Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.Cl[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[SH:26])[CH3:14].O>CO>[CH2:13]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[S:26][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:14]
Reactant: ClCc1ccccn1
Reactant: CCn1c(S)nc2ccccc2c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCn1c(SCc2ccccn2)nc2ccccc2c1=O
Reaction time: 4 h
Yield: 48.3 %

Procedure:
7.0 ml of 28% methanolic solution of sodium methoxide and 2.82 g of 2-chloromethylpyridine hydrochloride were added, in turn, to a solution of 3.56 g of 3-ethyl-2-mercapto-4(3H)-quinazolinone in 50 ml of methanol, and the stirring was continued at room temperature for 4 hours. The reaction solution was poured into about 300 ml of water and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 2.47 g of the title compound.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCc1ccccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2ccccc2F)nc1
Yield: 33.9 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(2-fluorophenyl)ethylamine (501 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (398 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(O)C.C(OC(=O)C)(=O)C>O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc2cccc(CCNC(C)=O)c2c1
Yield: 80 %

Procedure:
In a reactor, 5 g of the compound obtained in Step C and 2 g of sodium acetate are introduced into ethanol. The mixture is stirred, 2.3 g of acetic anhydride are then added, the reaction mixture is heated to reflux and 20 ml of water are added. The reaction mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off, washed with an ethanol/water 35/65 mixture to yield the title product in a yield of 80% with a chemical purity of 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-c1c(C)oc2ccc(Br)cc2c1=O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
Intermediate 11 (5.5 g, 16.38 mmoles) was taken in a RB flask and to this acetic anhydride (50 ml) and sodium acetate (9.40 g, 114.69 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (1.8 g, 30% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35 (d, J=1.7 Hz, 1H), 7.75 (d, J=6.7 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.35-7.26 (m, 3H), 7.09 (d, J=6.9 Hz, 1H), 2.20 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][C:18]=1[F:19].C(N(CC)CC)C>C(OC)(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:12][C:13]1[CH:14]=[C:15]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: Fc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCOc1ccc(C#Cc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-ethoxyphenylacetylene, 0.02 m of 3,4-difluoroiodobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with 100 ml of methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4-difluoro-4'-ethoxytolan, K 67 I, Δε=11.18.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[C:14]4[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:4][N:3]=1.[CH3:35][N:36](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[C:35]([C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[C:14]4[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:19]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[S:4][N:3]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4nc(Br)ns4)c3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4nc(C#N)ns4)c3)c12
Temperature: 95 °C

