Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:20][CH2:21][NH:22][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCCN1CCCC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCN2CCCC2)cc1

Procedure:
Starting from 4-acetylaminobenzenesulfonyl chloride and 2-pyrrolidin-1-ylethylamine, the title compound is prepared analogously to the method described in Example 10, intermediate 2. The crude product thus obtained can be used for further reaction without further purification. (MS-ES+: 312.1; LCMS Rt=1.957 min)
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([C:15]1[C:19]2[CH:20]=[CH:21][C:22](/[C:24](/[CH2:43][CH3:44])=[CH:25]\[CH2:26][N:27]([O:35]C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[CH:23][C:18]=2[O:17][C:16]=1[CH2:45][CH3:46])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([C:15]1[C:19]2[CH:20]=[CH:21][C:22](/[C:24](/[CH2:43][CH3:44])=[CH:25]\[CH2:26][NH:27][OH:35])=[CH:23][C:18]=2[O:17][C:16]=1[CH2:45][CH3:46])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC/C(=C/CN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC/C(=C/CNO)c1ccc2c(Cc3ccccc3)c(CC)oc2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of TFA (5 mL) in methylene chloride (10 mL) was added dropwise to the cold (ice bath) solution of tert-butyl (2Z)-3-(3-benzyl-2-ethyl-1-benzofuran-6-yl)pent-2-enyl[(tert-butoxycarbonyl)oxy]carbamate (4.0 g; 7.45 mmol) in methylene chloride (25 mL). The mixture was stirred at ° C. for 1 hour and at room temperature for 1 hour and solvent evaporated. The residue was extracted with ethyl acetate, washed with sodium bicarbonate solution, water, and evaporated to dryness. The residue was chromatographed on silica gel using 2% ethyl acetate in hexane as an eluent to give the title compound (1.8 g) as an oil. 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 2H, J=7.25 Hz), 1.05 (t, 3H, J=7.47 Hz), 1.2-1.25 (m, 6H), 2.35 (q, 2H, J=7.47 Hz), 2.85 (q, 3H, J=7.47 Hz), 3.95 (d, 2H, J=6.59 Hz), 3.96 (s, 2H), 5.55 (t, 1H, J=6.59 Hz), 6.05 (brs, 1H), 6.95 (dd, 1H, J=7.9, 1.32 Hz), 7.22-7.35 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12]1=[O:19].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:20]([O-:22])=[O:21])[C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]([CH3:17])=[C:13]([CH3:18])[C:12]1=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)ccc2F)C1=O
Agent: O=S(=O)(O)O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)c([N+](=O)[O-])cc2F)C1=O
Reaction time: 8 h

Procedure:
26.3 g of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide are introduced in portions, at 5°, into 230 ml of 96% sulphuric acid. There is then added dropwise to this mixture, while stirring vigorously at the same temperature, 5 ml of 100% nitric acid. The whole is further stirred overnight at room temperature and then poured into ice. The product which precipitates is filtered with suction, washed with water, dried and recrystallised from acetonitrile. 28 g of N-(2-fluoro-5-carboxy-4-nitrophenyl)-2,3-dimethylmaleic acid imide which has a melting point of 264°-265° is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)[CH:8]=[O:9].[CH3:15][O:16]C1C(OC)=CC(C=O)=C(O)C=1>>[CH3:15][O:16][C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:11][CH2:12][O:13][CH3:14])[CH:5]=1
Reactant: COCOc1ccc(OC)cc1C=O
Reactant: COc1cc(O)c(C=O)cc1OC
Product: COCOc1cc(OC)c(OC)cc1C=O

Procedure:
4,5-dimethoxy-2-methoxymethoxybenzaldehyde (F2) was prepared in a similar manner for the preparation of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) by using 4,5-dimethoxy-2-hydroxybenzaldehyde (1.75 g, 14.9 mmol) instead of 2-hydroxy-5-methoxybenzaldehyde in 76% (2.56 g): 1H-NMR (500 MHz, CDCl3) δ3.55 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 5.26 (s, 2H), 6.77 (s, 1H), 7.32 (s, 1H) 10.35 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:10](\[CH3:18])/[C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[CH:5][C:4]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:10](\[CH3:18])/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][C:4]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: