Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH3:34]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([NH2:34])=[O:32])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: N
Product: NC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 90 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with ammonia to give the title compound as a white solid (210 mg, 90%); NMR Spectrum 4.87 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.59 (br s, 1H), 7.76-7.66 (m, 3H), 7.84 (br s, 1H), 7.91 (m, 1H), 8.14 (s, 1H), 8.57-8.52 (m, 3H), 10.98 (br s, 1H); Mass spectrum MH+ 426.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(OO)(=[O:21])C>>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:21])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)OO
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccc(F)c1
Product: COC(=O)c1cc(Cl)c[n+]([O-])c1-c1cccc(F)c1
Yield: 60.6 %

Procedure:
A solution of methyl 5-chloro-2-(3-fluorophenyl)nicotinate (11 g, 41 mmol) in ethaneperoxoic acid (30 mL, 100 mmol) was heated at 90° C. for 1 hour. Evaporation and purification by flash column chromatography with ethyl acetate in hexanes (0-50%) gave the desired compound (7.0 g, 68%). LCMS calculated for C13H10ClFNO3 (M+H)+: m/z=282.0. found: 281.8. 1H NMR (300 MHz, DMSO-d6): δ 8.83 (s, 1H), 7.85 (s, 1H), 7.49 (m, 1H), 7.25 (m, 2H), 7.14 (m, 1H), 3.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:52](=[O:53])[N:31]2[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])=[C:33]([C@@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:52](=[O:53])[N:31]3[C:32]([C:41]([O:43][CH2:44][O:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])=[O:42])=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCOC(=O)C1=C([C@@H]2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (0.108g, 0.537mmol) in DMF (2ml) was cooled to -50° C. N,N-Diisopropylethylamine (0.103ml, 0.59mmol) followed by methanesulphonyl chloride (0.046ml, 0.59mmol) were added and the mixture was stirred at -50° C. for 30 min. A further quantity of N,N-diisopropylethylamine (0.086ml, 0.493mmol) was added and this mixture was added to a pre-cooled solution of pivaloyloxymethyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (0.185g, 0.482mmol) in DMF (2ml) at 0° C. The resulting mixture was stirred at 0° C. for 40 min., then it was partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, then triturated with ether to give the title compound (0.193g, 71%) as a white solid. The spectral data was identical with that obtained for Example 8.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:17][C:18]#[CH:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].[N+:20](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C1C=CC=CC=1>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([N:4]1[CH2:3][CH2:2][N:21]2[N:20]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=[C:18]2[CH2:17]1)(=[O:7])=[O:6])([O-:16])=[O:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CCN(CCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2n(n1)CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C

Procedure:
A solution of N-(2-chloroethyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.51 g, 1.69 mmol and ethyl diazoacetate (0.266 mL, 2.532 mmol) in benzene (2 mL) was heated in a microwave reactor at 140° C. for 1 hour. Upon cooling to room temperature, cesium carbonate (0.637 g, 1.95 mmol) along with tetrahydrofuran (1 mL) was added. The vial was again sealed and heated at 140° C. for 30 minutes in the microwave reactor. Upon cooling to room temperature, the solvents were then evaporated in vacuo and the residue obtained was partitioned between water (10 mL) and EtOAc (15 mL). The aqueous layer was washed with additional EtOAc (15 mL), the combined organic layers were dried over anhydrous MgSO4, concentrated and purified via silica chromatography (20-90% EtOAc/hexane) to afford Intermediate 16 as a semi solid (0.235 g, 37%). LC-MS: (FA) ES+381; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=7.5, 1.7 Hz, 1H), 7.79-7.67 (m, 3H), 6.63 (s, 1H), 4.64 (s, 2H), 4.41-4.31 (m, 4H), 3.92-3.89 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14](=[O:17])[NH:15][CH3:16])=[CH:10][C:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:8]1)=O)C.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C1(C)C(C)=CC=CC=1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:9]2[CH:10]=[C:11]([C:14](=[O:17])[NH:15][CH3:16])[C:12](=[O:13])[N:7]([CH2:6][C:4](=[O:3])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:8]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccccn1
Reactant: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)NC)c1=O
Solvent: Cc1ccccc1C
Product: CNC(=O)c1cc(-c2ccc(OC)cc2)nn(CC(=O)NCc2ccccn2)c1=O
Yield: 44.5 %

