Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[C:13]([CH:17]=[O:18])=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=C(O)c1cccc2c1Oc1ccccc1OC2=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc2c1Oc1ccccc1OC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 11-oxo-11H-dibenzo[b,e][1,4]dioxepine-4-carboxylic acid (256 mg, 1 mmol) in methylene chloride (15 ml) was added BH3-dimethyl sulfide complex (1.6 ml, 1 mol/L in methylene chloride) under ice bath. The mixture was stirred for 30 min at room temperature, refluxed for 5 h and then cooled. The reaction was quenched by addition of methanol, and the whole mixture was evaporated by a rotatory evaporator. The residue was diluted with saturated NaHCO3 (aq) and extracted with AcOEt. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, purified by column chromatography and evaporated by a rotatory evaporator. To a solution of the crude product in CH2Cl2 (20 ml) was added a suspension of pyridinium chlorochromate (PCC, 280 mg, 1.3 mmol) and neutral Al2O3 (350 mg) in CH2Cl2 (20 ml) in ice bath under N2. The mixture was stirred for 18 h at room temperature, filtered, evaporated by a rotatory evaporator, purified by column chromatography to obtain 11-oxo-11H-dibenzo[b,e][1,4]dioxepine-4-carbaldehyde.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[OH-].[Na+].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH2:35])[C:30]([OH:32])=[O:31])=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH:20]1[C:21]2[CH:22]([CH2:24][O:25][C:26]([NH:28][C@@H:29]([CH2:33][CH2:34][NH:35][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[C:30]([OH:32])=[O:31])=[O:27])[C:23]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)c1ccco1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Furan-2-carbonyl chloride (77 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (107 mg, 41%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[C:19](O)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:19]([C:16]2[C:17]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[CH:13]=[CH:14][CH:15]=2)=[O:20])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1cccc2ccc(OCc3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc3ccc(OCc4ccccc4)cc23)CC1

Procedure:
To the product from Step C (3.58 mmol), N-tert-butoxycarbonylpiperazine (733 mg, 3.93 mmol), EDC hydrochloride (750 mg, 3.93 mmol), HOBT (483 mg, 3.58 mmol), and triethylamine (0.498 mL, 3.58 mmol) were stirred in dry DMF (15 mL) at room temperature for two days. After concentration in vacuo, the residue was partitioned between EtOAc and 50% NaHCO3 solution, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30% EtOAc/hexane) to yield the desired product as a white foam.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[C:11]([N+:12]([O-])=O)=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2([CH3:26])[CH2:25][O:24][CH2:23]2)[CH2:18][CH2:17]1>CO.[Zn]>[NH2:12][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]3([CH3:26])[CH2:23][O:24][CH2:25]3)[CH2:18][CH2:17]2)[C:4]=1[Cl:3])[C:8]#[N:9]
Reactant: CC1(N2CCC(Oc3cc(C#N)cc([N+](=O)[O-])c3Cl)CC2)COC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC1(N2CCC(Oc3cc(C#N)cc(N)c3Cl)CC2)COC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Ammonium chloride (584 mg, 10.92 mmol) and zinc (356 mg, 5.46 mmol) were added to a solution of 4-chloro-3-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)-5-nitrobenzonitrile (96 mg, 0.273 mmol) in methanol (10 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated, the crude was purified by flash chromatography on silica gel using an automated ISCO system (loaded onto a 24 g dry column, 24 g column, eluting with 0-6% 2 N ammonia in methanol/dichloromethane). 3-amino-4-chloro-5-((1-(3-methyloxetan-3-yl)piperidin-4-yl)oxy)benzonitrile (87 mg) was obtained as a foaming solid.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>CN(C)C=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([O:7][CH:4]2[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]2)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: OC1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)ccc1OC1CCC(O)CC1
Reaction time: 2 h

Procedure:
To a stirred mixture of 46.46 parts of 1,4-cyclohexanediol and 135 parts of N,N-dimethylformamide were added 5.28 parts of sodium hydride dispersion 50% at a temperature below 20° C. Stirring was continued for 2 hours at room temperature under nitrogen atmosphere. Then there were added dropwise 15.9 parts of 1,4-di-fluoro-2-nitrobenzene at about 20° C. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was poured onto water. The precipitated product was filtered off and taken up in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was boiled in 2-propanol. Upon cooling, the precipitate was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in petroleumether. The product was filtered off and dried, yielding 17.1 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol; mp. 150.8° C. (intermediate 85).
