Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=O)[C@H:9]([CH2:11][CH3:12])[CH3:10])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:18]([CH3:20])[CH3:19].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>CN(C1C=CN=CC=1)C.CC(C)CO>[CH2:17]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:13](=[O:15])[C@H:8]([C@H:9]([CH2:11][CH3:12])[CH3:10])[NH:7][C:1](=[O:6])[CH2:2][CH:3]([CH3:4])[CH3:5])[CH:18]([CH3:20])[CH3:19]
Reactant: CC[C@H](C)[C@H](NC(=O)CC(C)C)C(=O)O
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: CN(C)c1ccncc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CC(C)CO
Product: CC[C@H](C)[C@H](NC(=O)CC(C)C)C(=O)N[C@@H](C)C(=O)OCC(C)C

Procedure:
Following General Procedure C and using N-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) and L-isoleucine methyl ester hydrochloride (Aldrich) using General Procedure C, followed by hydrolysis using General Procedure AF) and L-alanine isobutyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and 2-methyl-1-propanol (Aldrich) using General Procedure C (with catalystic DMAP), followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=142-146° C.). The reaction was monitored by tlc (Rf=0.4 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent to provide a 1:4 mixture of diastereomers.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:10]([CH:12]1[N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15][N:14]([CH3:28])[C:13]1=[O:29])[OH:11])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:10]([CH:12]1[NH:17][CH2:16][CH2:15][N:14]([CH3:28])[C:13]1=[O:29])[OH:11]
Reactant: [H][H]
Reactant: CN1CCN(C(=O)OCc2ccccc2)C(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCNC(C(O)[C@@H](N)Cc2ccccc2)C1=O

Procedure:
Treat a solution of 3-(2(S)-dibenzylamino-1-hydroxy-3-phenylpropyl)-4-benzyloxycarbonyl-1-methylpiperazin-2-one (Isomer-2) (210 mg, 0.36 mmol) in methanol (10 mL) with 20% palladium hydroxide on carbon (48 mg) in one portion and stir the mixture under 1 atmosphere of hydrogen gas for 24 h. Filter through a filtering agent, wash with methanol and concentrate to give the title compound as an oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[O:14]([C:16]#[N:17])[Na]>>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:16]([NH2:17])=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)OCO2
Reactant: N#CO[Na]
Product: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Yield: 83 %

Procedure:
The title compound was prepared from N-isopropyl-3,4-(methylenedioxy)aniline and NaOCN by the procedure described in example 5 in 83% yield. 1H NMR (CDCl3): 6.85-6.65 (m, 3H), 6.04 (s, 2H), 4.82 (m, 1H), 4.21 (br s, 2H), 1.06 (d, J=6.6, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[N:9]=[C:10]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][CH2:19]CN(C)C)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:37]NC>>[CH3:37][N:18]([CH2:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[N:9]=2)[CH2:16][CH2:15]1)[CH3:19]
Reactant: CN(C)CCNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1
Reactant: CNC
Product: CN(C)C[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
Prepared according to the procedure analogous to that described above for trans-N-{4-[4-Amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-N′,N′-dimethyl-ethane-1,2-diamine, except using dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:16][CH:17]=3)[C@@H:12]3[CH2:28][CH2:29][CH2:30][N:11]3[CH2:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.N>C(O)C.C(Cl)Cl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][CH2:22][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:16][CH:17]=3)[C@@H:12]3[CH2:28][CH2:29][CH2:30][N:11]3[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCOS(C)(=O)=O)ccc32)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCOCC4)ccc32)cc1
Temperature: 50 °C
Yield: 257.7 %

Procedure:
A mixture of crude cis-methanesulfonic acid 3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-9-yloxy]-propyl ester (28.5 mmol), Na2CO3 (4 equiv.), KI (0.5 equiv.), and morpholine (7.52 mmol, 10 equiv.) in ethanol (0.2 M) was heated to 50° C. overnight. The mixture was cooled to rt, diluted with CH2Cl2, and filtered. The filtrate was concentrated to give the crude product. Column chromatography (NH3 in MeOH/CH2Cl2) followed by HPLC give the desired product (8.19 g, 68%). The enantiomers were separated using a Chiralcel AD-h column on a SFC HPLC eluting with IPA/MeOH with 0.2% DEA. MS: exact mass calcd for C26H34N2O3, 422.3; m/z found, 423.5 [M+H]+. 1H NMR (MeOH-d4): 7.06 (d, J=8.5, 2H), 6.82 (d, J=8.5, 2H), 6.70 (d, J=2.5, 1H), 6.67 (d, J=8.5, 1H), 6.61 (dd, J=2.5, 8.5 1H), 4.08 (dd, J=8.5, 5.5, 1H), 3.97 (t, J=6.5, 2H), 3.79 (m, 1H), 3.74 (s, 3H), 3.67 (m, 4H), 2.91 (m, 3H), 2.78 (dd, J=5.0, 11.2, 1H), 2.47 (m, 6H), 2.34 (m, 1H), 1.91 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[C:15]([CH3:25])[CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:28][CH3:29]>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH:15]([CH3:25])[CH2:14]3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc(Oc2ccc(C3=CC(C)=CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Oc2ccc(C3CC(C)CN4CCS(=O)(=O)N=C34)cc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-3-methoxyphenoxy)phenyl]-7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (400 mg) in THF (dry) (15 mL) and MeOH (15 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (30 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. AcOH (10 mL) and platinum(IV) oxide (30 mg) were added and the mixture was stirred at room temperature under hydrogen for 1 day and at 50° C. for 1 day. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (30.3 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)nc(-c2ccccc2Cl)c1C(=O)O
Yield: 99.6 %

