Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]=[C:24]=[O:25]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=2[Cl:15])=[O:25])=[C:7]([OH:14])[C:6]=1[S:3]([NH:2][CH3:1])(=[O:5])=[O:4]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CNS(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 48.7 %

Procedure:
A solution of N-methyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (70 mg, 0.29 mmol) and 2,3-dichlorophenylisocyanate (57 μL, 0.44 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 66 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), gave the desired product (60 mg, 49%, three steps). EI-MS (m/z) 422.3, 424.3, 426.3 (M−).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:20][CH2:21][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:5]3[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:29][CH:28]=2)=[O:26])[CH2:23][CH2:24]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 23.5 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (107 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2oc(C(=O)OC)cc2c1
Reaction time: 16 h

Procedure:
A mixture of methyl 5-hydroxybenzofuran-2-carboxylate (4.14 g), potassium carbonate (5.95 g) and allyl bromide (3.73 ml) in dry acetone (100 ml) was refluxed and stirred for 16 hours. The solvent was evaporated and the residue was partitioned between water and ether. The ether was washed with water, dried and evaporated to give methyl 5-(prop-2-enyloxy)benzofuran-2-carboxylate (4.7 g) as a solid, characterised by NMR and mass spectral data. This ester (3.74 g) in N-methylpyrrolidinone (30 ml) was refluxed under nitrogen for 2 hr, cooled, and partitioned between water and ethyl acetate. The organic phase was washed with water, dried and evaporated to give the title ester (3.5 g), mp 114°-119°.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH:3]=[O:4].CC1C2C(C)(C)C(C2)CC=1>>[CH3:1]/[C:2](=[CH:5]\[CH2:6][C@@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH2:3][OH:4]
Reactant: CC1=CC[C@@H](C/C=C(\C)C=O)C1(C)C
Agent: CC1=CCC2CC1C2(C)C
Product: CC1=CC[C@@H](C/C=C(\C)CO)C1(C)C
Yield: 80 %

Procedure:
(E)-(S)-2-Methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from 1R,5R)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) was hydrogenated in the same manner as in Example 1 to obtain 3.08 g (yield 80%) of the title compound. The chemical purity of the product was found to be 98% by GC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][Br:40])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)cc(Sc2ccccc2CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(OC)cc(Sc2ccccc2CBr)c1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
2-(3,5-Dimethoxyphenylthio)benzyl alcohol (7.9 g) was dissolved in methylene chloride (40 ml), then triphenylphosphine (11.2 g) and carbon tetrabromide (11.2 g) were added thereto, the mixture was stirred at room temperature for ten minutes, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1) to give 2-(3,5-dimethoxyphenylthio)-benzyl bromide (9.53 g, yield of 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:12](OCC)=O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:17][CH3:18].C([O-])([O-])=O.[K+].[K+].BrC[CH2:27][F:28].[OH-].[Na+]>CC(N(C)C)=O.C1COCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:27][F:28])[C:8]2=[O:11])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: CCOC(=O)C1Cc2cc(OC)c(Cl)cc2C1=O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1Cl)C(=O)C(CCF)C2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate (crude product from the preceding step, ˜141 mmol) in anhydrous dimethylacetamide (540 mL) was added K2CO3 (39 g, 282 mmol), KI (46.8 g, 282 mmol) and 1-bromo-2-fluoroethane (13.5 mL, 183 mmol) and the mixture was stirred and heated at 65° C. for 6 hours. The reaction mixture was diluted with THF (540 mL) and water (540 mL) and then cooled to 0° C. and treated with 5N aqueous NaOH (84 mL, 423 mmol). After 2 hours at 0° C., the reaction was quenched with 1N aqueous HCl (˜450 mL). Most of the THF was removed by rotary evaporation under reduced pressure and the aqueous residue was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered through a pad of silica gel and concentrated to give 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH3:14])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH2:7]([O:6][CH2:5][CH:4]([CH3:14])[CH2:3][OH:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)COCc1ccccc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: CC(CO)COCc1ccccc1
Yield: 90.5 %

Procedure:
Reduction of the rac.-methyl-3-benzyloxy-2-methylpropionate was carried out with sodium bis(2-methoxyethoxy)-aluminum hydride using the procedure described in Example 9. Distillation of the crude product afforded the rac. 3-benzyloxy-2-methyl-1-propanol in 90.5% yield as a colorless liquid, b.p. 94°-98° C. (0.1 mm Hg.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][NH2:11].C([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C>C(O)(=O)C>[Cl:8][C:6]1[C:5]([OH:9])=[CH:4][C:3]([N:10]2[C:15](=[O:14])[CH:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:11]2)=[C:2]([F:1])[CH:7]=1
Reactant: NNc1cc(O)c(Cl)cc1F
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CC(=O)O
Product: O=C1C2CCCCC2=NN1c1cc(O)c(Cl)cc1F
Yield: 85.9 %