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:23][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[C:7]1=[O:22]
Reactant: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.77 g, 2.24 mmol) in tetrahydrofuran (40.0 mL) was added lithium hydroxide monohydrate (0.27 g, 11.2 mmol) in water (2.0 mL). The reaction mixture was heated at reflux for 16 h, cooled to an ambient temperature, then acidified with a solution of hydrochloric acid (3.0 N, 10.0 mL). The solvent was removed in vacuo to dryness and the precipitate was filtered, dried to afford the title compound as a colourless solid (0.49 g, 68%): mp 210-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.79 (br, 1H), 3.99 (t, J=9.0 Hz, 2H), 3.64-3.48 (m, 3H), 3.19-3.12 (m, 1H), 2.46 (s, 3H), 2.02-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.37-1.26 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 164.0, 159.8, 156.0, 155.2, 115.2, 114.9 (t), 42.4, 42.1, 41.1 (d), 20.3 (t, 2JC-F=43 Hz), 17.4, 14.9 (t, 2JC-F=43 Hz); MS (ES+) m/z 318.0 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12>CCCCCC.CCOC(C)=O>[C:47]1(=[O:57])[N:51]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=3[N:6]=[CH:5]2)[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ccc2c(c1)ncn2CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole (0.27 g, 1.3 mmol) was added triphenylphosphine (0.38 g, 1.4 mmol), DEAD (0.25 ml, 1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a portion and resulting mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo, yielding an oil which was subjected to column chromatography (40% Hexane/EtOAc) to provide 0.36 g (1.1 mmol, 82%) of 1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The nitrobenzimidazole was subsequently subjected to hydrogenation, bromination and coupling with ISA to produce 0.41 g of 1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole which was refluxed with 0.3 ml of hydrazine in 20 ml of MeOH for 0.5 h to yield the desired product (0.31 g, 0.96 mmol, 68% overall). The product obtained was converted to the fumarate salt and recrystallized from isopropanol to afford 0.21 g (24%) of the product as a white foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:22])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1
Reactant: CI
Reactant: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Oc2cc(Cl)ccc2C#N)c1
Reaction time: 16 h

Procedure:
4-Chloro-2-(3-formyl-5-hydroxyphenoxy)benzonitrile (0.20 g, 0.75 mmol) in DMF (5 ml) was treated with sodium hydride (60% in mineral oil, 30 mg, 0.78 mmol) followed after 10 min by methyl iodide (0.1 ml). After 16 h, a further amount of sodium hydride (8 mg) and methyl iodide (0.1 ml) were added. After 3 h, the mixture was diluted with water, extracted with ethyl acetate, the extracts washed with water, dried over, sodium sulphate and evaporated to give the sub-title compound as a pale yellow solid (213 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][NH:9][C:8]=12.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[C:8]=12
Reactant: COc1nccc2c(-c3ccccc3)n[nH]c12
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc2c(-c3ccccc3)nn(Cc3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
To a solution of 7-methoxy-3-phenyl-1H-pyrazolo[3,4-c]pyridine (193 mg) obtained in Step C of Example 10 in THF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. 4-(Bromomethyl)benzenesulfonamide (220 mg) was added thereto at room temperature, and the mixture was stirred at room temperature for 3 days, and then overnight at 60° C. Sodium hydride (60% dispersion in mineral oil, 70 mg) and 4-(bromomethyl)benzenesulfonamide (220 mg) were added thereto, and the mixture was stirred at 60° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (173 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:19]([NH:29][C:30](=[O:47])[CH2:31][N:32]2[C:36]3[C:37]([F:42])([F:41])[C@@H:38]4[CH2:40][C@@H:39]4[C:35]=3[C:34]([C:43]([F:46])([F:45])[F:44])=[N:33]2)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)=[N:4][CH:5]=[C:6]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=1>C(O)C.O.NN>[NH2:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]([C@@H:19]([NH:29][C:30](=[O:47])[CH2:31][N:32]2[C:36]3[C:37]([F:42])([F:41])[C@@H:38]4[CH2:40][C@@H:39]4[C:35]=3[C:34]([C:43]([F:44])([F:45])[F:46])=[N:33]2)[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)=[N:4][CH:5]=1
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of Compound 41B (100 mg, 0.14 mmol) in 15 ml of ethanol, 0.05 ml of hydrazine monohydrate was added and the reaction mixture was stirred at room temperature for 10 min. The solvent was removed and the residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title product. MS (m/z) 592.20 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:16][CH2:15][CH2:14][CH2:13][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: ClCCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCCCCl)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
