Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:6]=[N:7][CH:8]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>CN(C=O)C>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:5]4[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=4)=[CH:15][CH:14]=3)[CH:24]=2)[CH2:30][CH2:31]1
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)cc1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (250 mg, 0.929 mmol) in DMF (5 mL), sodium hydride (66.9 mg, 2.79 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (172 mg, 0.929 mmol).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12](Cl)[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O-:19].[Na+]>O1CCOCC1.CO>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([O:19][CH3:18])[CH:11]=[C:10]([CH:15]3[CH2:17][CH2:16]3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: Clc1cc(C2CC2)nc(Nc2ccccc2)n1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C2CC2)nc(Nc2ccccc2)n1
Temperature: 50 °C

Procedure:
6.87 g (28 mmol) of 2-phenylamino-4-chloro-6-cyclopropyl-pyrimidine in 25 ml of dioxane are added dropwise to 5.8 g (32.2 mmol) of sodium methylate in 10 ml of absolute methanol at room temperature in the course of half an hour, while stirring, and the mixture is then heated at 50° C. for 6 hours. To bring the reaction to completion, a further 0.76 g (4.2 mmol) of sodium methylate is added and the mixture is heated at 50° C. for a further 20 hours. After evaporation of the solvent, 300 ml of diethyl ether are added to the residue, the suspension is washed twice with 100 ml of water each time and then dried over sodium sulfate and filtered and the diethyl ether is evaporated off. 6.7 g of yellow oil which remain are purified by column chromatography over silica gel using toluene as the mobile phase. After evaporation of the toluene, a pale yellow oil of refractive index nD25 : 1.6225 remains. Yield: 5.8 g (24 mmol; 86% of theory).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH2:17][C:18]#[CH:19])[CH:6]=1)(=[O:3])[CH3:2].O(C1C=CC=CC=1)C1C=CC=CC=1>>[C:1]([NH:4][C:5]1[C:6]2[CH:19]=[CH:18][CH2:17][O:16][C:7]=2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: C#CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC=C2
Temperature: 230 °C
Reaction time: 0.75 h
Yield: 33.8 %

Procedure:
A mixture of 40 parts of methyl 4-(acetylamino)-5-chloro-2-(2-propynoxy)benzoate and 172 parts of phenoxybenzene was stirred for 45 min. at 230° C. After cooling, the reaction mixture was poured into petroleumether. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C2 /CH3OH 97:3). The eluent of the desired fractions was evaporated and the residue was crystallized from acetonitrile, yielding 11.9 parts (33.8%) of methyl 5-(acetylamino)-6-chloro-2H-1-benzopyran-8-carboxylate (interm. 11).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN1CCCC1=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]2[CH2:14][CH:15]([CH3:16])[N:7]3[C:8]=2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6]3
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCCCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 48.7 %

Procedure:
7-Amino-8,9-difluoro-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.5 g) and piperidine (0.8 g) are suspended in N-methylpyrrolidone (10 ml), and the mixture is heated at 110°-120° C. for 5 hours in a sealed tube. The reaction mixture is concentrated to dryness under reduced pressure, and to the residue is added ethyl acetate. The resulting crystals are separated by filtration and recrystallized from N,N-dimethylformamide to give 7-amino-8-fluoro-2-methyl-6-oxo-9-(1-piperidyl)-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (0.3 g) as yellow cubic crystals. m.p. 273°-276° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:18])([C:14]([O:16]C)=[O:15])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:18])([C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Cc1ccc(Cl)nc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(Cl)nc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of dimethyl 2-[(6-chloropyridin-3-yl)methyl]-2-methylmalonate (10.85 g, 40 mmol) in THF (80 mL) was added a solution of lithium hydroxide monohydrate (5.7 g, 0.136 mol) in water (43 mL). The resulting mixture was stirred overnight at room temperature and then poured into water (300 mL). The pH was adjusted to less than 2 by the addition of concentrated HCl. The resulting mixture was extracted with ether (3×100 mL) and the ether extracts were combined, washed with brine (100 mL) and dried over anhydrous MgSO4. After a filtration, the solvent was evaporated to give 9.26 g of the product as a white solid in 95% yield: m.p. 168° C. (decomp.).
