Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h
Yield: 79.1 %

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (1.06 g, 6.26 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (1.00 g, 7.51 mmol) in DMSO (25 mL). K2CO3 (1.73 g, 12.52 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. Then the reaction mixture was cool down to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc (4:6) and then with EtOAc, 100% to get the title compound (1.40 g). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.16 (d, J=9 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=O.[ClH:22].C(O)(=O)C>O1CCCC1.B>[ClH:22].[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:4]([NH:3][CH3:1])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=CNC(Cc1ccccc1[N+](=O)[O-])c1ccc(F)cc1
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(Cc1ccccc1[N+](=O)[O-])c1ccc(F)cc1

Procedure:
To a cooled mixture of 31.1 g of N-formyl-α-(4-fluorophenyl)-2-nitrophenethylamine in 500 ml of tetrahydrofuran, 441 ml of 0.98 M borane in tetrahydrofuran is added dropwise. The mixture is allowed to stand over the weekend. The mixture is cooled and 100 ml of 5% hydrochloric acid and 20 ml of glacial acetic acid are added cautiously. The solvent is evaporated in vacuum and the residue treated with 10% sodium hydroxide solution. The free amine is extracted with ether and dried over anhydrous sodium sulfate and filtered. Ethereal hydrogen chloride is added dropwise to the filtrate and the product precipitates as the hydrochloride salt. Recrystallization from ethanol gives crystals, mp 241°-243° C. of α-(4-flurophenyl)-N-methyl-2-nitrophenethylamine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][O:13][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](O)CCOCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
In toluene (100 ml) were dissolved (S)-4-benzyloxy-1,2-butanediol (25.8 g, 0.132 mol), triethylamine (20.2 ml, 0.145 mol) and 4-N,N-dimethylaminopyridine (DMAP) (0.80 g, 6.58 mmol). After cooling in ice bath, trityl chloride (36.69 g, 0.1316 mol) was added to the solution and the mixture was stirred at room temperature for 10 hours. The mixture was condensed in vacuo, diluted with ethyl acetate, washed with water and then saturated brine, dried on sodium sulfate, filtered and condensed in vacuo to give (S)-4-benzyloxy-1-trityloxy-2-butanol quantitatively (55.89, yield 100%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CCOC(C)=O.CN(C=O)C>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:20](=[O:22])[NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 966.9 %

Procedure:
A reaction mixture of BOC-L-4-nitrophenylalanine (4.65 g, 1.5 mmol), tert-butylamine (2.19 g, 30 mmol), DMF (10 mL), HBTU (5.69 g, 15 mmol), and diisopropylethylamine (2.48 g, 22 mmol) was stirred for 2 hours. After the reaction was finished, the reaction mixture was added EtOAc (75 mL), and the EtOAc solution was washed with NaHCO3 (100 mL, 4 times), dried over NaHCO3, and concentrated to dryness. The crude reaction mixture was further purified by column chromatography (SiO2, EtOAc/hexane 1:1) to yield the title compound (5.3 g), mp=158-159° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:15])[NH:5][C:4]=2[CH:3]=1.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:15])[N:5]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)[nH]c1cccc(F)c12
Reactant: BrCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c3c(F)cccc3n(CC3CO3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2,5-difluoro-9H-carbazole (0.530 g, 2.6 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.207 g, 3.1 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.432 mL, 5.2 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.59 g, 87%). 1H NMR (300 MHz, CDCl3) δ 8.13 (dd, 1H, J=8.7, 5.7 Hz), 7.38 (td, 1H, J=8.1, 5.4 Hz), 7.23 (d, 1H, J=8.4 Hz), 7.15 (dd, 1H, J=9.6, 2.1 Hz), 7.03 (ddd, 1H, J=9.6, 9.0, 2.4 Hz), 6.95 (ddd, 1H, J=9.9, 8.1, 0.6 Hz), 4.64 (dd, 1H, J=15.9, 3.0 Hz), 4.31 (dd, 1H, J=15.9, 5.1 Hz), 3.36 (m, 1H), 2.85 (t, 1H, J=4.5 Hz), 2.57 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:15][C:3]1[C:2]([N:1]2[C:19](=[O:20])[C:18]3[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=3[C:16]2=[O:21])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 18.9 %