Procedure:
A mixture of 3.0 g of compound C and 1.43 g of powdered KOH in 20 cc ethanol was heated under reflux for 2 hours. After cooling, the reaction mixture was acidified with 1N HCl, and extracted with chloroform. The extract was dried over magnesium sulfate, and distilled to remove the solvent. Thus, 2.75 g of 4-(2-chlorophenyl)-2-phenyl-6-methyl-5-pyrimidinecarboxylic acid was obtained. Yield: 99.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])[NH2:5].[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:13])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1ccc(N)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a stirred suspension of 3-chloro-4-(methylsulfonyl)aniline (3.0 g, 15.0 mmol, Ish. K. Khanna et al., J. Med. Chem. 40, 1619 (1997)) in 20% aqueous HCl (20 mL) was added dropwise a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (20 mL) below −5° C. After stirring for 1 hour at that temperature, tin(II) chloride dihydrate in 20% aqueous HCl (20 mL) was added dropwise below −5° C. The resulting suspension was stirred for 1 h at room temperature. The mixture was basified with aqueous NaOH (pH=14) and extracted with CHCl3 (200 mL×2), dried over MgSO4, and concentrated in vacuo. The solid (5 g) was dissolved in 10% methanolic HCl (30 mL), and volatiles were removed by evaporation. The residue was washed with ethanol to give the title compound (1.3 g, 34%).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:16][CH:15]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:37]>ClCCl>[ClH:37].[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:18][CH:19]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(COC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(COC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.5 %

Procedure:
To a suspension of 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl tert-butyl hydrazine-1,2-dicarboxylate (203.0 mg, 0.467 mmol) in anhydrous dichloromethane (2.3 ml) was added 4M hydrogen chloride dioxane solution (2.3 ml, 9.2 mmol). After stirring at room temperature for 2.5 hr, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. This operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate and filtered. The filtered product was washed with ethyl acetate and dried under reduced pressure to give the title compound (179.3 mg, quantitative) as a white solid.
Reaction SMILES: CN(C=O)C.B.[Na].O.S(=O)(=O)(O)O.[CH:14]12[CH2:20][CH:17]([CH:18]=[CH:19]1)[CH:16]1[C:21]([O:23][C:24](=O)[CH:15]21)=[O:22]>[Cl-].[Na+].O>[C:17]12[CH2:20][CH:14]([CH2:19][CH2:18]1)[CH:15]1[C:16]=2[C:21](=[O:22])[O:23][CH2:24]1
Reactant: O=C1OC(=O)C2C3C=CC(C3)C12
Agent: B
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCC2C1=C1CCC2C1
Reaction time: 2 h
Yield: 89 %

