Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12](=[CH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-:20].[Na+].OO.Cl>C1COCC1.O>[CH3:19][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][OH:20])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: C=C(CCCCC)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4,4-dimethyl-7-(1-methylene-hexyl)-chroman (0.442 g, 1.71 mmole) in 8 mL of THF at 0° C. was treated with 1.71 mL of 1M BH3.THF complex. The reaction mixture was stirred at room temperature for three hours and then cooled to 0° C. The mixture was treated successively with 0.3 mL of water, 0.34 mL of 3M sodium hydroxide and 0.34 mL of 30% hydrogen peroxide, stirred at room temperature for two hours and then diluted with 10 mL of water. The pH was adjusted to 4.0 with 10% HCl and extracted with three 12.5 ML portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The product was purified by flash chromatography (SiO2, 10-20% ethyl acetate in hexanes) to yield 0.366 g of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol as a colorless oil.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[C:17]([NH:20][C:21]1[CH:29]=[C:28]([NH2:30])[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=1[OH:31])(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:20][C:21]1[C:22]([OH:31])=[C:23]([C:24]([OH:26])=[O:25])[CH:27]=[C:28]([N:30]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:29]=1)(=[O:19])[CH3:18]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: CC(=O)Nc1cc(N)cc(C(=O)O)c1O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-n2c(-c3ccccc3)cc3c2CCCC3)cc(C(=O)O)c1O

Procedure:
A mixture of 10.3 g. (0.048 mole) of 2-phenacylcyclohexanone, 10 g. (0.048 mole) of 3-acetamido-5-aminosalicylic acid, and 70 ml. of glacial acetic acid was heated under reflux under nitrogen for 1 hour, cooled and filtered. Recrystallization of the collected solid from acetic acid gave 10.5 g. (57%) of crystals, m.p. 232°-234°.
Reaction SMILES: [C:1]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:12](I)[CH3:13].[H-].[Na+]>>[C:1]([C:6]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCI
Reactant: CCOC(=O)C1CCCC1=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1(CC)CCCC1=O

Procedure:
2-Carboethoxycyclopentanone is reacted with ethyl iodide in the presence of sodium hydride to produce 2-carboethoxy-2-ethyl-cyclopentanone.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32](=[O:34])(=[O:33])[NH2:35])=[O:15])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A benzene (20 ml) solution containing 1.40 (5.1 mmol) of 3-(4-nitrobenzyloxy)benzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (20 ml), this solution was added dropwise under ice-cooling to a pyridine (30 ml) solution containing 0.97 g (5.6 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The thus obtained crude crystals were washed with methanol to obtain 1.9 g (yield: 87.0%) of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C)(=[O:18])[CH:16]=[CH2:17].[OH-].[K+]>CO.O>[CH:4]1[C:5]2[CH:6]3[CH2:17][CH:16]([C:15]([OH:19])=[O:18])[CH:13]([C:12]4[C:7]3=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: C=CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CC2c3ccccc3C1c1ccccc12
Temperature: 162.5 °C
Reaction time: 72 h

