Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[SH:9].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[C:10]1([C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:9][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][C:3]=2[CH2:2][OH:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccncc1S
Solvent: CN(C)C=O
Product: OCc1ccncc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 24.6 %

Procedure:
4-hydroxymethyl-3-mercaptopyridine (100 mg, 0.71 mmol) was dissolved in DMF (5 mL) and diisipropylethylamine (0.12 mL, 0.71 mmol) was added followed by triphenylmethylchloride (197 mg, 0.71 mmol). After 30 min. the reaction mixture was partitioned between water and ethyl acetate, and the organic layer was thoroughly washed with water and dried with anhydrous sodium sulfate. Purification by radial chromatography on silica gel produced pure title material (67 mg, 25% yield).
Reaction SMILES: C(OC([N:11]([C:21]1[C:22]([C:33]([O:35][CH3:36])=[O:34])=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:21]2[C:22]([C:33]([O:35][CH3:36])=[O:34])=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2ccc(C)cc2)csc1-c1ccc(C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)c2ccc(C)cc2)csc1-c1ccc(C)cc1
Reaction time: 0.5 h

Procedure:
10% Pd/C is added to compound 179 in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 30 min The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 180.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O)=[O:21])[CH3:18]>>[CH:1]1([N:6]2[C:10]3=[N:11][C:27]([C:26]4[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH:25]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)COc1cccc(C=O)c1
Product: CCOC(=O)COc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1
Temperature: 160 °C
Yield: 37.9 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.54 g, 15.95 mmol), 3-(ethoxycarbonylmethoxy)benzaldehyde (4.3 g) and xylenes (20 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, a solid formed which was collected by filtration and washed with methanol and then ether. The product was recrystallized from acetonitrile to afford 2.48 g of 1-cyclopentyl-3-ethyl-6-[3-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3 4-d]pyrimidin-4-one. An additional 0.3 g of product was also obtained from the recrystallization of the filtrate for a total of 2.78 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].CN(C=O)C>C(#N)C.O>[NH:31]1[C:1]([C:3]2[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]3[C:16]4[CH:23]=[N:22][N:21]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)[C:17]=4[CH:18]=[N:19][CH:20]=3)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=2)=[N:2][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C#N)c1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(-c2nnn[nH]2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A sealed tube was charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide (75 mg, 0.19 mmol), sodium azide (37 mg, 0.58 mmol) and DMF (1 mL) and warmed at 120° C. After 16 hours, the reaction was diluted with a 4:1 mixture of acetonitrile in water, filtered and purified by reverse-phase chromatography. The desired fractions from the column were concentrated and dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[N:11]=2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:6]1.Br.C(=O)(O)[O-].[Na+]>>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[N:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:6]1
Reactant: COc1cccc(-c2cc(-c3ccccn3)nn2Cc2ccccc2F)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(-c2cc(-c3ccccn3)nn2Cc2ccccc2F)n1
Temperature: 100 °C
Yield: 70 %

Procedure:
A mixture of 2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-6-methoxypyridine (Compound I-25; 85.6 mg) and hydrobromic acid (1.2 ml, 33 wt % in acetic acid) in a sealed flask was heated to 100° C. for 18 h. The mixture was poured into ice and basified with saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic portions were combined, dried (with Na2SO4), filtered, and concentrated under vacuum to give crude oil. The crude oil was purified using SiO2 chromatography using ethyl acetate/methanol as gradient to give 6-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-pyrazol-5-yl)pyridin-2-ol (Compound I-79, 70%) as off white solid. 1H NMR (400 MHz, CDCl3) δ 11.54 (bs, 1H), 8.67-8.62 (m, 1H), 8.00-7.94 (m, 1H), 7.74 (td, 1H), 7.42-7.36 (m, 1H), 7.28-7.15 (m, 3H), 7.05-6.93 (m, 3H), 6.56 (d, 1H), 6.27 (d, 1H), 5.61 (s, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:36])[NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:26][NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[NH:35])[NH2:36])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CN(C(=O)c1ccccn1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)C(=O)c3ccccn3)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-pyridin-2-yl-carbonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O>[I:17][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: CS(=O)(=O)Nc1ccc(SCCCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(SCCCI)cc1
Yield: 92.4 %

Procedure:
A solution of N-[4-(3-chloro-1-propylthio)phenyl]methanesulfonamide (4.0 g, 0.014 mol) and sodium iodide (6.4 g 0.043 mol) in acetone (55 mL) was heated under reflux for 18 hours. The mixture was concentrated, taken up in EtOAc, washed with brine, 10% aqueous sodium bisulfite, brine, dried (MgSO4), and concentrated to give 4.8 g (91%) of product as an off-white and solid m.p. 59°-63° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reactant: Cc1cccc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2cc(C(=O)c3cnc(C)c(C)c3)c(=O)c3ccccc32)n1