With stirring at room temperature, 5.6 g (39.9 mmols) of 4-methoxythiophenol was added by small portions to 20 ml of a solution of 0.98 g (40.8 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 40 ml of a solution of 6.3 g (40.0 mmols) of 1-bromo-3-chloropropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further an hour. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate 3 times. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to afford 7.8 g (yield: 90%) of the title compound.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76](OCC#N)=[O:77])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.O1CCCC1>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][CH2:74][C@@H:75]([NH:82][C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[C:76]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:77])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 18.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (65.6 mg, 0.103 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 6-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk45) (173 mg, 0.412 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.75 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk46) (18.6 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1
Reactant: C1=COCCC1
Reactant: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2c1cnn2C1CCCCO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of 2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (100 mg, 0.266 mmol) in tetrahydrofuran (2.7 ml) were added 3,4-dihydro-2H-pyran (36 μl, 0.399 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.069 mmol), and the resulting mixture was stirred for 4 hours while being maintained at 70° C. The reaction solution was allowed to cool, and then was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (99.6 mg, 82%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4].C1C=CC(COC([NH:30][C@H:31]([C:37](OC2C=CC([N+]([O-])=O)=CC=2)=[O:38])[CH2:32][CH2:33][C:34]([NH2:36])=[O:35])=O)=CC=1>CN(C=O)C>[NH2:30][C@H:31]([C:37]([NH:1][C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:38])[CH2:32][CH2:33][C:34](=[O:35])[NH2:36]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.36 g H-Thr-Pro-OtBu is dissolved in 10 ml DMF, after which 1.93 g Z-Gln-ONp is added and the reaction mixture is stirred for about 20 hours at room temperature. After evaporation of the mixture to dryness, the residue is dissolved in EtOAc and washed consecutively with 5% KHSO4 solution, 5% NaHCO3 solution and a saturated NaCl solution. The solution is then dried over Na2SO4 and filtered, and the filtrate is evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.ClC1C2C=C(N(C)C)N=CC=2N=CN=1.N>C(O)C.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: CN(C)c1cc2c(Cl)ncnc2cn1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
4-(3-Fluorobenzyloxy)aniline was prepared from 4-nitrophenol (Aldrich) and 3-fluorobenzylbromide (Aldrich) according to Procedure D. This was reacted with 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine according to Procedure A to give the product; tic (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.48; m/z (M+1 )+390.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CO>[Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)cc1C
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(Cl)c(CN)cc1C
Yield: 127.3 %

Procedure:
2-(2-Chloro-4-methoxy-5-methylbenzyl)isoindoline-1,3-dione (174 mg, 0.55 mmol) was dissolved in MeOH (30 ml) and hydrazine hydrate (111 mg, 2.21 mmol) and then heated under reflux for 1 hour. The solvent was removed in vacuo and the precipitate was filtered off. The filtrate was evaporated to give a residue, which was chromatographed on a column of silica gel eluting with MeOH-DCM (1:10) to give the title compound (130 mg, 100%) as white solid. 1H NMR (270 MHz, DMSO-d6) δ ppm 2.12 (3H, s), 3.38 (2H, br s), 3.69 (2H, s), 3.78 (3H, s), 6.94 (1H, s), 7.29 (1H, s). MS (ESI) m/z 169 (M+H—NH2)+
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([CH3:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([CH3:17])=[CH:15]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(C)cn2Cc2ccccc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn(Cc2ccccc2)c2c(C#N)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-benzyl-7-cyano-3-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 365 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cccc(F)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 3-fluorophenol: 1H-NMR (CDCl3) δ 7.91 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.7, 2.8 Hz), 7.31–7.06 (1H, m), 6.99 (1H, d, J=8.7 Hz), 6.83–6.61 (3H, m), 3.81 (3H, s).