Procedure:
Anthracene (40 gm) was combined with methyl acrylate (30 gm) in a Parr bomb and heated to 150-175° C. for 6 hours. The mixture was allowed to remain in the bomb at room temperature for 72 hours. The mixture was dissolved in methanol (225 ml), treated with a solution of potassium hydroxide (40 gm) in water (40 ml) and heated to reflux for 4 hours. The solution was cooled to room temperature and most of the solvent was removed on a rotary evaporator. The residue was dissolved in water (200 ml), filtered through charcoal and acidified with concentrated hydrochloric acid. The resulting mixture was allowed to stand overnight and the precipitate was filtered. The white solid was dried at 80° and recrystallized from benzene to provide the product (mp=188-189° C.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([O:17]CC)=[O:16])[C:5]2=[O:20].[OH-].[Na+].Cl>CO>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:20]
Reactant: CCOC(=O)c1cn(C)c2nc(OC)c(I)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc2c(cc1I)c(=O)c(C(=O)O)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate (3.63 g) is dissolved in MeOH (200 mL). To this is added 6N NaOH (60 mL) and the resulting mixture is stirred at room temperature for 4 h. The white suspension is poured into a seperatory funnel and the organic layer is made acidic with HCl, extracted several times with CH2Cl2 (total volume 4 L), washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to afford 3.2 g (96%) of 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid. Physical characteristics are as follows:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[N:13][N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].I[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:28]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C:12]2[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=3)=[C:19]3[N:14]([N:15]=[CH:16][CH:17]=[CH:18]3)[N:13]=2)=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCI
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(O)cc3)nn3ncccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2nn3ncccc3c2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
4-[3-(4-Methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-2-yl]-phenol (663 mg, 1.82), iodoethane (1 eq) and potassium carbonate (2 eq) in acetonitrile (30 ml) were heated at reflux under nitrogen for 18 h. The cooled reaction mixture was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase was collected, dried and purified by chromatography to give the title compound (547 mg) as a cream foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:16]1([CH2:22][C:23](=[O:27])[C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:8]([O:7][C:3]([O:4][CH2:5][CH3:6])([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][NH:1][C:24](=[O:25])[C:23]([CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:27])[CH3:9]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CCOC(CN)(OCC)c1cccnc1
Product: CCOC(CNC(=O)C(=O)Cc1ccccc1)(OCC)c1cccnc1

Procedure:
In a manner analogous to Example 1, by condensing 3-(2-amino-1,1-diethoxyethyl)pyridine with phenylpyruvic acid there is obtained N-[2,2-diethoxy-2-(3-pyridyl)ethyl]-3-phenylpyruvamide as an amorphous, yellow solid. Subsequent acidic hydrolysis to 3-phenyl-N-[[(3-pyridyl)carbonyl]methyl]pyruvamide and ring closure gives 3-benzyl-5-(3-pyridyl)-2(1H)-pyrazinone as a solid, melting point 188°-190° (from ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[C:10](=[O:22])[CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:13]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C=O>[Si:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[C:10](=[O:22])[CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:13]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCCO)C(=O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Yield: 74.4 %

Procedure:
440 mg (1.28 mmoles) of 2-(6-hydroxyhexylthio)-4-t-butyldimethylsilyloxy-2-cyclopentenone and 225 mg (1.50 mmoles) of t-butyldimethylsilyl chloride were treated at room temperature for 2 hours in 3 ml of N,N-dimethyl formamide in the presence of 204 mg (3.0 mmoles) of imidazole. After the reaction, the reaction mixture was extracted with hexane to give 640 mg of a crude product. The crude product was purified by thin-layer chromatography (cyclohexane/ethyl acetate=4/6) to give 437 mg (75%) of 2-(6-t-butyldimethylsilyloxyhexylthio)-4-t-butyldimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:11][N:12]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: CNCCN1CCOCC1
Reactant: Clc1noc2ccccc12
Product: CN(CCN1CCOCC1)c1noc2ccccc12
Temperature: 140 °C
Yield: 23.5 %

Procedure:
To a sealed tube was added 3-chloro-1,2-benzisoxazole (3.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (12.7 g). The reaction was heated to 140° C. over 72 hours and then cooled to room temperature. The residue was partitioned between EtOAc and water, extracted again with EtOAc, and the organic phase was dried over MgSO4 and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1-3% MeOH/DCM provided the product (1.2 g), as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH2:16][CH3:17].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:15][CH2:16][CH3:17])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCN(c1ccc(I)cc1)c1ncccn1

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (300 mg) and propyl bromide (0.11 ml) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-propylpyrimidin-2-amine (348 mg).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.6 %

Procedure:
A solution of tert-butyl 3-(benzoylamino)piperidine-1-carboxylate (0.120 g) in DCM (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure to give a yellow oil which following neutralisation with aqueous ammonia solution, was purified using SPE (silica, eluting with methanol and 5% aqueous ammonia in methanol) to give the title compound (0.085 g) as an off-white solid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=1[C:7]#[N:8]>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:1][C:10]1[C:9]([CH3:13])=[C:6]([C:5]([O:4][CH3:3])=[CH:12][CH:11]=1)[C:7]#[N:8]
Reactant: COc1cccc(C)c1C#N
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C)c1C#N
Temperature: 0 °C

