Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([O:32][CH2:33]C2C=CC=CC=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrC[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:3]1([CH:9]([O:32][CH2:33][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]4=[O:31])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCc3ccccc3)c3ccccc3)cc2)CC1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2CN1C1CCN(c2ccc(C(OCCCc3ccccc3)c3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of sodium hydride (44 mg, 1.1 mmol) in DMF (5 mL) at 0° C. was added dropwise a solution of Example 293 Part A compound (400 mg, 1.0 mmol) in DMF (1 mL). The reaction was stirred at 0° C. for 30 min. 1-Bromo-3-phenylpropane (219 mg, 1.1 mmol) was added dropwise to the reaction at 0° C. The reaction was stirred at 0° C. for 1 h then warmed to RT overnight. The reaction was quenched with saturated ammonium chloride solution (2 mL). Ethyl acetate (100 mL) was added to the reaction, and the organic layer was washed with water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 50% ethyl acetate in hexane. Pure fractions were combined and evaporated to give title compound (335 mg, 65%) as a white solid.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH2:16][CH2:17][CH3:18])=[N:14][CH:13]=[N:12]2)=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[ClH:1].[CH2:16]([C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH2:2])=[CH:10][CH:9]=2)[N:12]=[CH:13][N:14]=1)[CH2:17][CH3:18]
Reactant: CCCc1ncnn1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCc1ncnn1-c1ccc(N)cc1
Yield: 91 %

Procedure:
A mixture of 38.3 parts of 1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole monohydrochloride and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and neutralized with sodium hydrogen carbonate. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 35 parts (91%) of 4-(5-propyl-1H-1,2,4-triazol-1-yl)benzenamine dihydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[CH3:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[NH:1]([C:2]1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[CH3:15])[C:16]([CH3:17])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2ccccc2c2c(N)cnn12
Product: CC(=O)Nc1cnn2c(C)nc3ccccc3c12
Yield: 89 %

Procedure:
1-Amino-5-methylpyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 5 to give 1-acetamino-5-methylpyrazolo[1,5-c]quinazoline. M.p.: 258°-260° C. Yield: 89%.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][N:27]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
According to Scheme 4 Step 1: Isobutyryl chloride (1.24 mmol, 0.13 mL) and Et3N (2.48 mmol, 0.35 mL) were added to a solution of 1-(2-chloro-4-nitrophenyl)piperazine (0.83 mmol, 200 mg) in DCM (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford 1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.83 mmol, 261 mg, 100%). The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][OH:7])=[O:5].[CH3:12][O:13][C:14](OC)(OC)OC>CO>[CH3:12][O:13][C:14]1[N:6]([OH:7])[C:4](=[O:5])[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)NO
Reactant: COC(OC)(OC)OC
Solvent: CO
Product: COc1nc2ccccc2c(=O)n1O
Temperature: 5 °C
Yield: 59 %

Procedure:
A mixture of 22.8 g (0.15 mol) of o-aminobenzohydroxamic acid, 50 ml of methanol and 27.2 g (0.2 mol) of orthocarbonic acid tetramethyl ester was boiled under reflux for 2 hours and was then cooled to 5° C. The product which had crystallized out was filtered off with suction. 17 g (60% of theory) of 2-methoxy-3-hydroxy-3,4-dihyro-4-oxo-quinazoline were obtained in the form of colorless crystals having a melting point of 220° C.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:19])[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:6].[C:20](OCC)(=[O:26])[C:21](OCC)=[O:22]>C(O)C>[CH2:12]([N:11]1[C:21](=[O:22])[C:20](=[O:26])[CH:9]([C:8]([O:7][CH2:5][CH3:6])=[O:19])[CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCNCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
21% Sodium ethoxide in ethanol (21:79, sodium ethoxide:ethanol, 56.0 mL) was added dropwise to a mixture of ethyl-beta-benzylaminopropionate (22.178 g, 0.10700 mol) and diethyl oxalate (15.0 mL, 0.110 mol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and then water (about 200 mL) was added. The mixture was stirred for 5 min and then 1M HCl was added until pH 1. The mixture was vacuum filtered. The solids were collected and dried in vacuo overnight, and then crystallized from ethanol to give the desired product (20.946 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[CH2:35][C:36]([OH:38])=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:39])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[CH2:35][C:36]([OH:38])=[O:37])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CC(=O)O)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.8 %

