Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[N+:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O-:21])=[O:20].[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([N+:19]([O-:21])=[O:20])[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:27]
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C(c1ccc(OC)cc1)c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a stirred (0° C.) solution of bis-(4-methoxyphenyl)methanol (2.5 g, 10.2 mmol) and ethyl nitroacetate (2.26 ml, 20.4 mmol) in CH2Cl2 (50 ml) under argon was added AlCl3 (1.36 g, 10.2 mmol) in one portion. After 1 h, the reaction mixture was allowed to warm to approximately 10° C. and poured into a mixture of ice and 2M HCl. The resulting mixture was stirred for 45 min, and the aqueous layer extracted with CH2Cl2. The combined organic layers were washed with 10% Na2CO3, dried over MgSO4, treated with activated carbon, and concentrated to give a reddish oil that was chromatographed (CHCl3 elution) to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by HPLC to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]butanamide, the title compound, mp 80°-82° (from ether) in 68% yield.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](Cl)(=[O:13])[CH3:12]>>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][C:11](=[O:13])[CH3:12])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CC(N)(C1)C2
Reactant: CC(=O)Cl
Product: CC(=O)NC12CC(OC(C)=O)(C1)C2

Procedure:
The commercially available 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid can be converted to the methyl ketone intermediate by treatment with either methyl lithium or methylmagnesium bromide (Scheme 1). Baeyer-Villagar type oxidation with mCPBA or other peroxycarboxylic acids can give 3-aminobicyclo[1.1.1]pentan-1-yl acetate. The amine can then be coupled with an appropriate carboxylic acid or acid chloride, such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3). Selective hydrolysis of the ester group with hydroxide ion gives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1). Alternatively, starting with the commercially available 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid and carrying out a Curtius reaction or modified Curtius reaction using diphenylphosphoryl azide gives the amino alcohol intermediate, which can then be treated with acetyl chloride (1 eq) in the presence of base (for example, K2CO3, Na2CO3, TEA, and the like) to give N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) or with acetyl chloride (>2 eq) in the presence of base (for example, K2CO3, Na2CO3, TEA, and the like) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[H-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.7 g (6.3 mL; 51 mMol) of N-hydroxyethyl-morpholine in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2.5 h. After stirring another hour at rt, the reaction mixture is poured onto 200 mL of water and stirred. The precipitated crystals are filtered and dried at 60° C. under vacuum to obtain 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine. Title compound: ES-MS: 253 [M+H]+; single peak at tR=4.8 min (System 2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:39]3[CH:40]=[CH:41][N:37]([CH3:36])[N:38]=3)[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(-c2ccn(C)n2)nc(N2CCOCC2)n1
Temperature: 20 °C
Yield: 68.5 %

Procedure:
A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 64) (313 mg, 0.61 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid (155 mg, 1.22 mmol), and aq. 2 M K2CO3 (4.1 mL) in 1,4-dioxane (20 mL) was degassed with N2 for 30 min and then Pd(dppf)Cl2 (30 mg) was added, and the mixture was degassed for a further 10 min. The reaction mixture was heated under reflux for 1 hr, cooled to 20° C., diluted with water, and extracted with CH2Cl2 (20 mL×3). The combined CH2Cl2 extracts were dried (Na2SO4) and the solvents were removed to gave a crude product which was purified by chromatography on silica, eluting with CH2Cl2/EtOAc (4:1) to give tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(1-methyl-1H-pyrazol-3-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate (233 mg, 69% yield): mp (CH2Cl2/hexanes) 224-227° C.; 1H NMR (DMSO-d6) δ 9.60 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.28 (m, 1H), 7.82 (t, JHF=53.1 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 3.99-3.96 (m, 4H), 3.96 (s, 3H), 3.92 (s, 3H), 3.76 (m, 4H), 1.53 (s, 9H); Anal. Calcd. for C25H29F2N9O4.0.25H2O: C, 53.4; H, 5.3; N, 22.4. Found: C, 53.3; H, 5.3; N, 22.3%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]1[C@@H:25]([C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24]1>CC(O)C>[C:1]([O:5][C:6]([NH:8][N:9]([CH2:24][CH:25]([OH:23])[CH:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN(Cc1ccc(-c2ccccn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 66 %