Reaction SMILES: [CH:1](/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:2][CH2:1]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:14]
Reactant: C[C@@]1(/C=C/C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5.80 g (14.2 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(2-formyl- vinyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 240 ml of toluene under argon and cooled to 0° C. Then, 14.2 ml (21.3 mmol) of a 20% diisobutyl-aluminium hydride solution (in toluene) were added dropwise and the cooling bath is removed. The reaction mixture was stirred at room temperature for 6 hours, poured into 150 ml of saturated ammonium chloride solution and extracted three times with 200 ml of methylene chloride each time. The combined organic extracts were washed once with 300 ml of water as well as saturated sodium chloride solution, dried over magnesium sulfate, filtered and freed from solvent on a rotary evaporator. The residual yellow oil was chromatographed over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:n-hexane (9:16) as the eluent. Yield: 1.90 g (32%) of colorless resin IR (film): 3480(br), 1778, 1750, 1202, 1080, 988 cm-1MS: (M+NH4)+ 427.6
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>O1CCCC1.CCCCCC>[S:4]1[CH:5]=[CH:6][C:2]([C:15]2([OH:19])[CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]2)=[CH:3]1
Reactant: Brc1ccsc1
Reactant: CC1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCC(O)(c2ccsc2)C1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of 36.3 g (0.223 mol) of 3-bromothiophene in 50 mL of dry tetrahydrofuran was cooled to -78° C. in a dry ice-acetone bath. To this solution was added dropwise 139.4 mL (14.3 g, 0.223 mol, 1.6 M in hexane) of n-butyllithium in hexane over 30 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for 1.5 hours, then 25.0 g 0.223 mol, of 3-methylcyclohexanone was added dropwise during 20 minutes. Upon complete addition, the reaction mixture was stirred at -78° C. for two hours. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature during 1.5 hours, then was stirred for an additional one hour. Diethyl ether saturated with water (50 mL) was added with stirring, and the mixture was poured into a mixture of 50 g of ice and 20 mL of concentrated hydrochloric acid. The layers were separated, and the aqueous layer was washed with two portions of 200 mL each of diethyl ether. The washings were combined with the organic layer, and the whole was washed with 300 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 44.0 g of 1-(3-thienyl)-3-methylcyclohexanol. Volatile components were removed from the product by distillation at 50° C./0.25 mm using a Kugelrohr distilling system.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([Cl:28])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:30]N>C(O)C>[Cl:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:2]([Cl:1])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:30]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: NN
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)C(=CN(C)C)C3)C2=O)c(Cl)c1
Solvent: O
Solvent: CCO
Product: COc1cc(Cl)c(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one in ethanol (Preparation 24) (50 mL), and hydrazine hydrate (2.6 mL, 54 mmol) stir the resulting orange solution for 3 days at room temp. Concentrate the mixture to dryness, dilute with ethanol (15 mL) and ether (20 mL), cooled to 0° C. and filter to give 3.6 g, 68%, as a tan solid. MS (m/z): 394 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[CH:8]1(O)[CH2:11][CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:8]1([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: Oc1ccncc1
Reactant: OC1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CCC2)ccn1
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Pyridin-4-ol (6.0 g, 63.09 mmol), cyclobutanol (5.00 g, 69.40 mmol) and triphenylphosphine (18.20 g, 69.40 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added diisopropylazodicarboxylate (13.49 mL, 69.40 mmol). Once the addition was complete the reaction was stirred at 50° C. for 1 hour. The solvent was evaporated and the crude residue was dissolved in diethyl ether. To this was added a small amount of triphenylphoshine oxide and the reaction was stirred for 30 minutes to afford a solid, this was filtered and discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0M HCl, extracted with diethyl ether (1×75 mL) and the aqueous was then basified with solid potassium hydroxide. This was then extracted with diethyl ether (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.60 mBar, collecting fractions that distilled at 80° C. to afford the desired compound as a colourless oil (4.70 g, 49.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.78-1.66 (1H, m), 1.95-1.86 (1H, m), 2.24-2.14 (2H, m), 2.51-2.43 (2H, m), 4.69 (1H, quintet), 6.70 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.76 (M+H 150).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH:17]1[CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1>>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([NH:16][CH:17]2[CH2:24][CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]2)=[O:15])[CH3:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1CCCNC(=O)C1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Product: C[C@H](NC(=O)Cc1ccccc1)C(=O)NC1CCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(phenylacetyl)-L-alanine (Example A) and 3-amino-ε-caprolactam (Sigma), the title compound was prepared as a solid having a melting point of 200-202° C. The reaction was monitored by tlc on silica gel (Rf=0.30 in 1:9 methanol/dichloromethane).