Procedure:
A solution of 2-fluoro-4-chloro-5-hydroxyphenylhydrazine (8 g) and 2-ethoxycarbonylcyclohexanone (8 g) in acetic acid (30 ml) was heated under reflux for 4 hours. After cooling, the precipitated crystals were collected by filtration and washed with ether to give 11 g of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,3a,4,5,6,7-hexahydroindazol-3-one. m.p., 273°-275° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[Br:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:17]1[CH:16]=[CH:15][C:14]([S:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Clc1ccnc2ncccc12
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Product: Oc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.30 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (120 mg, 0.30 mmol) for 40 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (87 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 5.15 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 6.66 (d, J=8.83 Hz, 2H) 7.08-7.47 (m, 6H) 7.56 (d, J=7.72 Hz, 1H) 7.65 (m, 1H) 7.92 (dd, J=4.41 Hz, J=8.46 Hz, 1H) 8.18 (d, J=6.99 Hz, 1H) 9.14 (dd, J=8.83 Hz, 1H) 9.17 (dd, J=5.88 Hz, J=1.84 Hz, 1H) 9.80 (s, 1H) 11.16 (br s, 1H) 14.53 (br s, 1H); MS (ESI+) m/z 529, 531 (M+H−TFA)=; (ESI−) m/z 528, 530 (M−H−TFA)−.
Reaction SMILES: N[C@H](C([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=O)CC(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH2:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C[C@H](N)C(=O)NCCCCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NCCCCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 67 %

Procedure:
In 80 ml of the tetrahydrofuran were dissolved 1.00 g of DL-trans-benzylhydrogenepoxysuccinate, 1.70 g of N-L-leucyl-N'-benzyloxycarbonyl-1,7-diaminoheptane, 0.73 g of 1-hydroxybenzotriazole and 0.55 g of N-methylmorpholine. To the solution was slowly added 0.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride under ice-cooling with stirring. The mixture was stirred for 2 hours under ice-cooling and then for 2 hours at room temperature. The solution was concentrated under reduced pressure and admixed with 100 ml of ethyl acetate and 100 ml of water and the mixture was shaken vigorously. The ethyl acetate layer was separated and washed successively with a 10% aqueous hydrochloric acid solution, an aqueous saturated bicarbonate solution and an aqueous saturated sodium chloride solution and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel (chloroform:acetone=10:1) and recrystallized from ethyl acetate-n-hexane to give 1.50 g of N-[N-DL-3-trans-benzyloxycarboxyloxirane-2-carbonyl)-L-leucyl]-N'-benzyloxycarbonyl-1,7-diaminoheptane m.p. 134° C. Yield: 67%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[OH:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)\[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[C:29]1(/[C:22](=[N:21]/[O:20][CH2:19][C:18]2[CH:35]=[CH:36][C:15]([O:14][CH2:2][C:3]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[O:5][N:4]=3)=[CH:16][CH:17]=2)/[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClCc1cc(-c2ccccc2)on1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)on2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
A mixture of 3-(chloromethyl)-5-phenylisoxazole (340 mg), methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain methyl E-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyrate (472 mg, yield 63%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:3])[CH3:2].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:19][C:20]1[N:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)=[O:18])(=[O:15])=[O:14])(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CC(=O)OCCc1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CCOC(C)=O)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2.3 g of the sulfonyl isocyanate from Example 7 in 25 ml dry acetonitrile was added 1.2 g of 2-amino-4,6-dimethoxypyrimidine. The reaction mixture was warmed to 50° C. for 11/4 hour and then stirred at room temperature for 2 days. Filtration of the insoluble solids and washing with 1-chlorobutane followed by drying afforded 1.8 g of 2-[2-(acetyloxy)ethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide as a light yellow solid, m.p. 160°-162° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20](OCC1C=CC=CC=1)=O)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:31]#CBr.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd].CCOCC>[C:1]([O:5][C:6](=[O:30])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:20]#[N:31])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 66.9 %