Procedure:
Into a 100 mL flask was placed (5) (1.0 g, 3.34 mmol), (6) (2S,3S)-1,2-epoxy-3-(Boc-amino)-4-phenylbutane (2.78 g, 10.5 mmol, 3.16 equivalents), and 2-propanol (15 mL). The reaction was heated to reflux. After approximately 61 hours of refluxing, the heat was removed, and the mixture cooled to room temperature. To the cooled mixture was added water/ice (50 mL). To the aqueous mixture was added dichloromethane (50 mL) and then transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organics were washed with water, then saturated sodium chloride, and then dried over sodium sulfate. The dried organic solution was filtered, and the filtrate was concentrated under reduced pressure, and then dried under high vacuum overnight. The yellow foam was purified by Biotage chromatography (40+M cartridge; 0 to 5% methanol/dichloromethane over 25 CV) to give 1.24 g (66%) of (7) as a white solid. TLC Rf (hexane/ethyl acetate, 1:2)=0.45; 1H NMR (CD3OD) δ 8.60 (d, 1H), 7.88 (m 4H), 7.50 (d, 2H), 7.36 (m, 1H), 7.25 (m, 4H), 7.18 (m, 1H), 3.93 (m, 2H), 3.70 (m, 2H), 3.0-2.6 (m, 4H), 1.33 (s, 9H), 1.30 (s, 9H); MS (M)+=563; HPLC tR 9.6 minutes.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH3:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH2:15][CH:14]=[CH2:13]
Reactant: Cc1c(Br)ccc2c1COC2=O
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1C)COC2=O

Procedure:
To a flask charged with 5-bromo-4-methyl-2-benzofuran-1(3H)-one (320 mg, 1.409 mmol) and a stir bar was added allyl tri-n-butyltin (0.655 ml, 2.11 mmol), Pd(PPh3)4 (244 mg, 0.211 mmol), lithium chloride (179 mg, 4.23 mmol), and toluene (15 mL). The reaction was purged with nitrogen 2 times then was heated at reflux for 4 hours. The product was separated by silica gel chromatography to give 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(c1ccc([N+](=O)[O-])cc1)CN2c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(c1ccc(N)cc1)CN2c1ccccc1
Yield: 96.8 %

Procedure:
To a refluxing solution of tert-butyl 3-(4-nitrophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.0 g, 2.2 mmol) and ammonium chloride (1.18 g, 22.0 mmol) in 2:1 mixture of ethanol/water (21 mL), was added iron powder (0.37 g, 6.6 mmol) over a period of 45 minutes. After refluxing for another hour, the reaction mixture was extracted with dichloromethane, washed the organic extracts with water and brine. The organic phase was dried over MgSO4 and concentrated to obtain tert-butyl 3-(4-aminophenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.9 g, 97%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:37]=2)[C:32]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)=[N:31]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[N:30]([CH3:29])[N:31]=[C:32]4[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cn1nc(-c2ccccn2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(-c3ccccn3)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.207 mmol), 1-methyl-3-(pyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (83.3 mg, 0.25 mmol), Pd(PPh3)4 (24 mg, 21 mmol), and K2CO3 (86 mg, 0.62 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to rt, the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 40% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 9.21-9.15 (m, 1H), 8.84-8.77 (m, 1H), 8.25 (dd, J=8.8, 1.7 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (td, J=7.7, 1.7 Hz, 1H), 7.59-7.49 (m, 4H), 7.47 (d, J=8.9 Hz, 1H), 7.29-7.24 (m, 1H), 5.21 (s, 1H), 4.17 (s, 3H), 3.75 (s, 3H), 2.59 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12]O.O=S(Cl)[Cl:24]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:6]2[CH2:11][CH2:12][Cl:24]
Reactant: O=S(Cl)Cl
Reactant: Nc1ncnc2c1nc(CCc1cccnc1)n2CCO
Product: Nc1ncnc2c1nc(CCc1cccnc1)n2CCCl
Reaction time: 12 h
Yield: 8 %