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[N:10]=[CH:11][C:12]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:13]=3[N:14]=2)C=CC=CC=1.CSC.CN(C=[O:27])C>CO>[O:19]=[C:16]1[NH:15][C:13]2[N:14]=[C:9]([CH:8]=[O:27])[N:10]=[CH:11][C:12]=2[CH2:18][CH2:17]1
Reactant: O=C1CCc2cnc(/C=C/c3ccccc3)nc2N1
Reactant: CN(C)C=O
Solvent: CSC
Solvent: CO
Product: O=Cc1ncc2c(n1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a round bottom flask was added 2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (600 mg, 2.39 mmol) in DMF (10 mL) and methanol (10 mL). Ozone was bubbled through the solution at room temperature for 20 minutes and the excess ozone was purged with a stream of nitrogen. Dimethyl sulfide (1.77 mL, 23.9 mmol) was added and the reaction was stirred at room temperature for 24 h. The solvent was evaporated and the resulting solid was dissolved in 20% MeOH-DCM. The crude product was added to a silica gel column and was eluted with 0-20% MeOH-DCM. The collected fractions gave the title compound (400 mg, 95% yield).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([NH:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH3:18])[N:13]=[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=3[N+:31]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.C1COCC1.[Zn]>[NH2:31][C:11]1[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:13][C:14]([NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])=[N:15][C:10]=1[NH:9][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[NH:8][N:7]=1
Reactant: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N[C@@H](C)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a suspension of (S)-ethyl 6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]-5-nitropyrimidine-4-carboxylate (Method 10; 0.7 g, 1.5 mmol) and zinc dust (0.5 g, 7.7 mmol) in EtOH:THF (1:1, 20 ml) was slowly added saturated aqueous NH4Cl solution (3 ml). After 1 hour, the reaction mixture was cooled to 0° C., to which was added saturated NH4OAc solution (10 ml). The resulting mixture was allowed to stir for 10 minutes at 0° C. and then filtered through a plug of celite with EtOAc (100 ml). The resulting aqueous layer was extracted with EtOAc (2×100 ml), dried, filtered, and concentrated to give the title compound (0.60 g, 92%) which was used without further purification.
