Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:23]([O-])=O)[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[BH4-].[Na+]>C1COCC1.C(O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:22][CH2:21]2
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc([N+](=O)[O-])ccc2O1)C[C@H](O)c1cccnc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(N)ccc2O1)C[C@H](O)c1cccnc1
Temperature: 0 °C
Yield: 30 %

Procedure:
tert-Butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 171, 500 mg, 1.2 mmol) was dissolved in degassed THF, and to the solution was added Pd/C (50 mg, 10%) under argon and cooled to 0° C. NaBH4 was dissolved in ethanol and added to the reaction slowly to avoid excessive bubbling. After gas evolution had stopped, the reaction was warmed to room temperature and monitored by TLC. When complete, the reaction was cooled to 0° C. and quenched by the addition of ice. The black precipitate was then filtered through Celite® and the filtrate was concentrated in vacuo until cloudy. The filtrate was then extracted with ethyl acetate and the crude material was purified via flash chromatography to yield the product (30%). 1H NMR (DMSO-d6, δ): 8.4 (m, 2H), 7.7 (m, 1H), 7.4 (m, 1H), 6.4 (d, 1H), 6.3 (s, 1H), 6.2 (d, 1H), 5.6 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.5 (m, 2H), 3.4 (m, 2H), 2.8 (m, 2H), 1.8 (m, 1H), 1.5 (m, 1H), 1.2 (d, 9H); LC/MS: m/z 399, MH+ 400
Reaction SMILES: C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)C[C@@H](C(C)C)[CH2:13][C:14]1[CH:19]=CC=[C:16]([OH:20])[CH:15]=1)CCC.C(OC1C=C(C=CC=1C(C)(C)C)CBr)(=O)C.[CH2:51]([O:58][C:59]1[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=1)[CH2:62]Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.CCCCCC>[CH:14]([C@@H:15]([CH2:62][C:61]1[CH:64]=[CH:65][CH:66]=[C:59]([O:58][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:60]=1)[CH2:16][OH:20])([CH3:19])[CH3:13]
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1cccc(O)c1)C(C)C)NC(=O)OC(C)(C)C
Agent: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)[C@H](CO)Cc1cccc(OCc2ccccc2)c1

Procedure:
The N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxyphenyl)-octanoic acid (N-butyl)amide used as starting material is prepared analogously to Example 5a)-5l), except that in step k) instead of 3-acetoxy-4-tert-butyl-benzyl bromide there is used 3-benzyloxy-benzyl bromide, so that in step i) 2(R)-isopropyl-3-(3-benzyloxy-phenyl)-propanol, Rf (dichloromethane/hexane=1:1)=0.19, is obtained directly.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Step A To a solution of 2-hydroxy-1-(4-nitrophenyl)ethanone (1 g, 5.52 mmol) in DMF (25 ml) was added imidazole (564 mg, 8.28 mmol), followed by the addition of tert-butylchlorodimethylsilane (915 mg, 6.07 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was poured into H2O (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (5×25 mL), brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)-1-(4-nitrophenyl)ethanone as a yellow solid (1.6 g, 98%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH2:49])=[CH:47][CH:48]=1)=[O:42])[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:34]2[CH2:40][CH2:39][CH:38]1[CH2:37][N:36]([C:41]([C:43]1[CH:44]=[N:45][C:46]([NH:49][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:25])[CH3:1])[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=5)[C:8]=4[N:9]=3)=[CH:47][CH:48]=1)=[O:42])[CH2:35]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1cccc(C(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1cccc(C(C)(C)C)c1
Yield: 63.5 %

