Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([O:30]CC4C=CC=CC=4)=[O:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][C:28]([OH:30])=[O:29])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)OCc4ccccc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)O)cc3)cc2)CC1
Reaction time: 1.5 h

Procedure:
1-[4′-(4-Benzyloxycarbonylmethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.171 g, 0.35 mmol) was stirred in THF (3 mL) and MeOH (3 mL) and 1 N aqueous NaOH (1 mL) was added. After 1.5 hours the reaction was submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:26]C1C=CC2C=C(C(O)=O)SC=2C=1>>[F:26][C:22]1[CH:23]=[CH:24][C:3]2[CH:2]=[C:6]([C:7]([NH:9][C@H:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([OH:13])=[O:12])=[O:8])[S:5][C:4]=2[CH:21]=1
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Reactant: O=C(O)c1cc2ccc(F)cc2s1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1cc2ccc(F)cc2s1
Yield: 93.1 %

Procedure:
Following the 2a synthetic method, using 8-1-acid (98.10 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 13a as a colorless oil (159.84 mg, 93.1%). [α]D25: −21.1 (c=0.33, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.03 (d, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.90-7.86 (m, 1H), 7.75-7.71 (m, 1H), 7.34-7.13 (m, 6H), 4.95-4.87 (m, 1H), 3.36-3.10 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 172.09, 163.11, 161.49, 159.87, 142.28, 139.46, 137.49, 136.19, 129.22, 128.33, 126.89, 126.63, 126.61, 124.44, 114.09, 108.67, 54.08, 37.01; HRMS (ESI): calcd for: C18H14FNO3S [M−H]−=342.0606, obsd [M−H]−=342.0594.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CO.[Pd]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
A suspension of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-6-chloropyrimidine (115.5 mg, 0.0002441 mol), sodium carbonate (62 mg, 0.00058 mol) and 10% Pd/C (26 mg, 0.000024 mol) in methanol (1.1 mL) was stirred under an atmosphere of hydrogen for 2 days. The reaction was purged with nitrogen and filtered through celite with EtOAc. The filtrate was concentrated and the residue was purified by flash chromatography (0 to 15% EtOAc/hexanes) to obtain 80 mg (70%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)[CH:10]=4)[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccnc1COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford N-(1H-indazol-5-yl)-2-(3-((1-methyl-1H-imidazol-2-yl)methoxy)phenyl)quinazolin-4-amine. (5.4 mg, 0.012 mmol).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:4]=2[N:3]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCC(CC)c1ccc(C#N)c2nc(Cl)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CC)c1ccc(C#N)c2nc(Oc3ccc(Cl)cc3Br)n(C)c12
Temperature: 120 °C
Reaction time: 12 h
Yield: 32.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole-4-carbonitrile (250 mg, 0.957 mmol), 2-bromo-4-chlorophenol (595 mg, 2.87 mmol), potassium carbonate (397 mg, 2.87 mmol) and 1-methyl-2-pyrrolidone (0.5 ml) was stirred at 120° C. for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (134 mg, 32%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[NH:15][N:16]=[C:17]([C:22](=[O:26])[CH2:23][O:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19].[CH3:27]OC(OC)N(C)C>>[F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:27]=[C:23]([O:24][CH3:25])[C:22](=[O:26])[C:17]([C:18]([O:20][CH3:21])=[O:19])=[N:16]1
Reactant: COCC(=O)C(=NNc1ccc(N2CCOCC2)c(F)c1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccc(N3CCOCC3)c(F)c2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methyl 2-[(2,3-difluoro-4-morpholin-4-ylphenyl)hydrazono]-4-methoxy-3-oxobutanoate (4.7 g, 13 mmol) in N,N-dimethylformamide dimethyl acetal (20 mL) was stirred at 100° C. for 80 min. After cooling to room temperature, the precipitate was collected by filtration and washed with iPr2O to give the title compound (4.1 g, 84% yield) as a brown powder: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.13 (4H, dt, J=4.4, 2.5 Hz), 3.49-4.05 (10H, m), 7.03 (1H, td, J=8.8, 2.5 Hz), 7.51 (1H, td, J=8.5, 2.3 Hz), 8.53 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 382 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Nc1cnccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN(Cc2ccncc2N)CC1
Temperature: 60 °C
Yield: 104.9 %

Procedure:
3-Amino-pyridine-4-carbaldehyde (5.00 g, 40.9 mmol) was dissolved in DCM (60 mL), ethyl 4-piperidinecarboxylate (7.57 mL, 49.1 mmol) and NaBH(OAc)3 (10.4 g, 49.1 mmol) were added and the reaction mixture was heated in a microwave reactor at 60° C. for 5 min. The reaction mixture was diluted with DCM (100 mL) and quenched with sat aq Na2CO3 (50 mL). The organic fraction was washed with sat aq NH4Cl (30 mL). The combined aq fractions were extracted with DCM (2×50 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow gum (11.3 g). LCMS (ES+): 264.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH2:5][C:6]2=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:10])[CH:8]2[CH2:9][CH:3]1[CH2:4][CH:5]=[C:6]2[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C2CCC(=O)C1C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C2CC=C(N3CCCC3)C1C2
Yield: 95.1 %