Procedure:
5-Amino-6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolone (0.43 g) and 3,4,5,6-tetrahydrophthalic anhydride (0.32 g) were suspended in acetic acid (5 ml), and the resultant suspension was heated under reflux for 5 hours. After being allowed to cool, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:4) to give 2-[6-fluoro-3-(2-propynyl)-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.13 g). m.p., 193°-195° C. Recrystallization from 2-propanol gave the purified product. m.p., 198°-199° C.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([CH:27]([CH3:29])[CH3:28])=[N:25][N:26]=3)[CH:23]=2)C=CC=CC=1.[CH2:31]([NH:33][CH3:34])[CH3:32]>CS(C)=O>[CH2:31]([N:33]([CH3:34])[C:8]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:27]([CH3:28])[CH3:29])=[N:25][N:26]=2)[CH:23]=1)=[O:7])[CH3:32]
Reactant: CCNC
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CNC(=O)Oc3ccccc3)cn12
Solvent: CS(C)=O
Product: CCN(C)C(=O)NCc1ccccc1Sc1ccc2nnc(C(C)C)n2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of [2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzyl]-carbamic acid phenyl ester (42 mg, 0.10 mmol) in DMSO (200 μL) was added ethylmethylamine (6.0 μL, 0.105 mmol). The reaction was stirred at ambient temperature for 30 minutes, then quenched with water. The reaction mixture was extracted with organics, the organics combined, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated with 1:1 hexane:diethyl ether to give the title compound (37 mg, 96%). MS (M+1)=384.4.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:14]([O:21][CH2:22]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOCCOC>[CH2:14]([O:21][CH2:22][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COC(=O)C(=O)c1cccn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
Methyl pyrrol-2-ylglyoxylate (306 mg) in diglyme was treated with sodium hydride (63mg) and stirred at room temperature for 3 hr. Benzyloxymethyl chloride (376mg) was added and the mixture stirred at room temperature for a further 3 hr. The suspension was filtered and the filtrate evaporated. The residue, in ether, was washed with sodium bicarbonate solution, water and dried. Evaporation gave the crude product as a brown oil (530mg). Purification by preparative thin-layer chromatography gave the title compound as a colourless oil (250 mg,46%); τ values (DMSO-d6) include 6.10 (--CH3), 4.20 (>N-CH2 --), 5.47 (--OCH2 --), 2.70 (--Ph).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:7])[CH3:6])[CH3:2].CCN(CC)CC.[SiH](CC)(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)N(N)C(=O)c1cc(C)cc(C)c1
Yield: 160.7 %

Procedure:
Into a flask containing 1.5 g (0.0036 mol, 80% pure) of 2-[N′-benzyloxycarbonyl-N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester, was added 20 mL of dry CH2Cl2, 1.5 mL of Et3N, and 1.27 g (0.010 mol) of Et3SiH. While stirring, small portions of a total of 0.010 g of Pd(OAc)2 was added and the reaction was stirred for 2 hours at room temperature. To the reaction mixture was added 100 mL of CH2Cl2 and some MgSO4 to aid in the filtration/removal of the Pd product. The CH2Cl2 solution was shaken with saturated NH4Cl, CH2Cl2 dried, and evaporated to yield 1.61 g of 2-[N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester. The product was purified by chromatography, elution with 21-24% ethyl acetate in hexane. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.045 (s 2H), 7.0 (s 1H), 4.4 (s, 2H), 2.324 (s 6H), 2.236 (s 3H), 1.487 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[C:12]([CH2:20][CH3:21])=[N:13][C:14]([C:17](=O)[CH3:18])=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1[CH:32]=[CH:31][C:27]([CH2:28][O:29][NH2:30])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34].[C:37](O)(=O)[CH3:38]>CO>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[C:12]([CH2:20][CH3:21])=[N:13][C:14]([C:17](=[N:30][O:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH:38]3[CH2:37][CH2:15][CH2:16][CH2:11][CH2:10]3)=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[CH3:18])=[CH:15][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NOCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCc1nc(C(C)=O)ccc1CNCCC(=O)OC(C)(C)C
Reactant: CC(=O)O
Solvent: CO
Product: CCc1nc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CNCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-[(6-acetyl-2-ethyl-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentration, the residue is purified by column chromatography to give 3-({6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionic acid tert-butyl ester. MS: (ES+) 562.3 (M+1)+. The tert-butyl group is subsequently removed by treatment with TFA/DCM (1/1) at room temperature. The final compound 3-({6-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-pyridin-3-ylmethyl}-amino)-propionic acid is purified by preparative LCMS. 1H NMR (400 MHz, CD3OD) δ 1.30-1.62 (m, 8H), 1.72-1.91 (m, 5H), 2.36 (s, 3H), 2.78 (t, 2H), 2.94 (m, 3H), 3.37 (t, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 7.51-7.80 (m, 5H). MS: (ES+): 506.3 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][C@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:13][C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: C[C@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN2C(=O)OC[C@@H]2C)cc1
Yield: 80.9 %