Procedure:
Following general N—C coupling procedure 1, 7-(3-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) to give 3-{6-[7-(3-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (116 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 1.43 (s, 9H) 1.59 (br. s., 2H) 1.81 (br. s., 2H) 2.86 (br. s., 3H) 2.94 (br. s., 3H) 4.12 (br. s., 2H) 6.91 (s, 1H) 7.37-7.43 (m, 2H) 7.45-7.58 (m, 2H) 7.67 (dd, J=8.84, 2.27 Hz, 1H) 8.32 (dd, J=5.81, 2.78 Hz, 2H) 8.96 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:36][CH2:35][CH2:34][NH:33]2)[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.Cl.C(OCC)(=O)C>[CH2:16]([O:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([C@H:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cc2cc(F)c(F)cc2nc1Cl
Reactant: c1ccc(COCC[C@H]2CC[C@H]([C@H]3CCCN3)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc2cc(F)c(F)cc2nc1N1CCC[C@@H]1C1CCC(CCOCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A suspension of 2-chloro-6,7-difluoroquinoline-3-carbaldehyde (8.30 g, 36 mmol), trans-(R)-2-[4-(benzyloxyethyl)cyclohexyl]pyrrolidine (10.5 g, 36 mmol), and potassium carbonate (7.60 g, 55 mmol) in toluene (90 mL) and water (12 mL) is stirred and refluxed for 4 hours. The reaction mixture is cooled to room temperature and then diluted with 1N HCl aq. and ethyl acetate. The organic layer is washed with sat. NaHCO3 aq., brine, dried over magnesium sulfate, filtered and concentrated to give 2-((R)-2-{4-[2-(benzyloxy)ethyl]cyclohexyl}pyrrolidin-1-yl)-6,7-difluoroquinoline-3-carbaldehyde as yellow syrup, which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([C:35]#[N:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C.[Cl-].[Na+].O>[C:35]([C@@H:18]([NH:17][C:14]([C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([F:34])[CH:27]=2)=[CH:22][CH:21]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: N#Cc1ccc(-c2ccc(C[C@H](N)C#N)cc2)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccc(C#N)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
A 50% solution of propane phosphonic acid anhydride (0.964 g) (T3P) in DMF was added to a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.290 g), (S)-4′-(2-amino-2-cyanoethyl)-3-fluorobiphenyl-4-carbonitrile (0.335 g) and triethylamine (0.880 mL) in DMF (3 mL) at 0° C. The resulting solution was allowed to warm to RT and stirred for 18 h. The mixture was poured into water and brine and the mixture extracted with ethyl acetate. The organics were washed with saturated brine, dried and evaporated. The crude product was purified by flash silica chromatography, eluting with 30% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford (S)-tert-butyl 2-((S)-1-cyano-2-(4′-cyano-3′-fluorobiphenyl-4-yl)ethylcarbamoyl)piperidine-1-carboxylate as a colourless solid (0.443 g).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:39])[CH2:35][C:36]([OH:38])=O)=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:36](=[O:38])[CH2:35][C:34]([NH:33][C:30]2[CH:29]=[CH:28][C:27]([N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[O:20])=[CH:32][CH:31]=2)=[O:39])[CH2:66][CH2:67]1)=[O:61]
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-n2ccccc2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-n2ccccc2=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
HOBt (75 mg, 0.55 mmol) and DIPEA (213 mg, 1.65 mmol) were added to a stirred solution of N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-malonamic acid (150 mg, 0.55 mmol) in DMF (2.0 mL). The reaction mixture was cooled to 0° C. and EDCI.HCl (126 mg, 0.66 mmol) followed by (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (185 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was recrystallized from ethyl acetate:hexane (1:1) to afford 180 mg (21%) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-propionamide. LCMS: 524.09 (M+1)+9.7%, 1H NMR: (DMSO-d6): δ 7.7-7.2 (m, 8H), 6.5 (m, 1H), 6.3 (m, 1H), 3.8-3.6 (m, 5H), 3.6-3.34 (m, 3H), 3.2 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:8][NH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]2[C:13]([CH3:16])=[N:14][N:15]=[C:3]12.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:16][C:13]1[N:4]2[C:5]3[CH:12]=[CH:11][C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][C:6]=3[NH:7][CH2:8][CH2:2][C:3]2=[N:15][N:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3ccccc3)cc1NCC2
Yield: 52.6 %