COc1nc(/C=C(\C)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(/C=C(\C)C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (400 mg), an allylpalladium chloride dimer (32.8 mg), tri-o-tolylphosphine (54.4 mg), sodium acetate (441 mg), dimethylacetamide (0.640 mL), tert-butyl methacrylate (0.724 mL) and toluene (2 mL) was stirred in a nitrogen atmosphere at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature. Then, a silica gel was added and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 313 mg of tert-butyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylate. The ester was diluted with trifluoroacetic acid (2.48 mL) and methylene chloride (2.48 mL), and the reaction solution was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure to obtain 260 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)=[N:16][C:17](=[O:18])[C:12]3=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]2)=[C:4]([Cl:31])[CH:3]=1.C([Mg]Cl)(C)C.CN([CH:40]=[O:41])C>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:40]=[O:41])[CH:3]=[C:4]([Cl:31])[C:5]=1[N:9]1[C:13]2=[N:14][C:15]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11]([CH:28]([CH3:30])[CH3:29])[NH:10]1
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Br)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(C=O)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO4), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469 (M−H)−.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=[O:18].[OH-].[K+]>CS(C)=O>[OH:18][CH2:17][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[C:7](=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 100 parts of benzoin in 240 parts of dimethyl sulfoxide was added dropwise over 10 minutes to a dispersion of 17 parts of paraformaldehyde having a purity of 75% and 2.6 parts of potassium hydroxide in 580 parts of dimethyl sulfoxide and the mixture was agitated for further 15 minutes to effect the reaction which was terminated with addition of diluted hydrochloric acid followed by the admixture of the reaction mixture with 900 parts of water. The thus obtained aqueous solution was extracted with ethyl acetate and the ethyl acetate extract was washed with a saturated aqueous solution of sodium chloride and concentrated by evaporating the solvent under reduced pressure to give 113 parts of α-hydroxymethyl benzoin. The yield was more than 99% of the theoretical value.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([OH:27])(=[O:26])[CH3:25].[H][H]>[Pd].CO.C(OCC)C>[C:24]([OH:27])(=[O:26])[CH3:25].[CH2:15]1[C:16]2([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)[CH2:17][NH:14]1
Reactant: [H][H]
Reactant: O=C1NC(=O)C2(CN(C(c3ccccc3)c3ccccc3)C2)N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: O=C1NC(=O)C2(CNC2)N1
Yield: 69.3 %

Procedure:
A mixture of 2-benzhydryl-2,5,7-triazaspiro[3.4]octane-6,8-dione (0.258 g, 0.839 mmol) and 10% palladium on carbon (0.179 g, 0.168 mmol) in 4 mL MeOH was treated with acetic acid (0.0961 mL, 1.68 mmol) and the slurry was stirred under a balloon containing hydrogen overnight. The reaction was filtered, rinsed with MeOH, and concentrated in vacuo to give an oil. Concentration from benzene gave a solid which was suspended in diethylether, sonicated, filtered, and dried in vacuo to give 2,5,7-triazaspiro[3.4]octane-6,8-dione acetate (0.117 g, 69.3% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:12][N:11]=[N:10][N:7]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(-c2nnn[nH]2)cc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
