (4 mL) and methanol (0.029 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.17 Hz, 3 H) 1.39 (dd, J=15.08, 7.35 Hz, 2 H) 1.50 (m, 2 H) 3.02 (t, J=6.43 Hz, 2 H) 6.65 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.72 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.77 (t, J=7.72 Hz, 1 H) 7.92 (d, J=8.09 Hz, 1 H) 8.34 (d, J=5.15 Hz, 1 H) 14.21 (s, 1 H) 14.83 (s, 1 H). MS (ESI−)m/z 417 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43][CH2:44][CH:45]([OH:49])[CH2:46][CH2:47][CH3:48])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:49][CH:45]([CH2:44][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:46][CH2:47][CH3:48])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(O)CCN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCN1CCCCC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-piperidino-3-hexanol (43 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (76 mg, yield 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ1.23-1.28 (m, 3 H), 1.38-1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50-4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65-8.13 (series of m, total 12 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[C:9]([Cl:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)(C)(C)[CH3:2]>C(O)C.Cl>[CH2:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[C:9]([Cl:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2)[CH3:2]
Reactant: Cc1ccc2ccc(Cl)c(CC(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C)nc12
Temperature: 90 °C
Yield: 63.3 %

Procedure:
(7-Chloro-2-methyl-quinolin-8-yl)-acetic acid tert-butyl ester (650 mg, 2.23 mmol) was dissolved in ethanol (13 ml) saturated with HCl gas. The solution was heated to 90° C. for 10 minutes. After cooling, volatiles were removed in vacuo, and the residue was purified via flash chromatography (gradient of hexane:EtOAc 95:5 to 80:20) to afford the title compound (372 mg, 63%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=8.00 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H); 4.52 (s, 2H), 4.19 (q, J=7.3 Hz, 2H), 2.81 (s, 3H), 1.27 (t, J=7.3 Hz, 3H). MS (ES+): 264.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:34][C:32]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28](=[O:35])[NH:29]2)=[C:24]([N:23]=[CH:11][C@@:10]([OH:17])([C:13]([F:14])([F:16])[F:15])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:22])[C:4]=2[O:20][CH3:21])[CH2:18][CH3:19])[CH:33]=1
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 271 mg (0.51 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 90 mg (0.51 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.32 ml (1.02 mmol) of titanium tert-butoxide are reacted to give 7-fluoro-5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]-amino}quinolin-2(1H)-one. 320 mg of crude imine are cyclized in the same way as in Example 130 at −30° C. with 4.1 ml (4.1 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) yields 165 mg of desired product.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([OH:16])=O)[CH:8]=[CH:9][CH:10]=2.ClC(OCC(C)C)=O.[CH3:25][C:26]([O:28][CH2:29][C:30]1[CH2:49][S:48][C@@H:33]2[C@H:34]([NH:37][C:38]([C@H:40]([NH2:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:39])[C:35](=[O:36])[N:32]2[C:31]=1[C:50]([OH:52])=[O:51])=[O:27].S([O-])([O-])(=O)=O>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]1[C:11]2[C:6]3=[C:7]([CH2:12][CH2:13][N:5]3[CH:4]=[C:3]1[C:14]([NH:47][CH:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:38]([NH:37][CH:34]1[C:35](=[O:36])[N:32]3[CH:33]1[S:48][CH2:49][C:30]([CH2:29][O:28][C:26](=[O:27])[CH3:25])=[C:31]3[C:50]([OH:52])=[O:51])=[O:39])=[O:16])[CH:8]=[CH:9][CH:10]=2
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)CC2
Agent: CC(C)COC(=O)Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)c3cn4c5c(cccc5c3=O)CC4)c3ccccc3)C2SC1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
2.1 g of 6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid was added to 50 ml of anhydrous dimethylformamide and 1.66 ml of triethylamine was added to the mixture while ice-cooling and stirred for 15 minutes. Then, 1.6 ml of isobutyl chloroformate was added thereto dropwise and stirred for 45 minutes while ice-cooling. On the other hand, 4.5 g of cephaloglycine was suspended in 60 ml of anhydrous dimethylformamide and 2.8 ml of triethylamine and 1 g of anhydrous sulfate were added to the resulting mixture while ice-cooling followed by stirring the mixture for 30 minutes. Insoluble materials were removed by filtration and the filtrate was added at one time to the former reaction mixture and allowed to react for 2 hours while ice-cooling. After completion of the reaction, insoluble materials were removed by filtration and the filtrate was mixed with 10 ml of a 20% butanol solution of sodium 2-ethylhexanoate followed by the addition of 500 ml of diethyl ether to precipitate crystals. The crystals were collected by filtration and dissolved in 300 ml of water. The resulting solution was rendered acidic (pH=3) with dilute hydrochloric acid to precipitate solid materials, which were washed with water and dried under reduced pressure to obtain 4.0 g of 7-[2-(1,2-dihydro- 6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamido)-2-phenylacetamido]-3-(acetyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid as white amorphous crystals having a melting point of 245° to 248° C. (decomposition).
