Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:30]2[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=2)([CH3:29])[CH2:6][C:5]1([CH3:39])[CH3:38])(=[O:3])[CH3:2].B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl.C(OCC)(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:28])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)([CH3:29])[CH2:6][C:5]1([CH3:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: COc1ccc(C2(C)CC(C)(C)N(C(C)=O)c3ccc(NC(=O)c4ccc(-c5ccccc5)cc4)cc32)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2C(C)(c2ccc(O)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 1-acetyl-4-(4-methoxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (0.46 g) in CH2Cl2 was added BBr3 under a nitrogen atmosphere. Complete conversion was reached after stirring for 3 h at room temperature. The mixture was cooled, 1 M NaOH was added until basic pH, subsequently ethyl acetate was added and the mixture was acidified with 1 M HCl. The organic layer was separated, dried (MgSO4) and concentrated. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/00/1 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:13]([CH:17]=[CH:18][S:19][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][S:15](=O)[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)Cl.C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:42](=[O:43])[N:11]2[C:12]([C:26]([O:28][CH:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:27])=[C:13]([CH:17]=[CH:18][S:19][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ncccn3)CS(=O)[C@H]12
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ncccn3)CS[C@H]12
Temperature: -30 °C

Procedure:
To a solution of benzhydryl 7-tert-butoxycarbonylamino-3-[2-(2-pyrimidinyl)thiovinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer) (4.8 g) in N,N-dimethylformamide (25 ml) was added phosphorus trichloride (0.8 ml) at -30° C. After being stirred for an hour at -30° C., the reaction mixture was poured into a mixture of ethyl acetate (300 ml) and water (300 ml). The separated organic layer was washed in turn with 5% aqueous solium bicarbonate, water and brine. The solvent was evaporated in vacuo to give benzhydryl 7-tert-butoxycarbonylamino-3-[2-(2-pyrimidinyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) and it was added with acetnitrile (100 ml) and p-toluene sulfonic acid (3.5 g). The mixture was stirred for 2 hours at 35° C. After removal of the solvent the residue was dissolved in ethyl acetate and 5% aqueous sodium bicarbonate. The separated organic layer was washed in turn with water and bine, dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-amino-3-[2-(2-pyrimidinyl)thiovinyl]-3-cephem-4-carboxylate (trans isomer) (2.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1.[CH3:16][N:17]([CH:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC[Al](Cl)CC.C1C=CC2N(O)N=NC=2C=1.C[N+]1([O-])CCOCC1>CN(C)C=O.O.CCOC(C)=O>[C:21]([O:20][C:18](=[O:19])[N:17]([C@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26]([N:11]1[CH2:12][CH2:13][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:14][CH3:15])=[CH:9][CH2:10]1)=[O:27])[CH3:16])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(F)cc1C1=CCNCC1
Reactant: CN(C(=O)OC(C)(C)C)C(Cc1ccccc1)C(=O)O
Agent: CC[Al](Cl)CC
Agent: C[N+]1([O-])CCOCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C1=CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
The crude product of 4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine (0.49 g, 2.4 mmole) was dissolved in N,N-dimethylformamide (10 mL) at 0° C., and the resulting solution treated with 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-3-phenyl-propionic acid (0.73 g, 2.6 mmole) in a minimal amount of DMF, DEAC (0.50 g, 2.6 mmole), HOBT (0.42 g, 3.1 mmole) and NMO (0.40 mL, 3.6 mmole). The mixture was stirred overnight, and was diluted with water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with HCl (1N), saturated NaHCO3, and the combined aqueous washings were extracted three times with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford (R)-{1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridin-1-yl]-2-oxo-ethyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:5].[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([N+]([O-])=O)[C:22]=1[C:23]#[N:24])([O-:20])=[O:19]>>[C:23]([C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=[CH:26][C:25]=1[O:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)=[O:5])#[N:24]
Reactant: COc1ccc(CNC(=O)C(C)(C)CO)cc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COc1ccc(CNC(=O)C(C)(C)COc2cccc([N+](=O)[O-])c2C#N)cc1
Yield: 95 %