Procedure:
A solution of 30 g of nopinone ([α]D20 =+39.90; c=8 in ethanol), 29 g of pyrrolidine and 0.4 g of p-toluene-sulfonic acid in 150 ml anhydrous benzene was heated at reflux for 40 h under nitrogen atmosphere in a vessel fitted with a water separator. After evaporation of the solvent and distillation of the residue, there were obtained 39.5 g (95% yield) of 1-(6,6-dimethylnorpin-2en-2-yl)-pyrrolidine having b.p. 117°-118° C./10 Torr.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:19](OC)(=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C1COCC1>[CH3:23][O:22][C:20](=[O:21])[C:19]([C:9]1[CH:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:24]
Reactant: COc1cc(Br)c2c(ccn2C)c1
Reactant: COC(=O)C(=O)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(OC)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 1-methyl-5-methoxy-7-bromoindole (1.6 g, 6.66 mmol) in THF (44.5 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 8.62 mL, 14.7 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (1.96 g, 16.7 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the extracts washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (0.9 g, 54.7%) as bright yellow oil. 1HNMR (400 MHz, CDCl3) 3.83 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 6.51 (d, J=3.12 Hz, 1 H), 7.07 (d, J=3.13 Hz, 1H), 7.21 (d, J=2.35 Hz, 1H), 7.7.40 (d, J=2.34 Hz, 1H); MS (ES, m/z): C13H13NO4: 188.06 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH2:38])[CH3:34]>O1CCCC1>[CH2:33]([O:35][C:36](=[O:39])[CH2:37][NH:38][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:34]
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: CCOC(=O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 56.3 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (9.50 g, 0.033 mole), 1,1'-carbonyldiimidazole (5.35 g, 0.033 mole) and anhydrous tetrahydrofuran (300 ml) was stirred at room temperature for 2 hrs with a stream of nitrogen bubbling through it. To the resulting suspension was added glycine ethyl ester (8.0 g, 0.078 mole) and the solution stirred over the weekend. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate (150 ml) and potassium bicarbonate solution (75 ml). The organic layer was washed with potassium bicarbonate solution (2×50 ml), water (50 ml), brine (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (10 g) was recrystallized from tetrahydrofuran-isopropyl ether to give 6.93 g (56%) of an off-white solid, m.p. 144°-145° C.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[C:30]1[O:34][CH:33]=[N:32][CH:31]=1)[C:24](O)=[O:25]>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:29]([C:30]4[O:34][CH:33]=[N:32][CH:31]=4)=[C:21]([F:20])[CH:22]=3)[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.26 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[C:6](O)[C:5](O)=[CH:4][C:3]=1O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>>[CH:7]1[C:6]2[NH:18][C:13]3[C:12](=[CH:17][C:16]4[NH:11][C:12]5[C:13]([NH:18][C:15]=4[CH:14]=3)=[CH:14][CH:15]=[CH:16][CH:17]=5)[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: Oc1cc(O)c(O)cc1O
Product: c1ccc2[nH]c3cc4[nH]c5ccccc5[nH]c4cc3[nH]c2c1

Procedure:
In some particular embodiments, one molar unit of the 1,2,4,5-tetrahydroxybenzene compound is reacted with about one molar unit of a first 1,2-diaminobenzene compound to form an intermediate, and the intermediate is subsequently reacted with about one molar unit of a second 1,2-diaminobenzene compound to form the 5,7,12,14-tetrahydro-5,7,12,14-tetraazapentacene compound. The first 1,2-diaminobenzene compound and the second 1,2-diaminobenzene compound are different.
Reaction SMILES: I/[CH:2]=[CH:3]/[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)#[CH:19]>>[CH3:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[C:4]([CH:3]=[CH:2][C:19]#[C:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:9]=1
Reactant: Cc1ccc(-c2ccc(C)cc2/C=C/I)cc1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: Cc1ccc(-c2ccc(C)cc2C=CC#Cc2ccc(C(=O)O)cc2)cc1
Yield: 10.4 %

Procedure:
In a similar manner to that of Example 1(e), by reaction of 4.00 g (12.0 mmol) of 2-((E)-2-iodovinyl)-4,4'-dimethylbiphenyl obtained in Example 12(f) with 1.74 g (10.9 mmol) of methyl 4-ethynylbenzoate, 400 mg (10%) of the expected compound are obtained in the form of yellow flakes with a melting point of 95-97° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C(=O)C(F)(F)F)=[N:4][C:3]=1[C:14](=[N:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[C:15]([NH:17][CH:18]1[C:31](=[O:32])[N:20]2[C:21]([C:28]([OH:30])=[O:29])=[C:22]([CH2:25][S:26][CH3:27])[CH2:23][S:24][C@H:19]12)=[O:16].C([O-])(=O)C.[Na+]>O>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:14](=[N:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[C:15]([NH:17][CH:18]2[C:31](=[O:32])[N:20]3[C:21]([C:28]([OH:30])=[O:29])=[C:22]([CH2:25][S:26][CH3:27])[CH2:23][S:24][C@H:19]23)=[O:16])[N:4]=1
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nc(NC(=O)C(F)(F)F)sc3Cl)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3nc(N)sc3Cl)[C@H]2SC1
Yield: 80.5 %