A mixture of 4-iodobenzonitrile (2.0 g), sodium azide (624 mg) and ammonium chloride (514 mg) in DMF is stirred 22 h at 100° C. DMF is evaporated and the residue is suspended in H2O and treated with conc. aq. HCl. The solid material is collected by filtration, washed with 1 N aq. HCl sol. and H2O and dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]3)=[CH:8][CH:9]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (550 mg, 2.4 mmol) and 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (505 mg, 2.18 mmol) in 50 mL THF was added ADDP (825 mg, 3.28 mmol) and triphenylphosphine (858 mg, 3.28 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The solid was removed by filtration, the filtrate was concentrated and the residue was purified by MPLC (80:20 hexane/EtOAc) to give the desired product 4-{2-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester 800 mg (83%). 1H-NMR (DMSO-d6) δ 7.40 (d, 2H), 7.00 (d, 2H), 5.35 (s, 1H), 5.0 (s, 2H), 4.0 (m, 2H), 3.90 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.20 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=443.3, RT=3.10 min.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH:14]=[N:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:49][O:48][CH2:47]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[C:24](=[O:25])[C:23]5[S:22][C:21]6[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=6[C:15]=5[CH:14]=[N:13]4)[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1)[CH3:51]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A mixture of 120a (120 mg, 0.16 mmol) and lithium hydroxide (38 mg, 1.6 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure. The resulting residue was extracted with ethyl acetate (2×10 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 120 (73 mg, 65%) as a white solid. MS: [M+H]+ 698.3. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=1.5 Hz, 1H), 8.26 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.11 (dd, J=2.5, 8.0 Hz, 1H), 6.82 (d, J=9.0 Hz, 1H), 4.72-4.62 (m, 4H), 4.31 (s, 2H), 4.01 (bs, 1H), 3.71 (s, 3H), 3.53 (t, J=6.0 Hz, 1H), 3.34-3.32 (m, 1H), 3.13 (t, J=6.0 Hz, 2H), 2.99 (t, J=5.0 Hz, 2H), 2.87 (t, J=5.0 Hz, 2H), 2.60-2.56 (m, 1H), 2.46-2.44 (m, 2H), 2.36-2.34 (m, 1H), 2.01-1.96 (m, 4H), 1.71-1.68 (m, 1H), 1.44-1.36 (m, 1H), 0.83 (t, J=7.5 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:63]=[CH:62][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:30][C@@H:31]4[C@H:35]5[O:36]C(C)(C)[O:38][C@H:34]5[C@H:33]([N:41]5[C:45]6[N:46]=[CH:47][N:48]=[C:49]([NH:50]CC7C=CC(OC)=CC=7OC)[C:44]=6[CH:43]=[CH:42]5)[CH2:32]4)[CH2:26][CH:27]4[CH2:29][CH2:28]4)[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:50][C:49]1[C:44]2[CH:43]=[CH:42][N:41]([C@@H:33]3[CH2:32][C@H:31]([CH2:30][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:62]=[CH:63][C:12]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH2:26][CH:27]4[CH2:29][CH2:28]4)[C@@H:35]([OH:36])[C@H:34]3[OH:38])[C:45]=2[N:46]=[CH:47][N:48]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc2[nH]c(CCC3CC(N(CC4CC4)C[C@H]4C[C@@H](n5ccc6c(N)ncnc65)[C@H](O)[C@@H]4O)C3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Trifluoroacetic Acid (10 mL) added to a mixture of Water (1 mL) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclopropylmethyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.52 g, 0.68 mmol) at RT. The reaction was stirred overnight at RT and Triethylsilane (0.22 mL. 1.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls), 500 mgs of K2CO3 and 8 drops H2O were added and the reaction stirred at RT for 1 hour. The mixture was filtered and the filter cake washed with 10 ml MeOH. The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to give the desired product (0.196 g) as an off white foam. MS (ESI+) for C33H45N7O2 m/z 572.6 [M+H]+; MS (ESP) for C33H45N7O2 m/z 570.3 [M−H]−; HPLC purity >90% (ret. time, 2.850 min.) 1H NMR (400 MHz, d4-MeOH) δH 7.944 (s, 1H), 7.361 (s, 1H), 7.280-7.259 (m, 1H), 7.172-7.150 (m, 1H), 7.092-7.078 (m, 1H), 6.484-6.475 (d, J=3.6 Hz, 1H), 4.222-4.185 (m, 1H), 3.815-3.779 (m, 1H), 3.329 (m, 0.5H (methine of trans isomer)), 2.961 (m, 0.5H (methine of cis isomer), 2.745-2.627 (m, 3H), 2.503-2.450 (m, 1H), 2.301-2.187 (m, 5H), 2.036-1.890 (m, 2H), 1.793-1.776 (m, 3H), 1.529-1.385 (m, 2H), 1.246 (s, 9H), 0.808-0.739 (m, 1H), 0.394-0.362 (m, 2H), 0.012-0.013 (m, 2H). Retention time: 2.850 minutes. HPLC Conditions:Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 urn packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA) 6 min gradient from 5 to 95% B; 1 min hold; then recycle.