Procedure:
A solution of bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (30 mg, 0.11 mmol), phenylboronic acid (26 mg, 0.22 mmol), Tetrakis(triphenylphosphine)palladium(0) (10 mg) and Cs2CO3 (72 mg, 0.22 mmol) in dioxane (5 mL) and water (1 mL) was heated at 120° C. under microwave for 20 min. The reaction mixture was concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=10:1) to afford 1-methyl-8-phenyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (16 mg, yield 55%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([C@H:29]([NH:31][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=4[C:14]#[N:15])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:30])=[CH:27][N:28]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: COc1ncc([C@@H](C)N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ncc([C@@H](C)Nc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (430 mg, 1.51 mmol) and (R)-1-(2-methoxypyrimidin-5-yl)ethanamine (238 mg, 1.56 mmol) (prepared similarly according to the method for Intermediate 16) in acetonitrile (6 mL) and N,N-diisopropylethylamine (2 mL, 9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield a light yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:8][CH2:9][NH:10][C:11]1[N:16]2[N:17]=[C:18]([CH3:28])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[C:15]2[N:14]=[C:13]([CH3:29])[CH:12]=1)(C)(C)C>C(O)C>[ClH:26].[CH:30]1([NH:7][CH2:8][CH2:9][NH:10][C:11]2[N:16]3[N:17]=[C:18]([CH3:28])[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[Cl:27])=[C:15]3[N:14]=[C:13]([CH3:29])[CH:12]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Cc1cc(NCCN(C(=O)OC(C)(C)C)C2CCCC2)n2nc(C)c(-c3cccc(Cl)c3Cl)c2n1
Solvent: CCO
Product: Cc1cc(NCCNC2CCCC2)n2nc(C)c(-c3cccc(Cl)c3Cl)c2n1
Product: Cl
Yield: 186.9 %

Procedure:
The cyclopentyl-{2-[3-(2,3-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-carbamic acid tert-butyl ester (21 mg, 0.040 mmol) was stirred for 1 hour in 2:1 ethanol/concentrated aqueous hydrochloric acid (1.5 mL), concentrated under reduced pressure, and then concentrated 2 additional times from ethanol to give the title compound (17 mg, 94%): +APcI MS (M+1)+ 418; 1H NMR (methanol-d4) δ: 7.69 (d, 1H), 7.50-7.40 (m, 2H), 6.78 (s, 1H), 4.06 (br s, 2H), 3.63 (br m, 1H), 3.42 (br s, 2H), 2.60 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([CH:15]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:22](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CCCCCC>[Si:1]([O:8][CH2:9][C:10]1[O:14][CH:13]=[C:12]([C:15]#[N:22])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C=O)co1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)co1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-furaldehyde (3.2 g, 13 mmol) that was obtained in Example 1 (1b) in dichloromethane (40 ml) were added successively hydroxylamine hydrochloride (1.0 g, 15 mmol) and triethylamine (3.7 ml, 27 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was evaporated in vacuo. Subsequently, to a solution of the residue obtained in toluene (40 ml) was added N,N′-dicyclohexylcarbodiimide (3.1 g, 15 mmol) with stirring, and the resulting mixture was stirred at 90° C. for 16 hours. After cooling to room temperature, hexane (40 ml) was added to the reaction mixture, and insoluble materials were removed by filtration with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:97) as the eluent to afford the title compound (1.8 g) in a yield of 57% as a colourless oily product.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])C1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C.O>[NH2:10][CH2:11][C@@H:12]([C:13]([NH:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
50 mg of palladium on activated carbon (10%) are added to a mixture of 0.41 g (0.847 mmol) of the compound from Example 260A in 80 ml of acetic acid/ethanol/water (4:1:1), and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>ClCCl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 72 h
Yield: 30.2 %

Procedure:
In a 3-neck, 500 ml round bottom flask, dichloromethane (100 ml) was added to 16.3 g (0.10 mole) of N-hydroxyphthalimide. To this was added 21.1 g (0.10 mole) of 4-chlorobenzenesulfonyl chloride. To this suspension at ice-bath temperature, with slow stirring, was added dropwise 10.1 g (0.10 mole) of triethylamine in 50 ml of dichloromethane. This stirred reaction mixture was held at ambient temperature for 72 hours. Then, more dichloromethane and 100 ml of water were added to the suspension. The dichloromethane extract was dried with magnesium sulfate. Solvent was removed under reduced pressure and the residue was recrystallized from 500 ml of ethyl acetate to give 10.2 g of a white solid, mp 178°-180° C.
Reaction SMILES: [ClH:1].[OH:2][C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:15][C:16]([CH3:18])=[O:17].C=O.[N+]([CH3:24])([O-])=O>C1CCCCC1>[ClH:1].[OH:2][C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][N:6]([CH2:24][CH2:15][C:16](=[O:17])[CH3:18])[CH2:5][CH2:4]1
Reactant: CC(C)=O
Reactant: C[N+](=O)[O-]
Reactant: OC1(c2ccccc2)CCNCC1
Agent: C=O
Agent: Cl
Solvent: C1CCCCC1
Product: CC(=O)CCN1CCC(O)(c2ccccc2)CC1