Procedure:
Compound 4h was prepared following the procedure described in Step 3 of Example 1. Briefly described here, 65 mg (0.23 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one 3c, 11 mg (0.28 mmol) of 60% sodium hydride and 52 mg (0.28 mmol) of 2-bromomethyl-6-methyl-pyridine (prepared as described by Paine, J. B.; J. Het. Chem. 1987, 351) in 0.7 mL N,N-dimethylformamide were stirred at rt for 2 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. HPLC fractions containing pure product 4h were lyophilized to give 41 mg of a white solid as trifluoroacetate salt: LC-MSD, m/z for C24H21N3O2 [M+H]+=384.5, HPLC retention time: 0.4 min; 1H NMR (400 MHz, CDCl3): δ 2.5 (s, 3H), 2.8 (s, 3H), 2.85 (s, 3H), 6.05 (s, 2H), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.6-7.7 (m, 1H), 8.0-8.1 (m, 1H), 8.3-8.4 (m, 1H), 8.4 (s, 1H), 8.7 (s, 1H), 8.9 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:28]3)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Product: C[C@@H](C(=O)N1CCCC(NC(=O)OC(C)(C)C)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
The title compound was prepared using Intermediate 29 and tert-butyl piperidin-3-ylcarbamate, and the synthetic procedure described for Example 1.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13](Cl)=[C:8]2[N:7]=[CH:6]1)CCC.ClC1[C:27]([C:28](OCC)=[O:29])=[C:26]([CH3:33])N=C2N(C)C=NC=12>>[CH2:28]([O:29][C:13]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:11]([CH3:20])[N:10]=[C:9]2[N:5]([CH3:1])[CH:6]=[N:7][C:8]=12)[CH2:27][CH2:26][CH3:33]
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2C
Yield: 61 %

Procedure:
By replacing 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 5 with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester of Example 2 c, 7-butoxy-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is formed. Yield 61%, b.p. 180°-190°/0.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[N:27][CH:26]=[CH:25]2>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH:28]1[C:29]2[C:24](=[CH:23][C:22]([CH2:21][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]([CH3:15])=[N:8][C:7]=3[OH:16])=[CH:31][CH:30]=2)[CH:25]=[CH:26][N:27]=1
Reactant: ClCc1ccc2cnccc2c1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(C)nc(O)c(Cc3ccc4cnccc4c3)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (158 mg, 721 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by MDE 32048 (185 mg, 864 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) gave 56 mg of 4-(isoquinolin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (5.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(isoquinolin-6-ylmethyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol dihydrochloride 21 as a brown solid (67 mg, 21% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21](OCC)=[O:22])[CH2:4]1)[CH3:2].O/[N:27]=[C:28](\[NH2:31])/[CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21]2[O:22][N:31]=[C:28]([CH2:29][OH:30])[N:27]=2)[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: N/C(CO)=N\O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H]1C[C@H](Cc2nc(CO)no2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 130 °C
Yield: 20 %

Procedure:
To a solution of ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate (0.195 g, 0.571 mmol, Example #38, Step H) in toluene (1.00 mL) and MeOH (1.000 mL) were added (Z)-N′,2-dihydroxyacetimidamide (0.515 g, 5.71 mmol, Tyger) and K2CO3 (0.195 g, 1.41 mmol). The reaction was heated in a CEM microwave at about 130° C. twice at about 45 min each (250 psi maximum pressure, 1 min ramp, 300 max watts). (Z)-N′,2-dihydroxy acetimidamide (0.200 g, 2.22 mmol, Tyger) was added and the reaction mixture was heated in a CEM microwave at about 140° C. for about 45 min (250 psi maximum pressure, 1 min ramp, 300 max watts). (Z)-N′,2-dihydroxyacetimidamide (0.200 g, 2.22 mmol, Tyger) and K2CO3 (0.100 g, 0.725 mmol) were added, and the reaction mixture was heated in a CEM microwave at about 140° C. for about 45 min (250 psi maximum pressure, 1 min ramp, 300 max watts). The solvent was removed under reduced pressure. The residue was dissolved with water (20 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (5×50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd to give a yellow residue. The crude material was purified via flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in EtOAc to afford (5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol (0.042 g, 20%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z: 368 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1.[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)[CH3:20])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3cccnc3)ccc2n1C)c1ccc(C(=N)N)cc1
Yield: 70 %

Procedure:
Prepared analogously to Example 26 from 1-Methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 70% of theory, C26H27N7O3 (485.6) ##EQU52##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].Br[CH2:29][C:30]1[O:31][C:32](=[O:36])[O:33][C:34]=1[CH3:35].C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][OH:26])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O:22][CH2:29][C:30]4[O:31][C:32](=[O:36])[O:33][C:34]=4[CH3:35])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Reactant: Cc1oc(=O)oc1CBr
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OCc2oc(=O)oc2C)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Yield: 26.5 %