Procedure:
Prepared as in Example 215c from 3-hydroxy-N-(4-methoxybenzyl)-2,2-dimethylpropanamide (Example 220d) and 2,6-dinitrobenzonitrile in 95% yield as a pale yellow solid. MS 384 (MH+).
Reaction SMILES: [N:1]([C:4]1[N:8]([C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[CH2:10]2)[C:7]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:6]=2[N:5]=1)=[N+]=[N-]>CCO.[Ni]>[NH2:1][C:4]1[N:8]([C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[CH2:10]2)[C:7]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:6]=2[N:5]=1
Reactant: [N-]=[N+]=Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: [Ni]
Solvent: CCO
Product: Nc1nc2cc(Cl)c(Cl)cc2n1[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
A mixture of 110b (1.032 g, 3 mmol) and Ra-Ni (0.24 g, wet) in 30 mL of EtOH was hydrogenated (50 psi of H2) at room temperature for 6 Hr. The reaction mixture was filtered and the filtrate was evaporated. The residue was suspended in 20 mL of MeCN and the suspension was filtered to give 0.856 g (90%, 2 crops) of 113 as a white solid. Analytical sample (as white needles) was obtained by recrystallization from MeOH/MeCN. MP: 216°-221° C. (dec.). MS: (El) m/e 317.0340 (37%, M+ =317.0334). 1H NMR (DMSO-d6): d 7.71 (s, 1, 7-H), 7.29 (s, 1, 4-H), 6.93 (br s, 2, 2-NH2), 6.23 (dd, 1, 1'-H, J1'-2' =8.5 Hz, J1'-2" =6.0 Hz), 5.40 (t, 1, 5'-OH, J5' -5'OH =4.5 Hz), 5.34 (d, 1, 3'-OH, J3'-3'OH= 4.0 Hz), 4.40 (m, 1, 3'-H, J3'-2' =7.0 Hz, J3'-2" =2.0 Hz, J3'-4' =2.5 Hz), 3.82 (m, 1, 4'-H, J4'-5' =2.5 Hz), 3.68 (m, 2,5'-H), 2.40 (m, 1, 2'-H, J2'-2" =13.0 Hz), 2.05 (m, 1, 2"-H). 13C NMR (DMSO-d6): d 155.85 (C2), 143.16 (C3a), 132.40 (C7a), 122.94, 119.77 (C5 and C6), 115.35 (C4), 110.69 (C7), 86.91 (C4'), 83.87 (C1'), 70.20 (C3'), 60.74 (C5'), 38.05 (C2'). Anal. Calcd. for C12H13Cl2N3O3 : C, 45.30; H, 4.12; N, 13.21. Found: C, 45.44; H, 4.10; N, 13.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:13])=O)=[O:8])=[CH:5][CH:4]=1.N1C=CC=C[CH:20]=1.CC(OC(C)=O)=O>O>[C:11]([CH:10]([NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1)[CH2:14][CH:15]=[CH2:16])(=[O:13])[CH3:20]
Reactant: C=CCC(NC(=O)c1ccc(OC)cc1)C(=O)O
Reactant: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CCC(NC(=O)c1ccc(OC)cc1)C(C)=O
Reaction time: 0.75 h

Procedure:
To a solution of 8.41 g of the above prepared 2-(4-methoxy-benzoylamino)-pent-4-enoic acid (33.7 mmol) was added successively 21.2 ml of pyridine and 15.95 ml of Ac2O (5 eq.). The reaction mixture was then kept for 45 min. at 90°. After cooling, 15.8 ml of water was added and the mixture again kept for 30 min. at 85° to ensure complete hydrolysis. Afterwards, it was poured onto crashed ice/HCl, extracted twice with AcOEt, washed with 2N HCl and water, and dried over natrium sulfate. Evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 6.45 g of the title compound as yellow solid of mp. 58-59°.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]=1.[Li+].[OH-]>O1CCCC1>[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH:11]=[C:6]([CH2:5][CH2:4][C:3]([OH:24])=[O:2])[C:7]2=[O:23])=[CH:14][CH:15]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(NC(C)=O)cc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CN2CCC=C(CCC(=O)O)C2=O)cc1

