Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]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].[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][N:48]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C@H:47]12[CH2:53][C@H:50]([NH:51][CH2:52]1)[CH2:49][N:48]2[CH2:43][C:39]1[CH:38]=[C:37]([C:32]2[C:33]([CH3:36])=[CH:34][CH:35]=[C:30]([CH2:29][N:20]([CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:45][CH3:46])[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[CH:31]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3C[C@@H]4C[C@H]3CN4)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), tert-butyl (1S,4S)-(−)-2,5-diazabicyclo[2.2.1]Heptane-2-carboxylate (17.51 mg, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-({3′-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-6-methyl-3-biphenylyl}methyl)-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide as a solid (34 mg, 54.6%). LC-MS m/z 705 (M+H)+, 0.68 min (ret time).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:18]([N:2]([CH3:1])[CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 63.9 %

Procedure:
N-methyl-1-[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (1.05 g, 4.1 mmol), benzylbromide (0.49 ml, 4.1 mmol), potassium carbonate (0.68 g, 4.9 mmol) and ACN (20 ml) were heated at 50° C. for 12 h. EtOAc was added, the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:2) afforded the title compound (0.91 g). 1H-NMR (400 MHz, MeOH): δ 7.38 (1H, dd, J 8.4 Hz, J2 1.6), δ 7.28-7.14 (7H, m), δ 5.17 (1H, t, J 4.0 Hz), δ 4.90 (2H, dd, J 52.0 Hz, J2 19.6 Hz), δ 3.59 (2H, dd, J 18.4 Hz, J2 13.2 Hz), δ 2.99 (3H, s), δ 2.78-2.67 (2H, m), δ 2.29 (3H, s). Chiral separation was performed according to Preparation 16. The flow rate was 30 ml/min. Repeated injections (˜40 mg) every 7-8 min. Totally 25 injections afforded the two different enantiomers. The first eluted peak consisted of (−)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.). The second eluted peak consisted of (+)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.).
Reaction SMILES: C(O[N:9]=[C:10]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:12][CH:11]1[OH:18])C1C=CC=CC=1.B.O.[OH-].[K+]>C1COCC1.[Cl-].[Na+].O>[NH2:9][C@@H:10]1[C:17]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:12][C@@H:11]1[OH:18]
Reactant: OC1Cc2sccc2C1=NOCc1ccccc1
Agent: B
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1c2ccsc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-hydroxy-5,6-dihydro-cyclopenta[b]thiophen-4-one O-benzyl-oxime (55.1 g, 0.212 mol) was added drop wise at about 5° C. to 1.0 M solution of borane in THF (650 mL) and the mixture was stirred at room temperature overnight. The mixture was refluxed for two hours and cooled to about 5° C. Water (70 mL) and 20% potassium hydroxide solution (80 mL) was added dropwise. The mixture was refluxed for two hours and cooled. Brine was added and the THF removed under reduced pressure. The mixture was extracted five times with DCM, dried with sodium sulphate and evaporated under reduced pressure. The product was purified by silica gel chromatography with DCM and 10% methanol. Yield: 17.8 g=54%
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:22]([NH:32]C(=O)C(F)(F)F)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[N:13][C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[N:5][N:6]2[CH3:39].[OH-].[Li+].Cl>CCO>[NH2:32][C@H:22]([C:12]1[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:39])[N:5]=[C:4]3[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:16][CH:15]=[C:14]([N:17]([CH2:19][CH2:20][OH:21])[CH3:18])[N:13]=1)[CH2:23][C:24]1[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CN(CCO)c1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(C)c23)c([C@@H](N)Cc2cc(F)cc(F)c2)n1
Temperature: 130 °C

Procedure:
To a solution of crude (S)—N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2,2,2-trifluoroacetamide (57E) in EtOH (1 mL) was added aqueous 2M lithium hydroxide (0.4 mL). The reaction was heated at 130° C. in a microwave reactor for 5 minutes. Upon cooling, aqueous 2N HCl was added until the solution became slightly acidic (pH 4-5). The reaction mixture was then concentrated and taken up in equal volumes of EtOAc and saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer was extracted with a second volume of EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and used without further purification. MS (m/z) 565.09 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[N:8][CH:7]=[CH:6][N:5]2[CH:16]=1.[NH:17]1[CH2:20][CH:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[CH2:18]1>>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH:19]1[CH2:18][N:17]([C:2]2[N:3]=[C:4]3[C:9]([N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[N:8][CH:7]=[CH:6][N:5]3[CH:16]=2)[CH2:20]1
Reactant: Clc1cn2ccnc(N3CCOCC3)c2n1
Reactant: c1ccc2nc(C3CNC3)ccc2c1
Product: c1ccc2nc(C3CN(c4cn5ccnc(N6CCOCC6)c5n4)C3)ccc2c1