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][N:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:44][C:41]6[CH:42]=[CH:43][C:38]([N:32]7[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]7)=[N:39][CH:40]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccc(N6CCCCC6)nc4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbaldehyde (88.2 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 16.99% yield, 22 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25]1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cn1cc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (85.8 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (42.9 mg) in DMF (1.42 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg). The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (114.8 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10](=[CH:15][CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:31]1([C:34]([CH:36](Br)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[CH:31]1([C:34]([CH:36]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[C:10](=[CH:15][CH3:16])[CH2:9]2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[O:35])[CH2:33][CH2:32]1
Reactant: CC=C1CN(C(=O)OC(C)(C)C)CCC1O
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC=C1CN(C(C(=O)C2CC2)c2ccccc2F)CCC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
In 20 ml of methylene chloride, 1.51 g (6.7 mmol) of 1-(t-butoxycarbonyl)-3-ethylidene-4-hydroxypiperidine were dissolved. To the resulting solution, 5 ml of trifluoroacetic acid were added under ice cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture, 11 ml of triethylamine and 1.70 g (6.7 mmol) of α-cyclopropylcarbonyl-2-fluorobenzylbromide were added under ice cooling, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and the solid so precipitated was filtered off. The filtrate was then concentrated by evaporation under reduced pressure. The residue was subjected to chromatography on a silica gel column (eluting solvent: chloroform/methanol=100/1), whereby 1.52 g (yield: 74.9%) of the title compound were obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: COc1cc(Cl)cc2cccnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc(Cl)cc2cccnc12
Temperature: 150 °C
Yield: 60.4 %

Procedure:
6-Chloro-8-methoxyquinoline (Preparation 43, 10 g, 51.6 mmol) was added to pyridine hydrochloride (43 g, 375 mmol) and the mixture heated at 150° C. 1 hour. The reaction mixture was diluted with water (200 mL), basified to pH=8 with saturated aqueous sodium bicarbonate solution, filtered and concentrated in vacuo. The resulting crude product was purified with silica gel chromatography eluting with 5 to 10% EtOAc in petroleum ether to yield the title compound as a pale yellow solid (5.6 g, 70%):
Reaction SMILES: F[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[C:20](=[O:31])[N:11]3[C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=C[CH:3]=1.CC[O:36]CC>>[O:36]1[CH2:3][CH2:2][CH2:33][CH2:32][CH:5]1[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[O:31])[N:11]2[C:12]=1[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccc(F)cc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Reactant: CCOCC
Product: CC(C)(C)OC(=O)C1=C(CC2CCCCO2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12

Procedure:
Trituration of the oil with ether gave the cephem (X) as a white solid (29 mg), m.p. 175°-185° decomp. M+ m/e 478 (parent peak) and the fragmentations expected for the cephem (X).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[C:18]2[NH2:23])=O)(C)(C)C.[ClH:24].CO>>[ClH:24].[NH2:23][C:18]1[C:19]2[C:14](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1cccc2c(N)nccc12
Agent: Cl
Solvent: CO
Product: NCCCOc1cccc2c(N)nccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 20 (159 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (116 mg) as white powdery solid.