Procedure:
18.0 kg of DMF and 1.17 kg (27.8 mol) of sodium boron hydride were placed in a 200 L glass lining reaction tank equipped with a jacket and an agitator, and sodium boron hydride was dissolved by stirring. Thereafter, brine was supplied to the jacket, and the inside of the tank was set at a temperature of 0° C. to 5° C. Moreover, nitrogen gas started to be supplied at 0.1 L/min from the end of the tank. 8.46 kg (51.5 mol) of a commercially available 5-norbornene-2,3-dicarboxylic anhydride and 12.7 kg of DMF were placed in a 25 L dissolution tank, and 5-norbornene-2,3-dicarboxylic anhydride was completely dissolved by stirring. Using a proportioning pump, the prepared DMF solution comprising 5-norbornene-2,3-dicarboxylic anhydride was fed to the reaction tank, while paying attention so that the internal temperature of the tank did not exceed 30° C. After completion of the feeding, while maintaining the internal temperature of the tank at 5° C. to 15° C., stirring was continued for 2 hours. 80 kg of water was slowly fed thereto so that the internal temperature did not exceed 30° C. Then, concentrated sulfuric acid was slowly fed thereto until the pH became 0.5, and stirring was continued for 3 hours. Subsequently, the supply of nitrogen gas was stopped, the solution was extracted twice with 40 kg of MIBK, and the combined organic extracts were washed with 45 kg of water. The organic layers were concentrated at 50° C. at 6.6 kPa, until the MIBK concentration in the solution became about 50% by weight. An aliquot of the concentrate was collected, and it was analyzed by gas chromatography. As a result, 6.90 kg (45.9 mol) of 4-oxatricyclo[5.2.1.02,6]decen-3-one was obtained at a yield of 89%. The MIBK concentration was 57%. Thereafter, the content in the tank was transferred to a 25 L container. This time, the solution had good flowability, and so the solution was eliminated from the reaction tank without any problem.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:34]2[NH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[C:25]([O:35][CH:36]2[O:38][C@H:37]2[CH3:39])=[CH:24][CH:23]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:10][N:11]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:12]1)[CH2:39][C@H:37]([OH:38])[CH2:36][O:35][C:25]1[C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:33][C:34]=2[CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Reactant: O=[N+]([O-])c1ccc(N2CC(NCc3ccccc3)C2)cc1
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3cccc4[nH]c5ccccc5c34)C2)cc1

Procedure:
Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine (which was obtained in Example 398) (1.95 g, 6.87 mmol) and (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (Berridge et al., Int. J. Radial. Appl. Instrum., 1992, 563) (1.64 g, 6.87 mmol) was stirred at reflux in anhydrous methanol for 24 hours. Methanol was removed in vacuo and the desired product was isolated using silica gel flash chromatography to give 3.01 g of product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ2.90 (m, 2H), 3.04(s, 1H), 3.85 (m, 3H), 3.98(m, 3H), 4.23(m, 3H), 6.01(d, 2H, J=7.26 Hz), 6.61(d, 1H, J=8.10 Hz), 7.06(d, 1H, J=8.04 Hz), 7.17(t, 1H, J=2.14 Hz), 7.34(m, 7H), 7.97(d, 2H, J=9.12 Hz), 8.14(t, 2H, J=8.79 Hz); MS (ES) m/z: 522.9 (MH+); Anal. Calcd. for C31H30N4O4: C, 71.25; H, 5.79; N, 10.72. Found: C, 70.77; H, 6.17; N, 9.61.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl[CH2:13][CH2:14][C:15](OCC)=O.C(=O)([O-])O.[Na+]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:15]([CH:14]=[CH2:13])=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=Cc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A reaction mixture of 1.54 g (10 mmol) of 2-amino-4-nitrophenol, 1.36 g (10 mmol) of ethyl 3-chloropropionate and 20 g polyphosphoric acid is stirred for 2 hours at 170° C. Then the mixture is neutralized by the addition of saturated sodium hydrogen carbonate solution at ambient temperature. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (20:1)). Yield: 0.3 g (15.8% of theory); C9H6N2O3 (M=190.16); calc.: molecular ion peak (M+H)+: 191; found: molecular ion peak (M+H)+: 191; Rf value: 0.8 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.O>[C:31]([N:12]1[CH2:13][CH2:14][C:10]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[CH2:9]2)[CH2:11]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 1 h
Yield: 94 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (48.2 mg, 0.105 mmol) obtained in Example 2 was dissolved in methylene chloride (1.0 mL). Thereafter, triethylamine (34.4 μL, 0.315 mmol) and acetyl chloride (7.5 μL, 0.105 mmol) were added to the above obtained solution under cooling on ice, and the obtained mixture was then stirred for 1 hour. The reaction solution was diluted with water, and was then extracted with methylene chloride. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (45.0 mg, 94%) in the form of a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[CH3:48])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[CH3:48])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1C)OCCN2CC=CCCc1ccccc1-c1cccc-3c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1C)OCCN2CCCCCc1ccccc1-c1cccc-3c1
Reaction time: 18 h

Procedure:
A solution of methyl (2S)-2-(tert-butoxy)-2-[4,32-dimethyl-29-oxa-5,7,8,26-tetraazaheptacyclo[24.6.2.16,9.110,14.02,7.015,20.030,34]hexatriaconta-1 (32),2,4,6(36),8,10(35), 11,13,15 (20),16,18,23,30,33-tetradecaen-3-yl]acetate in MeOH (4 mL), was treated with 10 wt % Pd/C (5 mg, 0.05 mmol), evacuated and hydrogen purged three times, then stirred under hydrogen atmosphere for 18 h. The reaction was filtered (0.45 μm syringe tip filter), concentrated to a film, and the residue was used immediately in the following step. LCMS (M+H)=645.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[CH:9]=2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[C:19]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([CH3:14])[N:11]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(I)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-methyl-pyridine (example A.29) (1.5 g, 5 mmol) and commercially available 3-bromo-benzene-boronic acid
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH:12]([CH2:23][OH:24])[CH2:13][CH2:14][P:15]([O:20]CC)([O:17]CC)=[O:16])=[C:4]([O:25]C)[N:3]=1.Br[Si](C)(C)C>CN(C)C=O>[OH:24][CH2:23][CH:12]([O:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:25])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2)[CH2:13][CH2:14][P:15]([OH:20])([OH:17])=[O:16]
Reactant: CCOP(=O)(CCC(CO)On1cnc2c(OC)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2OC(CO)CCP(=O)(O)O)c(=O)[nH]1
Yield: 56 %

