Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[N:26]=3)[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[N:20]=2)[CH2:10]1.[CH3:35][O:36][C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:38].CCN=C=NCCCN(C)C.C(N(CC)CC)C.CN1C=CN=C1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:17]2[C:18]3[N:19]([CH:21]=[CH:22][N:23]=3)[N:20]=[C:15]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:43]([C:42]4[CH:46]=[CH:47][C:39]([C:37]([O:36][CH3:35])=[O:38])=[CH:40][CH:41]=4)=[O:44])[CH2:10]3)[CH:16]=2)=[N:26][C:27]=1[O:33][CH3:34]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(Nc2cc(N3CCCC(N)C3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCCN(c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
A mixture of 6-(3-aminopiperidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine trifluoroacetate (350 mg, 0.94 mmol), 4-(methoxycarbonyl)benzoic acid (171 mg, 0.94 mmol), EDCI (725 mg, 3.79 mmol), triethylamine (288 mg, 2.84 mmol) and 1-methyl-1H-imidazole (311 mg, 3.79 mmol) in dichloromethane (15 mL) was stirred at room temperature for 16 h. The residue was concentrated in vacuo then purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoate (50 mg, 10%) as a white solid. LC-MS: 532 [M+1]+, tR=1.58 min.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][OH:6])=[CH2:3].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(N(CC)CC)C>[CH:5]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])=[CH:4][C:2](=[CH2:1])[CH3:3]
Reactant: C=C(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C=COS(C)(=O)=O

Procedure:
An example of the method for synthesizing Compound (1) includes a method described below in Production Examples 1 and 2. In such a method, first, isoprenol is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine to obtain methanesulfonic acid isoprenyl ester. Next, if needed, the obtained product is isolated and purified by a conventional method, and the obtained methanesulfonic acid isoprenyl ester is reacted with a malonic acid dialkyl ester in the presence of a base such as sodium ethoxide. As needed, a neutralization step is carried out using an acid to obtain Compound (1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[NH:15]1[CH2:20][CH:19]=[C:18]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:22]2=[O:30])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[O:14]=[C:6]1[N:5]([C:4]2[CH2:3][CH2:2][N:15]([CH2:16][CH2:17][CH2:18][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:20][CH:19]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: O=c1[nH]c2ccccc2n1C1=CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCCN1CC=C(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.15 parts of 1,3-dihydro-1-(1,2,3,6-tetrahydro-4-pyridinyl)-2H-benzimidazol-2-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours. After cooling to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol is eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of N,N-dimethylformamide and water, yielding 2.5 parts (64.5%) of 1-{3-[3,6-dihydro-4-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-1-(2H)-pyridinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 206.6° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C@H:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1.ClOC(C)(C)C.N>O1CCCC1.C(N(CC)CC)C>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@H:4]([NH:21][C:22](=[O:28])[N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:3]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3[C@@H](CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Under argon, 382 mg (1 mmol) of 3-(2,3β-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is dissolved in 30 ml of absolute, freshly distilled tetrahydrofuran in the presence of 0.5 ml of triethylamine and cooled to -40° C. At this temperature, 0.16 ml (1.34 mmol) of tert-butyl hypochlorite, dissolved in 10 ml of absolute, freshly distilled tetrahydrofuran, is added dropwise thereto. After 30 minutes of agitation at -40° C., the batch is stirred into 50 ml of ice and adjusted to be alkaline with 25% strength ammonia solution. Extraction is performed with methylene chloride. The combined organic phases are dried over magnesium sulfate and concentrated. The crude product is chromatographed under pressure on silica gel, with methylene chloride/methanol/diisopropyl ether in a ratio of 80:5:15 (yield 351 mg) and subsequently crystallized from ethyl acetate/diisopropyl ether, thus obtaining 272 mg of 3-(6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea (71.7% yield).
Reaction SMILES: [OH:1][C:2]1[N:3]=[N:4][C:5]([SH:8])=[CH:6][CH:7]=1.CC(O[CH2:13][C:14]1[CH2:23][S:22][C@@H:17]2[C@H:18]([NH2:21])[C:19](=[O:20])[N:16]2[C:15]=1[C:24]([OH:26])=[O:25])=O.C(=O)(O)[O-].[Na+].P([O-])([O-])([O-])=O>>[NH2:21][CH:18]1[C:19](=[O:20])[N:16]2[C:15]([C:24]([OH:26])=[O:25])=[C:14]([CH2:13][S:8][C:5]3[N:4]=[N:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:23][S:22][C@H:17]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1ccc(S)nn1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(O)nn3)CS[C@H]12