Procedure:
Compound 25a was prepared from compound 24a and compound 24d using the procedure described in Example 24, Step E. Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H22N6O: 387.2 (M+H). Found 387.2.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37]>>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH:32][CH:36]=[O:37])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28][CH3:29])=[O:27])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21)NC=O

Procedure:
195 mg of 5(S)-amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 18)) are reacted with 128 mg of 4-nitrophenyl formate in a manner analogous to that described in Example 17) and the product is purified over 30 g of silica gel (mobile phase M). The title compound is obtained as a yellowish-coloured solid: Rf (N)=0.20; FAB-MS: (M+H)+ =536.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH3:45])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:43][O:44][CH3:45])[C:10]([NH:12][C@@H:13]2[C:41](=[O:42])[N:15]3[C:16]([C:38]([O-:40])=[O:39])=[C:17]([CH2:20][N+:21]4([CH3:37])[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C:28]5[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=5)[CH2:23][CH2:22]4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4ccc(O)c(O)c4)CC3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
To a suspension of 7β-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(3,4-dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (1.52 g) in methanol (9 ml) was added concentrated hydrochloric acid (1.92 ml). After being stirred at room temperature for 4 hours, the solution was poured into ice water (40 ml) and adjusted to pH 2 with a saturated aqueous solution of sodium bicarbonate. The mixture was concentrated in vacuo to remove methanol. The concentrate was adjusted to pH 2 with a saturated aqueous solution of sodium bicarbonate and subjected to column chromatography on "Diaion HP-20" (40 ml), and the elution was carried out with 40% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and lyophilized to give 7β-[2-(2-aminothiazol-4-yl) -2-methoxyiminoacetamido]-3-[1-methyl-4-(3,4dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4carboxylate (syn isomer) (548 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][NH:23][C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl.O>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@@H:20]4[CH2:25][CH2:24][N:23]([CH3:35])[C@H:22]([C:26]([O:28][CH3:29])=[O:27])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
Methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylate (13) (0.35 g, 0.76 mmol) was dissolved in a solution of 15% Acetic acid/methylene chloride (6.1 ml). To this was then added powdered 4A° molecular sieves (0.63 g) and the resulting suspension stirred for 5 minutes. 37% formaldehyde in water (0.56 ml) was added drop-wise and the mixture stirred a further 2 minutes. Sodium triacetoxyborohydride (0.29 g) was added in one portion. The reaction mixture was stirred a further 2 hours at room temperature, filtered and evaporated. The residues were partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The crudes were purified by column chromatography on SiO2 eluting with increasingly polar mixtures of DCM/methanol (100/0-95/5). The fractions containing the desired product were combined and evaporated to give methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) as a foam (252 mg, 70%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.78 (2H, m), 2.05-2.35 (6H, m), 2.95-3.04 (2H, m), 3.63 (3H, s), 3.94 (3H, s), 4.51-4.59 (1H, m), 7.23 (1H, s), 7.29-7.31 (1H, m), 7.49-7.56 (2H, m), 7.84 (1H, s), 8.39 (1H, s), 9.55 (1H, s); Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:21]C[NH:19][C:18](=[O:22])[CH2:17]2)=[O:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.BrC1C=C(C(O)=O)OC=1C1C=CC=C(Cl)C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([N:16]2[CH2:17][C:18](=[O:22])[NH:19][CH2:21]2)=[O:15])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc(Br)c(-c2cccc(Cl)c2)o1
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 24A and the compound from Example 35A. 1.1 equivalents of PyBOP and 2.5 equivalents of N,N-diisopropylethylamine are used. During the reaction, the product precipitates. The precipitate is collected by suction filtration, washed with tetrahydrofuran and dried under high vacuum. 870 mg (71% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:13][C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)[NH:5][CH2:4]1.IC.[C:30]([O-])(O)=O.[Na+].O>CN(C=O)C>[OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:13][C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=3)=[CH:9][CH:10]=2)[N:5]([CH3:30])[CH2:4]1
Reactant: O=C([O-])O
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1)Nc1ccc2c(c1)NCC(CO)C2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1CC(CO)Cc2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (2E)-N-[3-(hydroxymethyl)(7-1,2,3,4-tetrahydroquinolyl)]-3-[4-(trifluoromethyl)phenyl]prop-2-enamide, Example 87, (75 mg, 0.20 mmol), iodomethane (0.014 mL, 0.22 mmol, Aldrich) and NaHCO3 (84 mg, 1.0 mmol) in DMF (1.0 mL, Aldrich) was stirred for 4 h at room temperature. Water (5 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (5 mL), satd NaCl (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/CH2Cl2) provided the title product as a white solid. MP 167-169° C. MS (ESI, pos. ion) m/z: 391 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40]([OH:42])=O)[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:43])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH3:63][O:64][NH:65][CH3:66].CN1CCOCC1.Cl>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[O:42])[N:65]([O:64][CH3:63])[CH3:66])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:43])[CH2:24][CH2:25]3)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CNOC
Reactant: COc1cc(C(=O)O)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N(C)OC)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 107.2 %