Procedure:
0.45 g of 2-(6-amino-8-(2-pyridin-3-yl-ethyl)-purin-9-yl)ethanol were cooled to −20° C. and 6 ml of SOCl2 were added. The temperature was gradually risen to 50° C. and the mixture was stirred at this temperature for 12 hours. The excess of SOCl2 was evaporated and the residue was taken up in dichloromethane washed with saturated aqueous NaHCO3 dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (CHCl3:MeOH 50:1) to give 40 mg (8%) of the desired product.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(N(CC)CC)C>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:34](=[O:35])[C@H:32]([CH3:33])[NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 12.9 g of glycine benzyl ester tosylate in 200 ml acetonitrile cooled to 0° C., was added dropwise triethylamine (5.3 ml), followed by addition of 12 g of N-tert-butyloxycarbonylalanine N-hydroxysuccinimide ester (prepared by reaction of N-tert-butyloxycarbonylalanine with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide). The resulting solution was stirred at 0° C. for one hour and then at room temperature for 18 hours. At the end of reaction, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the extract was washed with 5% acetic acid, water and saturated aqueous solution of sodium chloride in that order, giving 16 g of crude product. Purification of this crude product by silica gel chromatography (chloroform:methanol=40:1) afforded 12.6 g of pure N-tert-butyloxycarbonyl-L-alanyl-glycine benzyl ester.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N(C(C)C)CC)(C)C.[C:69]1([CH2:75][C:76](Cl)=[O:77])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:76](=[O:77])[CH2:75][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) (100 mg, 0-2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, 1 mmol) and phenylacetyl chloride (0.026 ml, 0.2 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane (2 ml) and washed with dilute hydrochloric acid (2 ml). The organic layer is separated and evaporated under reduced pressure to afford the title compound (114 mg). LCMS (electrospray): m/z [MH+] 583.27
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:39])C(=O)C1.CN(C=O)C>C(OCC)(=O)C>[Br:39][C:29]1[S:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:13]([CH2:12][C:8]3([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:10][CH2:9]3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:25]=2)=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2nccs2)nn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(Br)s2)nn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a 100 mL round bottom flask was added t-butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-(thiazol-2-yl)pyridazin-3-yl)carbamate (2.0 g, 4.6 mmol), NBS (1.6 g, 9.1 mmol), and DMF (20 mL). The reaction was heated to 100° C. and stirred overnight. The reaction mixture was then was poured into ethyl acetate (200 mL), washed with water (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAc/hex) to afford 1.8 g of t-butyl 6-(5-bromothiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:20]N1C(=O)CCC1=O.O>C1COCC1>[Br:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: COC(=O)C1CCOC1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(Br)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.0 g (38.419 mmol) of methyl tetrahydrofuran-3-carboxylate (prepared analogously to: J. Org. Chem. 1996, 2690) were dissolved in 200 ml of THF and cooled to −78° C., and then 76.83 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added. After 30 min at −78° C., 10.26 g (57.63 mmol) of N-bromosuccinimide suspended in 50 ml of THF were added gradually. Thereafter, the mixture was left to warm up to RT overnight. The mixture was then admixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel (eluent: dichloromethane). This gave 491 mg (6% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.ClC([C:17]1[CH:18]=[C:19](C(C)C#N)[CH:20]=[CH:21][CH:22]=1)=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]([CH3:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1

Procedure:
3-Carboxybenzyne prepared from 2-chlorobenzoic acid in the presence of a strong base is reacted with propionitrile to produce alpha-(m-carboxyphenyl)propionitrile (R. Biehl et al., J. Org. Chem., 31, 602 (1966)). The alpha-(m-carboxyphenyl)propionitrile is converted to alpha-(m-chlorocarbonylphenyl)propionitrile by using thionyl chloride. Friedel-Crafts reaction of alpha-(m-chlorocarbonylphenyl)propionitrile with benzene using aluminum chloride affords alpha-(m-benzoylphenyl)propionitrile. Hydrolysis of the alpha-(m-benzoylphenyl)propionitrile with methanol/sodium hydroxide gives alpha-(m-benzoylphenyl)propionic acid (see British Pat. No. 1,360,560).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-Bromo-3-nitropyridin-2(1H)-one (25.0 g, 114 mmol), anhydrous DMF (500 mL) and potassium carbonate (34.7 g, 251 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (17.8 g, 126 mmol) was added, and the mixture stirred at room temperature for 16 h. The reaction mixture was then diluted with water (500 mL) and extracted with methylene chloride (3×500 mL). The organic extracts were combined, washed with 10% aqueous lithium chloride (300 mL) and water (300 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was flash chromatographed eluting with a gradient from 50% to 100% of ethyl acetate in hexanes, and the fractions containing 122a were collected to afford, after concentrating under reduced pressure, an 89% yield (23.6 g) of 122a as a yellow solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).