Procedure:
A mixture of 0.60 g. (0.0047 mole) of 3-hydroxy-6-mercaptopyridazine, 1.27 g. (0.0047 mole) of 7-aminocephalosporanic acid, 0.78 g. (0.0094 mole) of sodium bicarbonate in 25 ml. of 0.1 M phosphate buffer (pH 6.4) was heated at 60° C. for 5 hours. The reaction mixture was filtered to remove a trace of insoluble material and the filtrate was adjusted to pH 5 with acetic acid to give brown precipitates, which were collected by filtration, washed with water and acetone successively and dried in vacuo to give 7-amino-3-(6-hydroxypyridazin-3-ylthiomethyl)-3-cephem-4-carboxylic acid; 1.03 g. (71%). M.p. 290°-300° C. (decomp.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[CH:27]=1>C(OCCO)C>[OH:32][C:31]1[CH:30]=[CH:29][C:28]([CH3:33])=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1ccc(O)c(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cc(C)ccc3O)c2cc1OC
Yield: 93.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 2-amino-p-cresol to give 315.0 mg (94.0%) of the product as a yellow solid, m.p. 198-200° C., mass (electrospray, m/e): M+H 335.8.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][C:8]([NH2:7])([CH3:23])[CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12]1
Reactant: Cc1cc(-c2ccccc2)nn1CCC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)nn1CCC(C)(C)N
Yield: 91.2 %

Procedure:
[1,1-Dimethyl-3-(5-methyl-3-phenyl-pyrazol-1-yl)-propyl]-carbamic acid tert-butyl ester (540 mg) was treated with TFA/CH2Cl2 3:1 (20 ml) at 0° C. for 2 hours. The resulting mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. The organic layer washed with a mixture of brine/sat. Na2CO3 and brine, dried and evaporated to give a crude oil. This was purified by flash chromatography (5% to 40% gradient of MeOH in CH2Cl2, 0.5% NH4OH content) to give the title compound (349 mg) as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([C:47](Cl)=[O:48])[CH2:43][CH2:42]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:8][C:9]=1[N:10]([C:47]([CH:44]1[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]1)=[O:48])[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:16]=1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Nc1ccc(Oc2ccccn2)cc1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)c1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a cooled (0° C.) THF (5 mL) solution of 5-(3,3-Dimethyl-but-1-ynyl)-3-[4-(pyridin-2-yloxy)-phenylamino]-thiophene-2-carboxylic acid methyl ester (0.225 g, 0.55 mmol) was first added KHMDS (0.66 mmol, 0.5 M in toluene), followed by neat trans-4-methyl-cyclohexanecarbonyl chloride (0.132 g, 0.825 mmol). The reaction was warmed slowly to room temperature and quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtrated and concentrated. The crude material was purified by silica gel column chromatography to give 5-(3,3-dimethyl-but-1-ynyl)-3-{(4-methyl-cyclohexanecarbonyl)-[4-(pyridin-2-yloxy)-phenyl]-amino}-thiophene-2-carboxylic acid methyl ester in 60% yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:33]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)[CH3:34])=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[N:14][CH:15]=2)[CH:5]=1
Reactant: CNc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 50 °C