Procedure:
In xylene, 2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one and 2-(aminomethyl)pyridine were refluxed at 150° C. for 7 hours. Post-treatments were conducted as in Example 47-(2), whereby the title compound was obtained in a yield of 44.5%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7].[C:34]([N:37]1[CH2:42][CH2:41][CH:40](C(O)=O)[CH2:39][CH2:38]1)(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:37]1[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]2)=[O:7])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)CC1NC(C(=O)NCCCN)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(NCCCNC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3)C2c2cccc(Cl)c2)CC1
Yield: 70.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-amino-propyl)-amide prepared in Example 29 (0.18 g, 0.37 mmol) was reacted with 1-acetylpiperidine-4-carboxylic acid (Lancaster) (0.7 g, 0.58 mmol), HATU (0.3 g, 0.78 mmol) and iPr2NEt (0.5 g, 3.9 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1-acetyl-piperidin-4-ylamino)-propyl]-amide as a white solid (0.16 g, 67%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CS(O)(=O)=O>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: NC(=O)Cc1cnc(Nc2ccccc2)cc1NCc1ccccc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To 25 mg of 4-(benzylamino)-6-chloropyridine-3-carboxyamide suspended in 0.2 mL of diphenylether, 18 mg of aniline and 9 mg of methanesulfonic acid were added and stirred at 180° C. for 30 minutes. After cooling, the reaction mixture was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1-10:1) to obtain 30 mg (99%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: CN(C)C1C=CC(CN[C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][OH:17])=[O:15])=CC=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][NH:10][C:9]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18]
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Reactant: NCCc1ccccc1
Product: O=C(CCCNC(=O)NCCc1ccccc1)NO

Procedure:
Compound 1 was prepared using the methodology described for the preparation of compound 2, by substituting 4-dimethylaminobenzylamine dihydrochloride with phenethylamine. 1H NMR (CD3OD) δ 7.30-7.15 (m, 5H), 3.34 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.09 (t, J=7.5Hz, 2H), 1.73 (m, 2H). 13C NMR (CD3OD) δ 172.7, 161.3, 140.9, 130.0, 129.6, 127.4, 42.8, 40.4, 37.7, 31.3, 27.8.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])C1C=CC=CC=1.C(O)=O>CCOC(C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:13]1[C:12](=[O:37])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[N:15]([CH:19]2[CH2:20][CH2:21][S:22][CH2:23][CH2:24]2)[C:14]1=[O:25]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCSCC3)c2=O)cc1OC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCSCC3)c2=O)cc1OC

Procedure:
A mixture of 0.200 g of the compound obtained in Step 3.2, and 1.22 g of formic acid is irradiated in a microwave field for 2 minutes at 180° C. The reaction mixture is taken up in EtOAc and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a CH2Cl2/MeOH mixture from (100/0, v/v) to (97/3, v/v) to give the expected product.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:39]5[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]5)[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: O=S1(=O)CCNCC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCS(=O)(=O)CC3)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 50 mg, 0.0934 mmol) and thiomorpholine 1,1-dioxide (20 mg, 0.148 mmol) using a similar method to that employed for Example 18, Step 2 (10 mg).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([O:29]C)=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]>C1COCC1.CO>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([OH:29])=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3cc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1Cc2cc(C(=O)NCc3cc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Reaction time: 20 h
Yield: 29.6 %