Procedure:
To a solution of potassium 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in N,N-dimethylacetamide (30 ml) was added 4-bromomethyl-5-methyl-1,3-dioxol-2-one (1.0 g) under ice-cooling with stirring. The reaction mixture was stirred at the same temperature for 30 minutes. The resulting mixture was poured into ethyl acetate (200 ml) and the organic solution was washed with water three times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (50 g) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.62 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([O:17][CH3:18])[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([OH:23])=[O:22].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([O:17][CH3:18])[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)=[CH:26][CH:25]=1)([OH:23])=[O:22]
Reactant: COc1nc(OS(=O)(=O)C(F)(F)F)cc2cccnc12
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1nc(-c2ccc(C(=O)O)cc2)cc2cccnc12
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-methoxy-1,7-napthyridine (1.5 g, 4.86 mmol) in DMF (40 ml) is added 4-carboxy-phenylboronic acid (0.866 g, 5.34 mmol), bis(dibenzylidenacetone) palladium (112 mg, 0.167 mmol), tri-o-tolylphosphine (96 mg, 0.32 mmol) and aqueous Na2CO3 (14.6 ml, 2N,). The reaction mixture is stirred at 110° for 3 h. The hot solution is filtred through cellit and the solution evaporated to dryness. The crude product is dissolved in hot water (60 ml) and the water phase washed with ethyl acetate (3×50 ml). The product is precipitated from the water phase by carefully adding aqueous HCl (2N, 6 ml). The suspension is filtered and the crude product is stirred again in hot ethyl acetate (50 ml). The cold suspension is filtered to yield the title compound (1.10 g). M+280; Melting point >300°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25](=[O:26])[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17]2)=[CH:12][CH:11]=1.[CH3:27][SiH:28]([CH3:30])[CH3:29]>C1COCC1.CCOC(C)=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][C:18]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:23][CH:24]=[C:25]2[O:26][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:12][CH:11]=1
Reactant: O=C1CCC2(CC1c1ccc(F)cc1)OCCO2
Reactant: C[SiH](C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCC2(CC1c1ccc(F)cc1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Step AAC (1): Followed a method described by A. de Meijer et. al Chem. Eur. J. 2007, 13, 3739. Lithium diisopropylamide (1.8 M in THF, 1.26 mL, 2.26 mmol) was added to a −78° C. solution of 7-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-one (515 mg, 2.06 mmol, O. Dirat et. al Tetrahedron Lett. 2006, 47, 1295) in THF (7 mL). The resulting mixture was allowed to stir for 1 hr. Trimethylsilane (0.289 mL, 2.264 mmol) was added and the mixture was allowed to warm to rt and stir for 30 min. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo to afford (9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-8-yloxy)trimethylsilane (696 mg, 100% yield) as a yellow solid. The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Fe]>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1nccn1Cc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1nccn1Cc1ccccc1

Procedure:
The nitroimidazole (1.5 mmol) from above reduced using iron powder and ammonium chloride employing the procedure described in Example 159 to yield 1-benzyl-2-amino-1H-imidazole which was used without any purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.C1N=C[N:13]([C:16](N2C=NC=C2)=[O:17])C=1.N>CN(C=O)C.O1CCOCC1>[C:8]([C:4]1[S:3][C:2]([NH:1][C:16]([NH2:13])=[O:17])=[N:6][C:5]=1[CH3:7])(=[O:10])[CH3:9]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)c1sc(NC(N)=O)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
2-Amino-4-methyl-5-acetylthiazole (3 g, 19.2 mmol) is dissolved in DMF (30 mL). CDI (3.5 g, 21.1 mmol) is added and the mixture is stirred at RT for 3 h. Ammonia 0.5 N in dioxane is added (60 mL, 30 mmol) is added and the mixture is stirred for 2 days in a closed system. The resulting precipitate is recovered by filtration, washed with petroleum ether and dried under vacuo, affording N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)urea as colorless solid (1.5 g, 39%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C1C=CC=CC=1.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Br)c1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
2-Bromo-4-aminopyridine (433 mg, 2.5 mmol) was added to 15 ml of dry benzene and the mixture warmed to dissolve the pyridine. 298 mg (2.5 mmol) of phenyl isocyanate was added to the solution and the resulting mixture stirred at room temperature for 20 hrs. The crystals which formed were collected by filtration and subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (2.5:1 volume) solvent mixture, the eluate containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from 70% methanol to give 308 mg of N-(2-bromo-4-pyridyl)-N'-phenylurea: yield 42.1%; m.p. 188°-189° C.