Procedure:
Methyl 5-(2-(bromomethyl)-5-chlorophenyl)picolinate (200 mg, 0.59 mmol), 4′-chloro-N-methyl-[1,1′-biphenyl]-4-amine (141 mg, 0.65 mmol), and K2CO3 (122 mg, 0.88 mmol) were diluted with acetone (3 mL) and heated to 50° C. After 18 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([N+:26]([O-])=[O:27])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[C:18]([NH:26][OH:27])[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1NO
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (150 mg, 0.354 mmol) in methanol (3 mL) was treated with 10% palladium on activated carbon (50 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure for 3 h. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) afforded 3-cyclopentyl-2-(3-hydroxyamino-4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (85 mg, 59%) as a white solid: mp 124-126° C.; EI-HRMS m/e calcd for C18H23N3O4S2 (M+) 409.1130, found 409.1131.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][CH:5]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([NH2:8])=[O:7].[CH:31]([CH:33]=[CH2:34])=O.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1([S:9]([CH3:12])(=[O:10])=[O:11])[CH2:34][CH:33]=[CH:31][NH:8][C:6]1=[O:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(C(N)=O)S(C)(=O)=O)c(Cl)cc2F)c1=O
Reactant: C=CC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(S(C)(=O)=O)CC=CNC3=O)c(Cl)cc2F)c1=O
Reaction time: 3.5 h
Yield: 39.2 %

Procedure:
To a mixture of 1.3 g of 2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(methylsulfonyl) acetamide, 0.21 g of acrolein and 20 ml of THF, 0.03 g of potassium t-butoxide was added at room temperature, and stirred for 3.5 hours. Then, 0.1 g of p-toluenesulsonic acid was added and the reaction mixture was refluxed under stirring for 4 hours. The reaction liquid was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 0.55 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-3-(methylsulfonyl)-3,4-dihydro-1H-pyridin-2-one.
Reaction SMILES: [I-].[Na+].[CH:3]([NH:5][CH:6]1[C:34](=[O:35])[N:8]2[C:9]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:10](OS(C)(=O)=O)[CH2:11][S:12][C@H:7]12)=[O:4].[Cl-].[Na+].C(O[CH2:42][CH3:43])(=O)C>C(#N)C.[Ag]>[CH:3]([NH:5][CH:6]1[C:34](=[O:35])[N:8]2[C:9]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:10]([S:12]/[CH:11]=[CH:10]\[C:43]3[CH:42]=[CH:34][CH:6]=[CH:7][N:8]=3)[CH2:11][S:12][C@H:7]12)=[O:4]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Agent: [Ag]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3ccccn3)CS[C@H]12
Reaction time: 0.5 h

Procedure:
To a suspension of [(Z and E)-2-(2-pyridyl)vinylthio]silver (2.26 g) in acetonitrile (140 ml) was added sodium iodide (8.18 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. To this mixture was added benzhydryl 7-formamido-3-mesyloxy-3-cephem-4-carboxylate (4 g) at once at the same temperature. The mixture was stirred under ice-cooling for 30 minutes. The insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue. The residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium chloride. The mixture was stirred for 1 hour. Sellaite was added to the mixture. The insoluble material was filtered off. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was subjected to column chromatography on silica gel (175 g) and eluted with a mixture of chloroform and ethyl acetate (4:1 v/v). The fractions containing the material having a larger Rf value in thin layer chromatography were combined and concentrated in vacuo to give benzhydryl 7-formamido-3-[(Z)-2-(2-pyridyl)vinylthio]-3-cephem-4-carboxylate (2.15 g) as a solid.
Reaction SMILES: C1(OP(O)OC2C=CC=CC=2)C=CC=CC=1.[CH:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=1.[NH:27]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:28][C:29](O)=[O:30]>N1C=CC=CC=1>[N+:23]([C:22]1[CH:21]=[CH:20][C:19]([O:26][C:29](=[O:30])[CH2:28][NH:27][C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])=[CH:18][CH:17]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: OP(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(CNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 75 %