Reaction SMILES: N1C=C[C:4]([S:7]CC(Cl)=O)=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:35](=[O:36])[N:15]2[C:16]([C:32]([OH:34])=[O:33])=[C:17]([CH2:20][S:21][C:22]3[O:23][C:24]([CH2:27][S:28]([OH:31])(=[O:30])=[O:29])=[N:25][N:26]=3)[CH2:18][S:19][C@H:14]12.C([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])C>CN(C)C=O>[N:39]1[CH:40]=[CH:41][C:2]([CH2:3][C:4]([NH:12][CH:13]2[C:35](=[O:36])[N:15]3[C:16]([C:32]([OH:34])=[O:33])=[C:17]([CH2:20][S:21][C:22]4[O:23][C:24]([CH2:27][S:28]([OH:31])(=[O:29])=[O:30])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[S:7])=[CH:43][CH:42]=1
Reactant: O=C(Cl)CSc1ccncc1
Reactant: CCN(CC)CC
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CS(=O)(=O)O)o3)CS[C@H]12
Solvent: CN(C)C=O
Product: O=C(O)C1=C(CSc2nnc(CS(=O)(=O)O)o2)CS[C@@H]2C(NC(=S)Cc3ccncc3)C(=O)N12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(4-Pyridylthio)acetyl chloride (0.53 g, 2.8 mmol) is dropwise added to a mixture of 1.0 g of 7-amino-3-(5-sulfomethyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and 0.9 g (9.0 mmol) of triethylamine in 10 ml of dry dimethylformamide. The reaction mixture is stirred for 1.5 hour at -10°, the it is warmed to ambient temperature and stirred for 1 hour. The mixture is filtered and the filtrate is diluted with 200 ml of ether-petroleum ether. The precipitate is collected by filtration and purified to give the title compound.
Reaction SMILES: [CH3:1]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:30]=[C:31](C)[CH:32]=1.[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48]([N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][C:30]=3[CH3:1])[CH2:39][CH2:38]2)=[O:49])[C:45]=1[CH3:46]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(C)cc(N2CCNCC2)c1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C)c(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Methoxy-5-methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.06 (d, 1H), 6.56 (m, 2H), 5.38 (s, 2H), 3.69 (s, 3H), 3.62 (m, 4H), 2.92 (m, 2H), 2.84 (m, 2H), 2.20 (s, 3H) ppm; MS (ES) M+H expected=431.1, found=431.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:27])[N:3]=1.[Si](Cl)(C)(C)[CH3:29]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11])[C:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:29])=[O:24])=[CH:18][C:17]=2[OH:26])=[C:4]([CH3:27])[N:3]=1
Reactant: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: CCC[C@@H](CO)Nc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step (i) (120 mg) was dissolved in MeOH (10 mL) and TMS-Cl (0.205 ml) was added and stirred at rt overnight. The crude product was purified by RPHPLC to give the title compound as a white solid, 35 mg.