Procedure:
3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid methyl ester (i) prepared by above Step 2 of Example 18 dissolved in organic solvent such as tetrahydrofurane was reacted with LiOH to give 3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid (k).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:45]([C:41]2[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=2)(=[O:47])=[O:46])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1CN(S(=O)(=O)c2cccnc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (30.2 mg, 0.071 mmol) in CH2Cl2 (3 mL) was added DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (22.8 mg, 0.106 mmol, Acme Bioscience). It was stirred at rt for 3 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and pyridine-3-sulfonyl chloride hydrochloride (Acme Bioscience, 25.2 mg, 0.118 mmol) were added. After 4 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (20.3 mg, 50.4%). HRMS (ES+) m/z Calcd for C27H25Cl2F2N3O2S+H [(M+H)+]: 564.1086; Found: 564.1087.
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)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N: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].[NH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C>CS(C)=O>[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:51]6[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]6)[CH:42]=5)[C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:30])[N: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: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)n1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide (40.0 mg. 0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing piperazine (0.178 mmol) and acetic acid (0.059 mmol, 3.55 mg) and with fitted magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.592 mmol, 138 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered off and purification was completed via a Gilson HPLC (basic conditions) to afford 8.32 mg of the title compound (18.9%). LC-MS m/z 746 (M+H)+, 1.27 min (ret time).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH:17][C:25](=[O:26])[CH2:24][Cl:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the product from Step B (6.200 g, 19.07 mmol) in 100 mL of EtOAc and 100 mL of saturated NaHCO3 solution at 0° C. was added chloroacetyl chloride (2.28 mL, 28.6 mmol). After one hour, the solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([O-])=[O:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])c1cnc2cc(-c3ccccc3)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cnc2cc(-c3ccccc3)ccc2c1
Yield: 39 %

Procedure:
In substantially the same manner as in Reference Example 72, 7-phenyl-3-quinolinecarboxylate was subjected to reduction with lithium aluminum hydride to obtain 7-phenyl-3-quinolylmethanol. The yield was 39%. Recrystallization from ethyl acetate-hexane gave colorless prisms, 128-129° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:19][CH2:20][CH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[C@H:31]2[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]2)=[C:24]([NH:41][CH2:42][CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:23]=1.[C:56]1(=O)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>ClCCl>[CH:56]1([NH:19][CH2:20][CH2:21][C:22]2[N:30]=[C:29]3[C:25]([N:26]=[CH:27][N:28]3[C@H:31]3[C@H:35]([OH:36])[C@H:34]([OH:37])[C@@H:33]([CH2:38][O:39][CH3:40])[O:32]3)=[C:24]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:23]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNC4CCCCC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
Sodium triacetoxyborohydride (75 mg, 0.35 mmol) and acetic acid (16 mg, 0.27 mmol) were added sequentially to a stirred solution of (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (120 mg, 0.24 mmol) and cyclohexanone (23 mg, 0.235 mmol) in dichloromethane (15 ml). The resulting mixture was stirred at room temperature for 24 hr, diluted with dichloromethane and washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate, water and brine. The organic phase was dried with anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (95:5:0.5) changing to dichloromethane:methanol:ammonia (90:10:1) to afford the title compound as a solid (78 mg). MS: 587 (MH+).
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]4)=[CH:49][CH:50]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O
Yield: 82 %