Procedure:
1.0 N NaOH (1 mL, 1.0 mmol) was added dropwise to a solution of methyl (±)-7-[[[(2-indolyl)methyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.35 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) at RT. The resulting mixture was stirred for 20 h then was concentrated. The residue was dissolved in H2O (20 mL) and acidified with TFA. ODS chromatography (27% CH3CN/H2O-0.1% TFA), concentration and lyophilization gave the title compound (100 mg, 30%) as an off-white solid: HPLC (ODS, 5-60% CH3CN/H2O-0. 1% TFA gradient elution over 20 min) K'=10.2; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (t, 1H), 7.57 (s, 1H), 7.56 (d, 1H), 7.43 (d, 1H), 7.33 (d, 1H), 7.01 (t, 1H), 6.93 (t, 1H), 6.55 (d, 1H), 6.33 (br, 1H), 6.25 (s, 1H), 5.49 (d, 1H), 5.08 (t, 1H), 4.55 (d, 2H), 3.82 (d, 1H), 2.92 (s, 3H), 2.75 (dd, 1H), 2.53 (d, 1H); MS (ES) m/e 407.2(M+H)+. Anal. Calcd for C22H22N4O4.H2O: C, 62.25; H, 5.70; N, 13.20. Found: C, 62.66; H, 5.64; N, 12.99.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:16]1[N:21]=[C:20]2[N:22]([C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]3)[C:23](=[O:26])[CH2:24][NH:25][C:19]2=[N:18][CH:17]=1>CN(C)C=O>[OH:12][C:9]([C:6]1[N:7]=[CH:8][C:3]([C:16]2[N:21]=[C:20]3[N:22]([C@H:27]4[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]4)[C:23](=[O:26])[CH2:24][NH:25][C:19]3=[N:18][CH:17]=2)=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(-c4ccc(C(C)(C)O)nc4)nc32)CC1
Temperature: 120 °C

Procedure:
2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (9.43 g, 31.4 mmol), 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (10.02 g, 29.4 mmol), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (2.398 g, 2.94 mmol) and N,N-dimethylformamide (25 mL) were combined in a round-bottom flask with a stirbar. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas three times. The resulting mixture was stirred vigorously and heated at 120° C. under nitrogen for 35 min. The resulting mixture was purified using flash chromatography, split into 4 separate columns, (2-15% methanol in dichloromethane). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The resulting mixture was purified using reverse-phase preparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min), split into 6 runs. Fractions containing the desired product were combined and all of the acetonitrile and some of the water were removed under reduced pressure at 25° C. The remaining yellow solution was loaded onto 50 g of Strata X-C ion exchange resin from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol wash and was concentrated under reduced pressure and dried under high vacuum to give the desired product (4.85 g, 12.20 mmol, 42% yield) as a pink foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (d, J=1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J=2.34, 8.20 Hz, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J=3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J=4.00, 10.84 Hz, 1H), 2.58 (qd, J=2.93, 12.82 Hz, 2H), 2.14 (d, J=10.15 Hz, 2H), 1.68 (d, J=10.93 Hz, 2H), 1.47 (s, 6H), 1.17-1.35 (m, 2H); MS (ESI) m/z 398.3 [M+1]+; mp 196-198° C. (uncorrected).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([SH:35])[N:30]=[C:29]([CH3:36])[CH:28]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:31]3[N:30]=[C:29]([CH3:36])[CH:28]=[C:27]([CH3:26])[C:32]=3[C:33]#[N:34])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1cc(C)c(C#N)c(S)n1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nc(C)cc(C)c3C#N)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,6-dimethyl-2-mercaptonicotinonitrile was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.53-1.71 (m, 8H) 2.01 (s, 3H) 2.06 (m, 2H) 2.34 (m, 1H) 2.37 (s, 3H) 2.58 (m, 2H) 2.83 (d, J=17.9 Hz, 1H) 2.93 (d, J=15.0 Hz, 1H) 3.80 (s, attenuation due to proximity to H2O peak) 6.98 (s, 1H) 7.02 (d, J=8.2 Hz, 1H) 7.11 (d, J=5.0 Hz, 1H) 7.23 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C27H29ClN2O4S: 513.06; found M=513.1.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH3:9][C:10](=[CH:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:11]>C(#N)C.C1(NN)C=CC=CC=1>[CH3:8][CH2:7][O:6][C:4]([CH:3]1[C:14]([CH3:16])([CH3:15])[CH:13]1[CH:12]=[C:10]([CH3:11])[CH3:9])=[O:5]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)=CC=C(C)C
Solvent: NNc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 50.9 %