Procedure:
A suspension of (S)-9-chloro-5-[p-tert-butoxycarbonylaminomethyl-o-(carboxymethyl)phenylcarbamoylmethyl]-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.499 g) in 2N hydrogen chloride in 1,4-dioxane (30 mL) was stirred overnight at room temperature and diluted with diethyl ether. The precipitates were collected and recrystallized from water to give 1.247 g of the title compound (79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6](/[CH:19]=[CH:20]/[C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].CO>C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(/C=C/c4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 55 °C

Procedure:
To a solution of 65.0 mg (0.190 mmol) of ethyl (E)4-[2-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)- 2-naphthalenyl)ethenyl)-benzoate (Compound 44) in 4.0 ml of THF was added 30.0 mg of LiOH (0.909 mmol, 1.0 ml of a 1.1M solution) and 1.0 ml of MeOH. The solution was heated to 55° C. for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in H2O and extracted with hexanes. The aqueous layer was acidified to pH 1 with 10% HCl, and extracted with Et2O. The combined organic layers were washed with saturated aqueous NaCl, diluted with EtOAc to give a clear solution, and dried over Na2SO4. The solvents were removed under reduced pressure to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.86 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 7.58 (1H, dd, J=1.7, 8.1 Hz), 7.41 (1H, d, J=8.1 Hz), 7.28 (1H, d, J=16.5 Hz), 7.23 (4H, s), 7.08 (1H, d, J=1.7 Hz), 7.07 (1H, d, J=16.5 Hz), 5.97 (1H, t, J=4.6 Hz), 2.35 (3H, s), 2.31 (2H, d, J=4.6 Hz), 1.29 (6H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18]Cl)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.Cl>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:12]([NH:15][CH3:16])=[N:13][NH:14][C:8]=2[N:7]([CH2:17][CH2:18][NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCCl)c1=O
Reactant: NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(CCNCc2ccccc2)c1=O

Procedure:
A mixture of 5-butyl-7-(2-chloroethyl)-3-methylaminopyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.6 g, 2 mM) and benzylamine (0.66 ml, 6 mM) in dioxane (20 ml) was refluxed for 20 hours. The reaction solution was concentrated to dryness under reduced pressure to give a syrup, which was poured onto ice-water to give colorless crystals. The crystls were dissolved in 1N-HCl and insoluble material was filtered off, followed by addition of 1N-ammonia water to give crystals. Recrystallization from DMF/methanol/water afforded colorless needles (0.32 g, 43%), m.p. 198°-200° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O.Cl>CO>[CH3:23][O:22][C:20]1[CH:19]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:15]=[C:14]([O:13][CH3:12])[CH:21]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Solvent: CO
Product: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3,5-dimethoxybenzaldehyde 1.23 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.42 g.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([OH:25])=O)=[CH:16]2.[NH2:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[CH:28]([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([NH:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:25])=[CH:16]2
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMAP (257 mg, 2.08 mmol) and EDAC (427 mg, 2.23 mmol) were added as solids to a solution of 5-fluoro-1-methylindole-2-carboxylic acid (359 mg, 86 mmol in 3 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. N-(Valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (579 mg, 1.86 mmol) in DMF (3 mL) was added and the resulting solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid (0.827 mg). TLC: (methanol/methylene chloride, 1:9): Rf =0.52.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[O:9][CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:7]=2[CH:6]=1)=O.[OH-].[NH4+:21]>>[C:15]([NH:14][CH2:13][CH2:12][C:11]1[C:7]2[CH:6]=[C:5]([C:3]([NH2:21])=[O:2])[CH:19]=[CH:18][C:8]=2[O:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc2occ(CCNC(C)=O)c2c1
Agent: [OH-]
Product: CC(=O)NCCc1coc2ccc(C(N)=O)cc12
Temperature: 60 °C