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11]([OH:25])[C@@H:10]1[OH:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1N=C2C(N=CN2[C@@H]2C[C@H](N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C=C2)=C([NH:64][CH2:65][CH:66]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)N=1>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([NH:64][CH2:65][CH:66]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[N:18]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (1S,2R,3S,5R)-3-(di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol by replacing di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine with {2-chloro-9-[(1R,4S)-4-(di-Boc-amino)-cyclopent-2-enyl]-9H-purin-6-yl}-(2,2-diphenyl-ethyl)-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: BrCCc1ccccc1
Product: Cc1cc(CCCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (2-bromoethyl)benzene to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-phenylpropyl)pyridine.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:11][C:12]1[C:16]([CH2:17][C:18]2[S:33][C:21]3[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[C:19]=2[C:34]([N:36]2[CH2:40][C@H:39]([OH:41])[CH2:38][O:37]2)=[O:35])=[C:15]([CH3:42])[NH:14][N:13]=1>CN(C)C=O.O>[OH:41][C@@H:39]1[CH2:38][O:37][N:36]([C:34]([C:19]2[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=3[S:33][C:18]=2[CH2:17][C:16]2[C:15]([CH3:42])=[N:14][N:13]([CH:2]([CH3:4])[CH3:3])[C:12]=2[CH3:11])=[O:35])[CH2:40]1
Reactant: CC(C)I
Reactant: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C(C)C)c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (0.1 ml) and potassium carbonate (100 mg) were added to a solution of 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (example 11, 100 mg) in dimethylformamide (1 ml) and the mixture stirred at 100° C. After 2 hours, further 2-iodopropane (0.2 ml) and potassium carbonate (200 mg) were added. After a further 16 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). Combined organic extracts were treated with pyrrolidine (0.1 ml) and after 1 hour were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium acetate/acetonitrile elution to give the title compound (58 mg) as a foam. MS (APCI) 504 [M+H]+. δ 1HDMSO 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 (8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a suspension of 508 mg of 4-carbamoylimidazolium-5-olate and 486 mg of triethylamine in 6 ml of anhydrous dimethylformamide was added 770 mg of p-chlorobenzoyl chloride in 3 ml of anhydrous dimethylformamide at a temperature below 5° C. The mixture was stirred under ice cooling for 4 hours. The insoluble crystals were filtered off, then the filtrate were concentrated to a residue under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 5-carbamoyl-1H-imidazol-4-yl p-chlorobenzoate. The crude solid was washed with ethyl acetate to give 340 mg of pure product, m.p. 220° C. (charred).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH:21]C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:1][C:2]1[NH:3][C:4](=[O:29])[C:5]2[N:6]=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]([C:18]3([NH2:21])[CH2:20][CH2:19]3)=[O:17])[C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)OCCOCn2cnc3c(=O)[nH]c(N)nc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(ncn2COCCOC(=O)C2(N)CC2)c(=O)[nH]1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Suspend 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester (0.20 g, 0.49 mmol) of Preparation 1 in methylene chloride (2 mL) and stir at room temperature. Add trifluoroacetic acid (2 mL) dropwise and continue stirring. The suspension dissolves to give clear solution. Concentrate to dryness under vacuum. Triturate with ethyl acetate several times to isolate a white solid. Yield: 67.7% MS (ES+): 309.2 (M+1) MS (ES−): 307.2 (M−1)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Cc1nc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1
Temperature: 90 °C
Yield: 100.5 %

Procedure:
18.0 g of 6-hydroxy-2-methylbenzoxazole synthesized from Synthesis 1, 36.6 g of 1-bromohexadecane, 24.0 g of potassium carbonate and 120 ml of N,N-dimethylformamide were mixed with stirring at 90° C. for 4.5 horus. Solids were removed from the reacting solution, and the filtrate was poured into 500 ml of methanol. The separated crystals were separated by filtration to obtain 45.0 g of 6-hexadecyloxy-2-methylbenzoxazole.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[N:7]([C:18]([O:20][CH:21](Cl)[CH3:22])=[O:19])[C:6]=2[CH:5]=[C:4]([O:24][CH3:25])[C:3]=1[OH:26].[C:27]([OH:30])(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:30][CH:21]([O:20][C:18]([N:7]1[C:6]2[CH:5]=[C:4]([O:24][CH3:25])[C:3]([OH:26])=[C:2]([Br:1])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)=[O:19])[CH3:22])(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)OC(C)=O

Procedure:
A mixture of 4-bromo-10-(1-chloroethoxycarbonyl)-2,7-dimethoxy-3-hydroxy-10H-phenothiazine (1g) and mercuric acetate (1.46g) in glacial acetic acid (30 ml) was stirred and heated at 85° for 10 minutes. After cooling the mixture was diluted with ethyl acetate, washed with water, aqueous NaHCO3 solution, and brine, dried and evaporated. Flash chromatography on a column of silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, afforded the pure title product (599 mg) m.p.: 162°-164° C.