Procedure:
To 10 mL of a tetrahydrofuran solution containing 600 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-carboxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 420 mg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 108 mg of O,N-dimethylhydroxylamine hydrochloride and 112 mg of N-methylmorpholine were added, and stirred at room temperature for 22 hours. Hydrochloric acid was added to the reaction mixture to make acidic, the organic layer was separated, washed sequentially with water, aqueous saturated sodium hydrogen carbonate solution and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate], to give 0.69 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-5-((methoxy)(methyl)carbamoyl)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 82.6 %

Procedure:
The nitrile 20A (3 g, 12 mmol) dissolved in 50 ml of diethyl ether was added dropwise to a mixture of LiAlH4 (912 mg, 2 equiv.) in diethyl ether (80 mL) and stirred at 0° C. Then, the mixture was stirred at room temperature overnight. The excess of LiAlH4 was destroyed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was dried over Na2SO4 and evaporated to dryness to obtain 2.5 g of the amine as a yellow oil. The amine was used for the following step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:25]#[N:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:34]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:34][C:15]1[N:14]([CH2:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:13]2[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:9][C:10]([C:25]#[N:26])=[CH:11][C:12]=2[N:16]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1 g, 2.73 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.16 g, 8.20 mmol) was added and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (0.938 g, 3.28 mmol) was added in 1 portion and the reaction was continued with stirring at 35° C. After 1 hour, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 75% EtOAc/hexanes provided 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1B1OC(C)(C)C(C)(C)O1.ClCCl.C(OCC)(=O)C>CO.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Temperature: 25 °C

Procedure:
A solution of 28.4 g (99.0 mmol) of Na2CO3(H2O)10 in a mixture of 150 ml of methanol and 580 ml of water was added to a mixture of 7.38 g (39.7 mmol) of 6-bromopyridine-2-carbaldehyde, 14.8 g (39.7 mmol) of 2-methyl-N-{ [1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}aniline and 2.29 g (2.00 mmol) of Pd(PPh3)4 in 720 ml of toluene by vigorous stirring at room temperature. The resulting mixture was stirred at 80° C. for 12 h. Further on, this mixture was cooled to room temperature, the organic layer was separated, dried over MgSO4, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-ethyl acetate=100:1 and then 20:1). Yield 10.7 g (76%). Anal. calc. for C24H20N2O: C, 81.79; H, 5.72; N, 7.95. Found: C, 81.91; H, 5.80; N, 7.81. 1H NMR (CDCl3): 10.10 (s, 1H, CHO), 8.01-8.05 (m, 2H, 3,4-H in Py), 7.96 (d, J=8.6 Hz, 1H, 4-H in naphthyl), 7.90 (m, 1H, 8-H in naphthyl), 7.68-7.70 (m, 2H, 5-H in Py and 3-H in naphthyl), 7.60 (m, 1H, 7-H in naphthyl), 7.41 (m, 1H, 6-H in naphthyl), 7.81 (m, 1H, 5-H in naphthyl), 7.03 (m, 2H, 3,5-H in Ph), 6.63 (m, 1H, 4-H in Ph), 6.50 (m, 1H, 6-H in Ph), 4.22 (m, 2H, CH2N), 3.93 (br. s, 1H, NH), 2.10 (s, 3H, Me).