Procedure:
The starting material is prepared as follows: The solution of 20 g of 4-hydroxy-4-phenylpiperidine hydrochloride, 10 ml of acetone, 5.6 g of paraformaldehyde and 100 ml of nitromethane is refluxed for 12 hours. It is diluted with 500 ml of cyclohexane and the precipitate collected, to yield the 4-(4-hydroxy-4-phenylpiperidino)-2-butanone hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]=[N+]=[N-])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:65][C:66]([F:73])([F:72])[C:67](OCC)=[O:68]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:67](=[O:68])[C:66]([F:73])([F:72])[F:65])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCN=[N+]=[N-])O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCNC(=O)C(F)(F)F)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76.5 %

Procedure:
To Compound (5) (450 mg, 0.56 mmole) in dry methanol (7.5 mL) was added under stirring 1,3-propanedithiol (0.284 mL, 2.82 mmole) followed by triethylamine (0.394 mL, 2.82 mmole). The mixture was stirred at room temperature for 5 days. The mixture was diluted with methanol (7 mL) and ethyl trifluoroacetate (0.675 mL, 5.6 mole) and triethylamine (0.237 mL, 1.7 mole) was added. Stirring at room temperature was continued for 24 hours. The resulting suspension was diluted with dichloromethane (5 mL) and the solvent was removed under reduced pressure. Column chromatography on silica gel with ethyl acetate/hexane mixtures gave 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-trifluoroacetamido-1-hepten-1-yl)-thymidine (6) (371 mg, 76%), m.p. 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[O:29])[C@@H:13]([O:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])[CH2:12]2)=[C:4]([N:37]2[CH:41]=[CH:40][N:39]=[C:38]2[CH2:42][CH2:43][CH3:44])[N:3]=1.[CH2:45]([I:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CC#N>>[I-:52].[CH2:45]([N:39]1[CH:40]=[CH:41][N+:37]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[O:29])[C@@H:13]([O:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])[CH2:12]2)=[C:38]1[CH2:42][CH2:43][CH3:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Reactant: ICc1ccccc1
Solvent: CC#N
Product: CCCc1n(Cc2ccccc2)cc[n+]1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Product: [I-]

Procedure:
2-Chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (0.615 g, 1 mmol) was treated with a solution of BnI in CH3CN (0.3 M, 40 mL, 12 mmol) by method 3 to give 3-benzyl-1-{2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purin-6-yl}-2-propylimidazolium iodide (0.83 g, crude): 1H NMR (500 MHz, CDCl3) δ 8.94 (s, 1H), 8.49 (s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.81 (s, 1H), 7.46-7.50 (m, 5H), 7.32 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 6.67 (t, J=7.3 Hz, 1H), 5.75-5.85 (m, 3H), 4.71-4.82 (m, 3H), 3.67-3.74 (m, 2H), 2.99-3.02 (m, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.75-1.81 (m, 2H), 1.17 (t, J=7.5 Hz, 3H); HRMS m/z 705.2606 (M+[C39H38ClN6O5=705.2592]).
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]([CH3:20])[CH:6]([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=O)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O>C(O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]([CH3:20])=[N:2][NH:3][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccccn1

Procedure:
1.170 g (23 mmol) of hydrazine hydrate were added to a solution of 5 g (21 mmol) of methyl 4-oxo-3-(pyridin-2-ylcarbonyl)pentanoate in ethanol (50 ml). The mixture was heated at reflux for 7 hours, added to water and extracted with ethyl acetate. The combined organic phases were dried with magnesium sulfate, filtrered and concentrated. This gave 2.290 g of product (41.9% of theory).