Procedure:
The compound of example 259 was prepared analogous to compound of example 257 by hydrolysis of compound of example 258.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[C:50]([C:52]1[C:56]([C:57]2[N:62]=[C:61]([C:63](=[O:66])[NH:64][CH3:65])[C:60]([NH:67][C:68]3[C:73]([C:74]([F:77])([F:76])[F:75])=[CH:72][N:71]=[C:70]([NH:78][C:79]4[CH:93]=[CH:92][C:82]([CH2:83][P:84](=[O:91])([O:88]CC)[O:85][CH2:86][CH3:87])=[CH:81][C:80]=4[O:94][CH3:95])[N:69]=3)=[CH:59][CH:58]=2)=[CH:55][N:54]([CH2:96][CH2:97][CH2:98][OH:99])[N:53]=1)#[N:51]>>[C:50]([C:52]1[C:56]([C:57]2[N:62]=[C:61]([C:63](=[O:66])[NH:64][CH3:65])[C:60]([NH:67][C:68]3[C:73]([C:74]([F:77])([F:75])[F:76])=[CH:72][N:71]=[C:70]([NH:78][C:79]4[CH:93]=[CH:92][C:82]([CH2:83][P:84](=[O:88])([OH:91])[O:85][CH2:86][CH3:87])=[CH:81][C:80]=4[O:94][CH3:95])[N:69]=3)=[CH:59][CH:58]=2)=[CH:55][N:54]([CH2:96][CH2:97][CH2:98][OH:99])[N:53]=1)#[N:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4C#N)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4C#N)nc3C(=O)NC)n2)c(OC)c1
Yield: 100.4 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[3-cyano-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 52B, 259 mg, 0.361 mmol) to afford 250 mg of the title compound (100%). 1H NMR (400 MHz, CD3OD) δ 9.09 (d, J=7.8 Hz, 1H), 8.88 (br. s., 1H), 8.30 (s, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.51 (br. s., 1H), 7.11 (s, 1H), 6.97 (d, J=7.8 Hz, 1H), 4.39 (t, J=6.8 Hz, 2H), 3.83-3.94 (m, 5H), 3.62 (t, J=5.9 Hz, 2H), 3.00-3.08 (m, 2H), 2.97 (s, 3H), 2.10-2.20 (m, 2H), 1.14 (t, J=7.1 Hz, 3H). MS (ESI): m/z=690.49 [M+H]+. UPLC: tR=1.26 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1>O.C(O)C>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Step D) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was acidified with concentrated hydrochloric acid and was extracted with ethyl acetate (3×20 mL). The combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), m.p. 178-179° C. (after crystallization from hexanes-ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.I.[C:20](SC)(=[NH:22])[CH3:21]>CO>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)(=[NH:22])[CH3:21]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CSC(C)=N
Agent: I
Solvent: CO
Product: CC(=N)Nc1ccc(CCc2csc(NC(C)=O)n2)cc1
Temperature: 25 °C
Yield: 142.6 %

Procedure:
N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (100 mg) prepared in a similar manner according to Step 6 of Production Example 1, methyl ethanimidothioate hydriodide (166 mg) and methanol (3 ml) were combined, and refluxed for 1.5 hours. After cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography over NH silica gel with chloroform/methanol (20:1→10:1) as an eluent to give N-(4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (165 mg) as a pale yellow amorphous substance.
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl.O>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCNCC3)c2n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2cnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 0 °C
Yield: 0.1 %

Procedure:
A mixture of 75 mg (155 mmol) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidine and 65 mg (465 mmol) of powdered K2CO3 in CH2Cl2 was cooled to 0° C., and 27 mg (233 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water and washed with aq. NH3. The organic layer was dried (Na2SO4) and concentrated under vacuum to give 80 mg (92% yield) of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1-[1-(methylsulfonyl)-4-piperidinyl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidine: mp (MeOH) 273-276° C.; 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.82 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, J=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.85 (tt, J=11.1, 4.1 Hz, 1H), 4.07 (s, 3H), 4.06 (m, 4H), 4.02 (m, 1H), 3.99 (m, 1H), 3.92 (m, 4H), 3.02 (dt, J=12.2, 2.5 Hz, 2H), 2.88 (s, 3H), 2.44 (dq, J=11.6, 4.2 Hz, 2H), 2.17 (m, 2H); Anal. Calcd. for C24H28F2N8O4S: C, 51.2; H, 5.0; N, 19.9. Found: C, 50.85; H, 5.0; N, 19.7%.