Procedure:
A solution of 2-amino-9-[3-(diethoxyphosphoryl)-1-(hydroxymethyl)propoxy]-6-methoxypurine and bromotrimethylsilane (1.98 ml, 15 mmol) in dry dimethylformamide (5ml) was stirred at ambient temperature for 4 hours. The solvent was evaporated and the residue was coevaporated with methanol (5 ml) and acetone:water (1:1) solution. The product was crystallised from acetone:water (1:1) to give the title compound (90 mg, 56%) m.p. 177°-178° C. UV: λmax (H2O) 254 (12400)nm. λsh(H2O) 268 (9365)nm. IR: max (KBr) 3393, 3388, 3347, 3196, 3125, 2929, 2763, 2357, 1700, 1641, 1534, 1474, 1443, 1394, 1317, 1257, 1219, 1162, 1101, 1075, 992, 958, 818, 792, 772 cm-1. 1H NMR δH [CD3)2SO] 1.67-1.94 (4H, m, CH2CH2P), 3.45-3.57 (2H, m, CH2OH), 4.25-4.31 (1H, m, NOCH), 6.59 (2H, br.s, D2O exchangeable NH2), 7.88 (1H, s, H-8), 10.65 (1H, br.s, D2O exchangeable NH), 2.75-6.25 (3H, broad, D2O exchangeable OH, PO(OH)2). Found: C, 33.21; H, 5.01; N, 21.42%. C9H14N5O6P 0.4 H2O requires: C, 33.11; H, 4.56; N, 21.45%. m/z (FAB+ve ion, thioglycerol) MH+ 320.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:4][CH:5]3[C:14](=[N:15]O)[CH:8]([CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:6]3>CC(O)=O.[OH-].[Na+].[Pt](=O)=O>[F:1][C:2]1[C:3]2[CH2:4][CH:5]3[CH:14]([NH2:15])[CH:8]([CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)[CH2:7][CH2:6]3
Reactant: ON=C1C2CCC1Cc1c(F)cccc1C2
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC1C2CCC1Cc1c(F)cccc1C2
Yield: 95.1 %

Procedure:
The oxime from Step 3 (590 mg, 2.69 mmol) and platinum dioxide (40 mg) in AcOH (20 ml) were hydrogenated in a Parr reactor at 30 psi for 2 hours. The mixture was filtered through Celite and the filtrate was concentrated by lyophilization to give an off-white solid. The solid was dispersed in 1N NaOH and extracted with DCM. The organic extract was dried and concentrated to dryness to give a yellow oil 525 mg (95%). m/z 206 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:16][CH3:17])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Yield: 54.2 %

Procedure:
A solution of 5-bromopyridin-3-ol (70 g, 402 mmol), K2CO3 (111 g, 805 mmol), iodoethane (69.0 g, 443 mmol) in DMF (900 mL) was stirred for 16 h at 25° C. Then the mixture was concentrated and water (100 mL) was added, the mixture was extracted with DCM (400 mL×2), the combined organic phase were dried over Na2SO4, filtered, and concentrated to give 3-bromo-5-ethoxypyridine (53 g, 218 mmol, 54% yield): 1H NMR (400 MHz, CD3OD) δ 8.19-8.17 (m, 2H), 7.60-7.59 (m, 1H), 4.13-4.07 (m, 2H), 1.40 (t, J=7.0 Hz, 3H); ES-LCMS m/z 202 (M+H).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: Fc1ncccc1I
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2ncccc2I)cc1)c1nc2ccccc2[nH]1
Temperature: 115 °C
Reaction time: 64 h

Procedure:
A solution of 2-fluoro-3-iodopyridine (3.052 g, 13.69 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (4.89 g, 20.53 mmol) and cesium carbonate (7.58 g, 23.27 mmol) in N-Methyl-2-pyrrolidinone (20 mL) was degassed and heated to 115° C. After 64 h, the reaction was cooled to 23° C., diluted with EtOAc (250 mL) and washed with water (100 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-1.5% methanol/dichloromethane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 404.1 (M+1).