Procedure:
Using methyl 4-bromomethylbenzoate (500 mg) and (S)-4-methyloxazolidin-2-one (243 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (440 mg) was obtained.
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])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[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:34]([NH:51][C@H:49]([C:46]2[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (33 mg, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29]COC)=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.Cl.O1CCOCC1>O1CCOCC1.CO.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(2-methoxy-4-methoxymethoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-1, 2.73 g, 5.52 mmol) was dissolved in a mixed solution of 1,4-dioxane (25 mL) and methanol (5 mL), and 4N hydrochloride/1,4-dioxane solution (7.0 mL, 28 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 1 hour, the mixture was diluted with ethyl acetate (130 mL). The mixture was washed with aqueous sodium hydrogen carbonate solution (130 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure to give the titled reference compound (2.41 g) as a pale yellow solid. (Yield 97%)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[C:24]([F:25])=[CH:23][N:22]=[CH:21][C:20]=1[F:26]>C(O)C>[F:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Fc1cncc(F)c1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2c(F)cncc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (227 mg, 1.6 mmol) was dissolved in absolute ethanol (20 mL), then triethylamine (335 μL, 2.4 mmol) and 4-(bromomethyl)-3,5-difluoropyridine (350 mg, 1.7 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was removed by evaporation. The residue was triturated in methanol, filtered, washed with water plus diethyl ether, and then dried in vacuo to afford to 2-{[(3,5-difluoropyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (179 mg, 42% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.45 (s, 2H), 6.01 (bs, 1H), 8.49 (s, 2H); LRMS (ES+) m/z 270 (100%, M+1).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3](C(OC)=O)[CH2:2]1.C(=O)([O-])[O-:19].[K+].[K+].Cl.Cl[CH2:26][C:27]1[N:28]([CH3:34])[C:29](=[N:32][CH3:33])[S:30][CH:31]=1>CN(C=O)C>[CH3:34][N:28]1[C:27]([CH2:26][N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:2][C:3]2=[O:19])=[CH:31][S:30]/[C:29]/1=[N:32]\[CH3:33]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CN=c1scc(CCl)n1C
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: C/N=c1\scc(CN2CCN(C(=O)OC(C)(C)C)CC2=O)n1C
Yield: 57.4 %

Procedure:
1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate (1.5 g) was dissolved in DMF (50 mL). Potassium carbonate (1.7 g) and N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine hydrochloride (1.4 g) were added thereto, and the mixture was mixed at 80° C. overnight. The solvent was distilled off, the residue was poured into water, extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl 4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate (1.2 g) as a pale brown oily matter. The resulting oily matter was dissolved in trifluoroacetic acid (10 mL) and mixed at room temperature for 1 hour. The mixture was dissolved in dichloromethane (50 mL), and triethylamine (0.87 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (0.97 g), HOBt (0.53 g) and WSC (0.65 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (1.8 g) as a white powder.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:15]([NH:16][C:17](=[O:24])[CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:14](=[O:25])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12].C(C(CCCC)C([O-])=O)C.[K+:36]>C(OCC)(=O)C.C(O)CC>[OH2:2].[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:15]([NH:16][C:17](=[O:24])[CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:14](=[O:25])[N:9]2[C:10]=1[C:11]([O-:13])=[O:12].[K+:36]
Reactant: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CON=CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Product: O
Reaction time: 15 h
Yield: 181.3 %

Procedure:
To a solution of 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (10.1 g) in ethyl acetate (50 ml) is added a solution of potassium 2-ethylhexanoate (4.5 g) in propanol (8.9 ml), and the mixture is kept in a refrigerator for 15 hours. The crystals formed are collected by filtration, washed with ethyl acetate, and recrystallized from a mixture of methanol and ether to give potassium 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylate monohydrate (10.5 g). m.p. 206°-209° C. Yield: 91%.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)=[O:29])[N:22]=[N:21]2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>ClCCl.C(OCC)(=O)C>[CH2:43]([NH:50][C:5]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH2:25][CH2:26][CH3:27])=[C:23]([C:28]([NH:30][CH:31]3[CH2:32][CH2:33]3)=[O:29])[N:22]=[N:21]2)=[CH:16][CH:15]=1)=[O:11])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)NCc2ccccc2)cc1
Yield: 52 %

Procedure:
To a solution of triphosgene (0.08 g) in dichloromethane (7 ml) was added dropwise a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.21 g) obtained in Example 1d) and N,N-diisopropylethylamine (0.13 ml) in dichloromethane (3 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. A solution of benzylamine (0.12 ml) and N,N-diisopropylethylamine (0.13 ml) in dichloromethane (3 ml) was added. The mixture was stirred at room temperature for 20 hr and diluted with ethyl acetate. The ethyl acetate solution was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate). The resultant product was recrystallized from diethyl ether/methanol to give the title compound as a colorless powder (0.16 g, 52%).