Procedure:
A solution of Br2 (261 mg, 1.63 mmol) in CCl4 (1 mL) was added over 15 min to a solution of 2-methoxy-6-methylbenzonitrile in CCl4 (3 mL) at −10° C. containing 4 mg of Fe powder. After 45 min the reaction was poured into ice water (10 mL). The organic layer was washed with Na2SO3 (aq.) solution (10 mL*2), brine (20 mL) and dried over Na2SO4, concentrated in vacuo to give 3-bromo-6-methoxy-2-methylbenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-bromophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (19.5 g, 40.7 mmol) in methanol (100 ml) was added 2N aqueous sodium hydroxide solution (40.7 ml, 81.4 mmol) and the mixture was stirred at room temperature for 2.5 hrs. 6N Hydrochloric acid (50 ml) was added to acidify the solution and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane to give the objective substance (16.7 g, 91%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH3:32])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[CH3:50][C:51]([O:54][C:55]([C:57]1[N:58]2[CH:61]([S:62][CH2:63][C:64]=1[CH2:65][O:66][C:67](=[O:69])[CH3:68])[CH:60]([NH2:70])[C:59]2=[O:71])=[O:56])([CH3:53])[CH3:52]>ClCCl>[CH3:53][C:51]([O:54][C:55]([C:57]1[N:58]2[CH:61]([S:62][CH2:63][C:64]=1[CH2:65][O:66][C:67](=[O:69])[CH3:68])[CH:60]([NH:70][C:27](=[O:28])[C:26](=[N:30][O:31][CH3:32])[C:24]1[N:25]=[C:21]([NH:20][C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:22][CH:23]=1)[C:59]2=[O:71])=[O:56])([CH3:50])[CH3:52]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 76 %

Procedure:
To a stirred suspension of 48 g (0.1 mole) of 2-[2-(tritylamino)thiazole-4-yl]-2-methoxyiminoacetic acid in 750 mL of anhydrous dichloromethane was added 13.94 mL (0.1 mole) of triethylamine and the mixture was mechanically stirred until a clear solution formed (approx. 45 min). After complete dissolution 20.6 g (0.1 mole) of N,N-dicyclohexylcarbodiimide and 13.5 g (0.1 mole) of 1-hydroxybenzotriazole were added and the mixture stirred at ambient temperature for 2 hours. A solution of 32.8 g (0.1 mole) of [6R-[6 alpha,7 beta(z)]]-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid 1,1-dimethylethyl ester (from Example 1) in 250 mL of anhydrous dichloromethane was added and the resulting solution was stirred overnigh (16 hours) at ambient temperature. The precipitate was removed by filtration and the filtrate was washed successively with 2×250 mL=500 mL of saturated aqueous sodium bicarbonate and 2×250 mL=500 mL of saturated aqueous sodium chloride and dried over sodium sulphate. Removal of the dichloromethane afforded the crude product as a gummy-oil which was purified by preparative liquid chromatography (0-10% EtoAc in CH2Cl2), to give 57.2 g (76%) of pale yellow solid. NMR (CDCl3): 1.54 (s) 9H (t-bu) 2.09 (s) 3H (OAc); 3.35, 3.56 (d of d, J=18 Hz) 2H (CH2S); 4.08 (s) 3H (OCH3); 4.86 5.04 (d of d, J=14 Hz) 2H (CH2O); 5.04 (d, J=6 Hz) 1H (C6); 5.93 (d of d, J=6 Hz J=10 Hz), 1H (C7); 6.71 (s) 1H (thiazole); 6.91 (d, J=10 Hz) 1H (NH); 7.08 (s) 1H (NH); 7.30 (s) 15H (CPh3).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH:14]=2)=[CH:5][CH:4]=1)[NH2:2].N(C1C=CC=CC=1)=[C:19]=[S:20]>CN1C(=O)CCC1.C(Cl)Cl>[SH:20][C:19]1[N:8]2[CH:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12](=[O:17])[N:13]([CH2:15][CH3:16])[CH:14]=3)[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: CCn1cc(-c2ccc(NN)nc2)ccc1=O
Reactant: S=C=Nc1ccccc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCn1cc(-c2ccc3nnc(S)n3c2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
A mixture of 5-(6-hydrazinylpyridin-3-yl)-1-ethylpyridin-2(1 H)-one (1.2 g, 5.22 mmol) and isothiocyanatobenzene (775 mg, 5.74 mmol) in NMP(3 ml) and DCM (10 ml) was stirred at room temperature for 30 min. The DCM was removed via rotary evaporation and the reaction was diluted with 1,3-dichlorobenzene (7 mL). The mixture was then heated in a microwave at 160° C. for 1 hr. Ether (10 ml) was added to the reaction and the resulting solid was collected by filtration and washed with ether to provide the title compound, 5-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1-ethylpyridin-2(1 H)-one (600 mg, 42.3% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([NH2:19])[CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:12]2[CH:13]=[C:14]3[C:18](=[C:10]([CH3:9])[CH:11]=2)[NH:17][N:16]=[CH:15]3)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(N)cc2cn[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2cn[nH]c12
Temperature: 25 °C