Procedure:
0.2 g of the catalyst whose preparation is described in example 44 are suspended in 3 ml of acetonitrile then 0.096 mmol (0.01 g) of phenylhydrazine in 3 ml of acetonitrile are added. The reaction mixture is heated to 50° C. and 0.1 ml of a solution containing 0.21 ml (2 mmol) of ethyl diazoacetate in 3 ml acetonitrile is added. 10 mmol of 2,5-dimethyl-2,4-hexadiene (1.4 ml) are then added, followed by the remaining 2.9 ml of the ethyl diazoacetate solution in acetonitrile, added over a period of about 1 hour. The reaction mixture is maintained under stirring at 50° C. for 6 hours. The catalyst is removed by filtration and washed with 20 ml of dichloromethane. 0.2 g of ethyl chrysanthemate are obtained.
Reaction SMILES: C([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)C1C=CC=CC=1.[Li]CCCC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[C:19]([N:9]1[CH2:8][CH2:12][O:11][C:10]1=[O:13])(=[O:22])[CH2:20][CH3:21]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1CCOC1=O

Procedure:
Compound 28 was prepared by reaction of (R)-(+)-4-benzyl-2-oxazolidinone with BuLi and propionyl chloride in THF according to standard literature procedures (See, Evans, D. A. Aldrichimica Acta 1982, 15, 23).
Reaction SMILES: [Na].CS([C:5]1[N:20]=[C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[C:12]([NH2:13])[N:7]2[N:6]=1)=O.[C:21]1([CH2:27][CH2:28][OH:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:28]([O:29][C:5]1[N:20]=[C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[C:12]([NH2:13])[N:7]2[N:6]=1)[CH2:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: OCCc1ccccc1
Agent: [Na]
Product: Nc1cc(-c2ccccn2)cc2nc(OCCc3ccccc3)nn12
Reaction time: 16 h
Yield: 83 %

Procedure:
0.06 g (0.003 mol) sodium in 50 ml 2-phenylethanol were stirred overnight at 60° C. 0.2 g (0.0007 mol) 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine added and stirring was continued at 160° C. for 16 hours. Evaporation of the solvent and chromatography on silicagel with ethylacetate gave 0.2 g (83%) 2-phenethyloxy-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, MS m/e (%):332 (M+H+,100).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH:10]1([NH:18][C:2]2[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1c(I)ccnc1F
Reactant: NC1CCCCCCC1
Solvent: ClCCl
Product: Cc1c(I)ccnc1NC1CCCCCCC1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in cyclooctanamine (3.8 g) was heated at 130° C. overnight, cooled and diluted with dichloromethane. The resulting mixture was loaded onto a silica gel cartridge, eluting with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@H:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH:21]([CH3:22])[CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc([N+](=O)[O-])cc3)[C@H]2SC1
Reactant: [H][H]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](NC(=O)Cc3ccc(N)cc3)[C@H]2SC1
Reaction time: 0.08 h

Procedure:
The catalyst was added to a solution of 406 mg of DL cis 7-p-nitrophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid in 3.8 ml of dimethylformamide and 1.12 ml of N hydrochloric acid and a current of hydrogen was passed therethrough until saturated. The mixture was filtered and the filter was washed with a 50--50 water-ethanol solution containing a few drops of hydrochloric acid. The filtrate was evaporated to dryness and the residue was taken up in 3 ml of water. Ammonium formate was added thereto to a pH of 4.5 and the mixture was stirred 5 minutes and vacuum filtered. The precipitate was empasted with water and dried to obtain DL cis 7-p-aminophenylacetamido-3-isopropyl-3-cepheme-4-carboxylic acid melting at 150° C with decomposition. The product occurred as ocre crystals slightly soluble in water, ethanol and chloroform and insoluble in ether.