Procedure:
The ester (0.1 mol) obtained in Example 62, dissolved in an aqueous 20% ammonium hydroxide solution (50 ml), is heated for 5 hours at 60° C. The reaction mixture is cooled and is then evaporated to dryness. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]([NH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) and 3-benzyloxycarbonylamino-3-methylbutanoic acid (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.38 (s,3H), 1.39 (s,3H), 1.82 (m,1H), 2.52 (s,2H), 2.5-3.0 (m,3H), 4.51 (m,1H), 5.07 (br s,2H), 5.58 (br s,1H), 6.68 (d,7 Hz,1H), 6.96 (d,8 Hz,1H), 7.1-7.4 (m,8H), 7.62 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:16][C:17]1[CH:18]=[C:19]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C:13]1[N:14]=[C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([S:16][C:17]4[CH:18]=[C:19]([C:23]5([C:29]#[N:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:20]=[CH:21][CH:22]=4)[CH:3]=3)[N:8]2[CH:12]=1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Reactant: Cc1cn2c(ccc3cc(I)ccc32)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cn2c(ccc3cc(Sc4cccc(C5(C#N)CCOCC5)c4)ccc32)n1
Temperature: 80 °C

Procedure:
1m (30 mg, 0.13 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (1n, 35 mg, 0.11 mmol) were dissolved in 1,4-dioxane (4 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.04 mL, 0.22 mmol), Pd2dba3 (catalytic), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (catalytic) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 80° C. overnight, then cooled to room temperature, concentrated, and purified by preparative HPLC to give the desired product, 1o.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:20]([N:23]([CH3:25])[CH3:24])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2([OH:17])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[CH:8][C:9]=1[N:10]=[CH:20][N:23]([CH3:25])[CH3:24])=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCOCC2)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(C2(O)CCOCC2)cc1N=CN(C)C

Procedure:
3-Amino-5-(4-hydroxytetrahydropyran-4-yl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 312.39 (C14H20N2O4S) was obtained in this way; MS (ESI): 313 (+H+).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: Oc1ccccc1
Reactant: C=CCC1C(=O)C=CC1(C)O
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(Oc2ccccc2)CC1=O
Reaction time: 4 h

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), phenol (6 parts) and triethylamine (1/5 part) were charged and stirred at a temperature of 50° to 80° C. for 4 hours. The reaction mixture was treated in the same manner as in Example 25 to obtain 2-allyl-3-methyl-4-phenoxy-2-cyclopentenone. Yield, 95%. nD20 1.5539.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OCC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
The product of Example 57, 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (3.8 g, 8.1 mmol), was dissolved in dichloromethane (3 mL). To this solution was added trifluoroacetic acid (3 mL) and the reaction was allowed to stir overnight. The reaction was then concentrated in vacuo and the residue triturated with dichloromethane to provide 2.64 g (88%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][NH:4][N:3]=1.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[CH:5][N:4]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.4 g, 0.0356 mol), 1,1′,1″-(chloromethanetriyl)tribenzene (9.9 g, 0.0356 mol) and triethylamine (7.2 g, 0.0712 mol) were suspended in N,N-dimethylformamide (70.0 mL) and stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of water (30.0 mL) and extracted with ethyl acetate (3×30.0 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (40.0 mL), dried over sodium sulfate and concentrated in vacuo. This crude residue was initially purified via column chromatography eluting with petroleum ether:ethyl acetate (10:1, by volume) and then purified by preparative HPLC to yield title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:44]([O:47][CH:48](Br)[CH3:49])(=[O:46])[CH3:45].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][CH:36]=[CH2:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:28]([O:30][CH:48]([O:47][C:44](=[O:46])[CH3:45])[CH3:49])=[O:29])=[C:15]([CH2:18][S:19]/[CH:20]=[CH:21]\[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylic acid (syn isomer) in N,N-dimethylformamide (30 ml) was added cesium carbonate (0.47 g). The mixture was stirred for 30 minutes at 25° C., and 1-bromoethyl acetate (1.35 g) was added dropwise thereto at 0°-3° C. After stirring for 1 hour, the reaction mixture was poured into ethyl acetate (200 ml) and the insoluble material was filtered off. The filtrate was washed with water (200 ml×2), an aqueous solution of sodium bicarbonate (100 ml×1) and a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was pulverized with diisopropyl ether to give 1-acetoxyethyl 7-[2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (0.63 g).