Procedure:
To a solution of 6.1 g (14.4 mmol) N5-((Benzyloxy)carbonyl)-N2-(tert-butoxycarbonyl)-L-ornithine tert-butyl ester in 100 mL ethyl acetate was added 1.0 g 10% palladium on carbon. The suspension was shaken at 22° C. under 50 psi H2 for 45 minutes in a 500 mL Parr bottle. The catalyst was removed by filtration through celite. The resulting solution was concentrated to yield a crude oil. The oil was dissolved into 50 mL of diethyl ether and added dropwise to a 0° C. stirred solution of 1.52 g (14.3 mmol) of cyanogen bromide in 30 mL ether. The solution was stirred for 2 h, poured into aqueous sodium bicarbonate, and extracted with ether. The ether solution was dried (magnesium sulfate), concentrated, and purified by silica gel chromatography (100 g, 130-400 mesh silica gel). Elution with a gradient of ethyl acetate in hexanes (30%-60%) gave 3.0 g (67% yield) N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:30][C:31]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[S:33][C:32]=1[C:40](O)=[O:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:40]([C:32]4[S:33][C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:31]=4[OH:30])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1sc(C(F)(F)F)cc1O
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2sc(C(F)(F)F)cc2O)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 3-hydroxy-5-(trifluoromethyl)thiophene-2-carboxylic acid (32 mg, 0.15 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][C:6]=1[O:15][CH3:16])([CH3:3])[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=[C:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:7][C:6]=1[O:15][CH3:16])([CH3:3])[CH3:2]
Reactant: COc1cc(C=CC=O)ccc1OC(C)C
Reactant: O=C1CSC(=O)N1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)ccc1OC(C)C
Yield: 61 %

Procedure:
According to the same manner as that described in Example 1, 4-isopropoxy-3-methoxycinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-(4-isopropoxy-3-methoxycinnamylidene)-2,4-thiazolidinedione (yield: 61%). This product was recrystallized from ethyl acetate-hexane. Yellow prisms, mp: 230-231° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]CC)=O.[OH-].[Na+]>C(O)C.CN(C)C=O>[CH3:1][S:2][C:3]1[C:4]2[O:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6](=[O:8])[C:5]=2[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCCOc1c(SC)cccc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2c(SC)cccc2C1=O
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 79.3 %

Procedure:
To a solution of ethyl 3-methylthio-2-(3-ethoxycarbonylpropoxy)benzoate (3.83 g) in a mixture of ethanol (34 μl) and N,N-dimethylformamide (40 ml) was added 60% sodium hydroxide (1.03 mg) at 5° C. After the mixture was allowed to stir at room temperature for 15.5 hours, it was poured into ice-water and extracted with ethyl acetate (x 3). The combined extracts were washed with water (x 2) and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (20:1) to give ethyl 9-methylthio-5-oxo-2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate (2.61 g, colorless crystals).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1.[CH3:17][N:18]=[C:19]=[S:20]>CO>[CH3:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1
Reactant: NC1=NN(c2ccc3ccccc3c2)CC1
Reactant: CN=C=S
Solvent: CO
Product: CNC(=S)NC1=NN(c2ccc3ccccc3c2)CC1

Procedure:
3-Amino-1-(2-naphthyl)-2-pyrazoline (1 g) and methylisothiocyanate (1.4 g) were heated at 130° for 7 hours. The cooled reaction mixture was diluted with methanol and the solid product collected by filtration.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.C(N(CC)CC)C.CN(C)C1C=CC=CC=1.[C:37]1([CH2:43][C:44](Cl)=[S:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:44](=[S:45])[CH2:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:5]2[S:4]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: S=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=S)Cc3ccccc3)[C@H]2S1
Temperature: -15 °C
Yield: 90.2 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.0 g) was suspended in dried dichloromethane (50 ml) and then dissolved by adding triethylamine (0.72 g) and dimethylaniline (1.9 g) under cooling at -15° C. To a mixture was dropwise added a solution of phenylthioacetyl chloride (2.2 g) in dried dichloromethane (10 ml) under stirring, and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water and then dried. After the solvent was distilled off, ether was added to the residue, after which the precipitated crystals were collected by filtration and dried to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylthioacetamido)-3-cephem-4-carboxylate (3.4 g), mp 140° to 142° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:22][C:23](O)=O)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:9]=2)[C:4]1=[O:21])[CH3:2].[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C=O>[CH2:1]([C:3]1([CH2:22][C:23]#[N:28])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:9]=2)[C:4]1=[O:21])[CH3:2]
Reactant: CCC1(CC(=O)O)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CC#N)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (3-ethyl-1-(2-((1-methyl-H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidin-3-yl)acetic acid (100 mg) obtained in Example 30 and 1-hydroxybenzotriazole ammonium salt (88 mg) in N,N-dimethylformamide (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (110 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue and pyridine (70 mg) in tetrahydrofuran (5 mL) was added trifluoroacetic anhydride (0.12 mL), and the mixture was stirred at 70° C. for 30 min. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (17 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>C1COCC1>[C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])[CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)c3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-naphthoyl chloride: ESMS m/e: 444.2 (M+H)+.