Procedure:
A solution of 7-[2-(5-chloro-2-trifluoroacetamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.5 g) and sodium acetate (5.6 g) in water (25 ml) was stirred at ambient temperature for 13 hours. The resultant solution was washed with ethyl acetate and the separated aqueous layer was treated with active-charcoal. And the aqueous layer was adjusted to pH 2.3 with 10% hydrochloric acid. The precipitates were collected by filtration and washed with water. The precipitates were dried under reduced pressure to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.7 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37]>C1COCC1.CCOC(C)=O>[OH:37][CH2:36][C:35]([NH:34][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][N:11]=2)[CH:15]=1)(=[O:21])=[O:22])([CH3:39])[CH3:38]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)Cl)c3)c2)n1
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1
Temperature: 25 °C
Yield: 16 %

Procedure:
The title compound was prepared from the solution of 3-[6-methyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonyl chloride (example 346 step 2) (ca. 0.2 g, 0.41 mmol) by treatment with excess 2-amino-2-methyl-1-propanol in THF (5 mL) at 50° C. for 16 h. Cooled to rt, diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.035 g, 16%) as a white solid. MS (ISP) 542.2 [(M+H)+]; mp 92° C.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:45])[N:41]([CH2:43][CH3:44])[CH:42]=1>>[CH2:43]([N:41]1[C:40](=[O:45])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1)[CH3:44]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCn1cc(Br)ccc1=O
Product: CCn1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccc1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1. LC-MS Method 2 tR=1.224 min, m/z=475.1; 1H NMR (CDCl3) 1.11 (s, 3H), 1.19 (s, 3H), 1.39 (t, 3H), 1.56 (d, 3H), 2.20 (s, 2H), 2.26 (m, 1H), 2.36-2.57 (m, 2H), 2.87 (m, 1H), 4.03 (m, 2H), 5.69 (m, 1H), 6.62 (d, 1H), 7.00 (d, 2H), 7.17 (d, 2H), 7.28-7.51 (m, 6H), 7.50 (d, 1H). Recrystallization from isopropyl acetate following a procedure analogous to that described for Example 37 in Recrystallization Method B afforded a crystalline solid with mp 167-168° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]([CH2:13][OH:14])([CH2:11][OH:12])[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH3:19])=O.COC(OC)(C)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([C:7]1([C:8](=[O:10])[CH3:9])[CH2:11][O:12][C:17]([CH3:19])([CH3:16])[O:14][CH2:13]1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(CO)(CO)C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC(=O)C1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 2,2-bis-hydroxymethyl-3-oxo-butyric acid tert-butyl ester (8.67 g, 40 mmol), acetone (30 mL, 400 mmol), 2,2-dimethoxypropane (41.6 g, 50 mL, 400 mmol) and 4-toluenesulfonic acid hydrate (152 mg, 0.8 mmol) was stirred at room temperature for 18 h. The solvent was partially evaporated to a volume of ˜20 mL. Saturated sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine. The organic layer was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 9:1 to 4:1 to afford the title compound (7.82 g, 75%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 3H), 1.44 (s, 3H), 1.48 (s, 9H), 2.32 (s, 3H), 6.36 (ABq, ΔδAB=0.05, JAB=11.8 Hz, 4H). LCMS (m/z) 281.2 [M+Na], Tr=2.44 min.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCN(C)CC4)c3)ccc2OC)c1

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylhexahydro-1H-1,4-diazepine (13.7 mg, 15.2 μL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid. Further purification was carried out on an Agilent HPLC with RP-CH3CN:H2O-conc. aq. NH3 gradient [4.5 mg (7.25%)]. LC-MS m/z 773.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[C:16]#[N:17].[CH3:18][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:18])[N:7]=1
Reactant: C[O-]
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccco1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 210 mg (0.87 mmol) 6-amino-4-furan-2-yl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.16 ml (0.87 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.11 ml (1.73 mmol) methyl iodide and stirring continued for 90 minutes at room temperature. The reaction mixture was then poured onto 100 ml ice-water and the resulting crystals collected by filtration and dried in vacuo to afford 135 mg (61%) 2-amino-4-furan-2-yl-6-methylsulfanyl-pyridine-3,5-dicarbonitrile as a light brown crystalline solid. EI-MS m/e (%): 256 (M+, 49), 255 ([M—H]+, 100).