Procedure:
500 mg (3.40 mmol) 4,6-dichloropyrimidine, 500 mg (3.40 mmol) 7-methyl-1H-indazol-5-ylamine and 1.30 mL (7.60 mmol) DIPEA were combined in 5.0 mL DMF and refluxed for 5 h. The reaction mixture was cooled to RT and evaporated down i.vac. The residue was taken up in EtOAc and extracted several times with saturated sodium chloride solution. The organic phases were combined, dried on magnesium sulphate, filtered and evaporated down. The residue was stirred with DIPE, suction filtered and dried i. vac.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[CH2:21](Br)[C:22]#[CH:23].O>CN(C)C=O.C(=O)([O-])[O-]>[CH2:23]([C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16])[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC1(Oc2nc(OC)cc(OC)n2)C=CC=CC1C=NO
Temperature: 100 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 7.1 g of propargyl bromide were dissolved in 100 ml of N,N-dimethylformamide containing 1.4 g of potassisum carbonate, and the solution was stirred at 100° C. for 4 hours. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=10:1) to obtain 4.8 g of 0-(2-propynyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as an oily substance.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([S:26][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1cccnc1SCc1ccccc1
Yield: 78.5 %

Procedure:
10 g of 2,3-dichloropyridine, 11.2 g of anhydrous potassium carbonate and 100 ml of dimethylsulfoxide were mixed to obtain a suspension. To this suspension, 10 ml of a dimethylsulfoxide solution of 10.1 g of benzyl mercaptan was dropwise added over a period of about 20 minutes at 110° C. Then, the mixture was reacted at a temperature of from 120 to 130° C. for about 1.5 hours. Thereafter, the reaction product was put into water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate. Then, methylene chloride was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 12.5 g of oily 2-benzylthio-3-chloropyridine.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2=[O:22])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])[C:37]([C:45]#[N:46])=[CH:36][N:35]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[C:45]([C:37]1[C:38]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:39][C:34]([NH:33][C:32]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH2:14][N:15]4[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]4=[O:22])=[C:4]([CH:3]([O:23][CH3:24])[O:2][CH3:1])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:31])=[N:35][CH:36]=1)#[N:46]
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 1.03 g, 3.08 mmol), phenyl(5-cyano-4-(2-methoxyethoxyl)pyridin-2-yl)carbamate (intermediate 108, 2.19 g, 6.16 mmol) and DMAP (753 mg, 6.16 mmol) in DMA (15 ml) was heated at 90° C. for 3.5 h. The cooled reaction mixture was partitioned between EtOAc and, the organic layer dried over MgSO4 and evaporated. The residue was purified by reversed phase chromatography (RP 4) and the product containing fractions were partitioned between saturated aqueous NaHCO3 and EtOAc, the organic layer dried over MgSO4 and vaporated. The residue was then triturated with a mixture of DCM, Et2O and heptane to give the title compound as a white solid. (UPLC-MS 7) tR 0.80; ESI-MS 554.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-brombenzaldehyde (27 mmol, 5.0 g) in THF (20 mL) was added at −78° C. a solution of isopropylmagnesium chloride (41 mmol, 20.2 mL, 2M in ether). The mixture was stirred at −78° C. for 1 h and warmed to 0° C. for 1 h. NH4Cl was added an the mixture was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated to an oil. Chromatography (5-15% EtOAc/hexane) gave the desired alcohol.