Procedure:
A mixture of 2.93 g. (0.0125 mole) of phosphorous diphenyl ester and 3.37 g. (0.0125 mole) of mercuric chloride was refluxed for 1 hour in 20 ml. of pyridine. Thereafter, 1.74 g. (0.0125 mole) of p-nitrophenol and 10 ml. of pyridine were added, and the mixture was further reacted for 1 hour. To the reaction mixture were added 2.61 g. (0.0125 mole) of Z-Gly.OH having an amino group protected with Z and 10 ml. of pyridine, and the mixture was reacted under reflux for 1 hour. After completion of the reaction, pyridine was removed by distillation under reduced pressure, and the residue was extracted with 100 ml. of ethyl acetate. The ethyl acetate layer was washed with 2N-HCl, a saturated aqueous NaHCO3 solution and water in this order and then dried over anhydrous Na2SO4, and thereafter ethyl acetate was removed by distillation under reduced pressure. The resulting residue was allowed to stand to form a solid, which was then recrystallized from ethanol to obtain N-benzyloxycarbonyl glycine p-nitrophenyl ester (hereinafter represented by ##STR9## in a yield of 75% (3.0 g.).
Reaction SMILES: [OH:1][C:2]1[C:12]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][C@@H:21]([CH:24]2[CH2:28][CH2:27][CH:26]([CH3:29])[O:25]2)[CH2:22][CH3:23])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]>CC#N.O>[OH:1][C:2]1[C:12]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][C@@H:21]([C@H:24]2[CH2:28][CH2:27][C@H:26]([CH3:29])[O:25]2)[CH2:22][CH3:23])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: CC[C@@H](Nc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O)C1CCC(C)O1
Solvent: CC#N
Solvent: O
Product: CC[C@@H](Nc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O)[C@H]1CC[C@H](C)O1

Procedure:
This compound is isolated from a diastereomeric mixture of 2-hydroxy-N,N-dimethyl-3-{2-[(R)-1-(5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide (Example 1) using reverse phase mass directed HPLC Column HICHROM HIRPB: 250×20 mm, 10 μm, eluent: 5-20% MeCN/H2O-0.1% diethylamine.
Reaction SMILES: NC1C2N(C([C@H]3CC[C@H](C(O)=O)CC3)=NC=2C2C=CC=C(OCC3C=CC=CC=3)C=2)C=CN=1.C[O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([C:44]2[N:48]3[CH:49]=[CH:50][N:51]=[C:52]([NH2:53])[C:47]3=[C:46]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]4[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=4[F:69])[CH:55]=3)[N:45]=2)[CH2:40][CH2:39]1)=[O:37]>>[NH2:53][C:52]1[C:47]2[N:48]([C:44]([CH:41]3[CH2:40][CH2:39][CH:38]([C:36]([OH:37])=[O:35])[CH2:43][CH2:42]3)=[N:45][C:46]=2[C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]3[C:63]([F:69])=[CH:64][CH:65]=[CH:66][C:67]=3[F:68])[CH:55]=2)[CH:49]=[CH:50][N:51]=1
Reactant: COC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1
Agent: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Product: Nc1nccn2c(C3CCC(C(=O)O)CC3)nc(-c3cccc(OCc4c(F)cccc4F)c3)c12

Procedure:
The saponification procedures applied to the synthesis of trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid was applied to 4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid methyl ester to afford the title compound; MS (ES+): m/z 479.10 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[CH:4][N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C#N)c(C)cn1-c1c(Cl)cc(Br)cc1Br

Procedure:
In 5 ml of acetic acid, 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile and 1.48 g of acetic anhydride were dissolved. The reaction mixture was heated under reflux for 30 minutes. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to yield crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide. To the obtained crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide, 8 ml of 85% phosphoric acid were added. The reaction mixture was heated for 0.5 hours at 130° C., and subsequently, water was added thereto. The reaction mixture was extracted with chloroform, and subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) and was allowed to stand for crystallization. The precipitated crystals were washed with ethyl acetate to yield 1.1 g of 2,5-dimethyl-7-(2,4-dibromo-6-chlorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one.