Procedure:
A mixture of ethyl 4-(3-(3-bromo-1,2,4-thiadiazol-5-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (51 mg, 0.092 mmol), tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.046 mmol), and zinc cyanide (107 mg, 0.915 mmol) in DMF (1.0 mL) was heated to 95° C. overnight. The resulting mixture was filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with 0-50% ethyl acetatehexane gave ethyl 4-(3-(3-cyano-1,2,4-thiadiazol-5-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C24H27N6O3SSi [M+H]+: 507, found 507.
Reaction SMILES: P(=O)(O)(O)[OH:2].[CH3:6][CH:7]([CH3:16])[CH2:8][CH:9]([S:13][C:14]#[N:15])[C:10](=O)[CH3:11]>O>[CH3:11][C:10]1[NH:15][C:14](=[O:2])[S:13][C:9]=1[CH2:8][CH:7]([CH3:16])[CH3:6]
Reactant: CC(=O)C(CC(C)C)SC#N
Reactant: O=P(O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)sc1CC(C)C
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
25 ml of 85% strength phosphoric acid were added to 20.07 g (117.26 mmol) of 5-methyl-2-oxohexan-3-yl thiocyanate, and the mixture was heated to 95° C. over a period of 1 h. At a temperature of 95-100° C., the mixture was stirred for another 0.5 h. After cooling, the reaction mixture was added to 40 ml of water and extracted repeatedly with tert-butyl methyl ether. The combined organic phases were washed with water, dried over sodium sulfate and concentrated on a rotary evaporator. This gave 18.11 g of the target compound, which was reacted further without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1ccccn1
Product: O=C(CCCSc1ccccn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 53 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptopyridine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 53% yield.
Reaction SMILES: O(Cl)[Cl:2].[P+5].[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=O)[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=2)[CH:9]=[CH:10][CH:11]=1>>[Cl:2][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=2)[N:21]=1
Reactant: ClOCl
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)nc2c1CCCC2
Agent: [P+5]
Product: Clc1cccc(-c2nc(Cl)c3c(n2)CCCC3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Phosphorus(V) oxychloride (17.6 g, 114.7 mmol) was slowly added to 2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (2.2 g, 8.5 mmol) at 0° C. The reaction mixture was warmed to 100° C. and held at that temperature for 2 h. After this time, the mixture was cooled, quenched with saturated sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (2.1 g, 23%) as a white solid. MW=279.16. 1H NMR (CDCl3, 300 MHz) δ 8.43-8.37 (m, 1H), 8.32-8.24 (m, 1H), 7.49-7.33 (m, 2H), 3.03-2.87 (m, 2H), 2.86-2.70 (m, 2H), 1.98-1.83 (m, 4H); APCI MS m/z 279 [M+H]+.
Reaction SMILES: [O:1]1[C@@H:5]2[CH2:6][O:7][CH2:8][C@@H:4]2[C:3]([CH2:9]O)=[N:2]1.C(N(S(F)(F)[F:17])CC)C>ClCCl>[F:17][CH2:9][C:3]1[C@H:4]2[CH2:8][O:7][CH2:6][C@H:5]2[O:1][N:2]=1
Reactant: OCC1=NO[C@@H]2COC[C@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCC1=NO[C@@H]2COC[C@H]12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
Intermediate IV-2: A solution of (3aS,6aS)-rel-1-(3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazol-3-yl)-methanol (14.0 mmol) in dichloromethane (40 ml) was treated dropwise with a solution of (diethylamino)sulfur trifluoride (15.4 mmol) in dichloromethane (5 ml) at −70° C. The colorless turbid solution was stirred at −70° C. for 30 minutes and then allowed to warm to room temperature while its color turned to brown. After stirring for one hour the dark brown solution was cooled in an ice-bath and quenched with a saturated solution of sodium hydrogencarbonate (50 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 80:20 as the eluent. The (3aS,6aS)-rel-3-fluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole (814 mg, 40% yield) was obtained as a light yellow solid. MS: m/z=146.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH3:22]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:11][CH2:12][O:13][CH3:22])=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(CCO)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
Sodium hydride (35.0 mg, 0.87 mmol) was added to tert-butyl 1-(4-chlorophenyl)-3-hydroxypropylcarbamate (Intermediate 30) (200 mg, 0.70 mmol) in THF (10 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 minutes. Methyl iodide (0.044 mL, 0.70 mmol) was added dropwise, and the resulting suspension was stirred at 22° C. for 4 hours. The reaction was quenched with KHSO4 solution (1M, 0.5 mL) and water (15 mL). The mixture was extracted with diethyl ether (3×20 mL); the combined extracts were washed with saturated brine (20 mL), dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(4-chlorophenyl)-3-methoxypropylcarbamate (80 mg, 38.1%) as a white solid.
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(CC)CC)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)C(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 69.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(2-ethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (510 mg) was dissolved in methanol (24 ml), aqueous lithium hydroxide monohydrate (175 mg) solution (12 ml) and tetrahydrofuran (12 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, isopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 339 mg of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N:19]1[CH2:23][C:22](=[O:24])[NH:21][S:20]1(=[O:26])=[O:25])[CH:15]=[C:14]([C:27]1[CH:28]=[C:29]([CH2:33][C:34]([OH:36])=[O:35])[CH:30]=[CH:31][CH:32]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](O)([C:39](F)(F)F)=O>CCO>[CH2:37]([O:35][C:34](=[O:36])[CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][C:18]([N:19]4[CH2:23][C:22](=[O:24])[NH:21][S:20]4(=[O:26])=[O:25])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:15]=2)[CH:28]=1)[CH3:39]
Reactant: O=C(O)Cc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)c1
Temperature: 40 °C

Procedure:
To a solution of {3-[6-benzyloxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-naphthalen-2-yl]-phenyl}-acetic acid (600 mg, 1.2 mmol) in EtOH (50 mL) is added TFA (25 mL) and the mixture is heated at 40° C. for 2 h. EtOH and TFA are removed via vacuum and the residue is purified by HPLC to give the title compound.
Reaction SMILES: C1N(/C=C2/CC/2CO)C2N=C(N)N=C(O)C=2N=1.[C@@H:18]1([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=3[N:29]=[CH:28]2)O[C@H:23]([CH2:24][OH:25])[C@@H:21](O)[C@H:19]1O>ClCCl.CO>[CH2:21]1[C@@H:23]([CH2:24][OH:25])/[C:19]/1=[CH:18]\[N:27]1[C:36]2[N:35]=[CH:34][N:33]=[C:31]([NH2:32])[C:30]=2[N:29]=[CH:28]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Nc1nc(O)c2ncn(/C=C3/CC3CO)c2n1
Solvent: CO
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2/C=C1/C[C@H]1CO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of racemic synadenol (1, B=adenin-N9-yl, 200 mg, 0.92 mmol) from Example 5 in 0.05 M Na2HPO4 (pH 7.5, 100 mL) was briefly sonicated. Adenosine deaminase from calf intestine (Type II, Sigma Chemical Co., St. Louis, Mo., 30 mg, 45 units) was added and the mixture was stirred at room temperature. The progress of the reaction was followed by TLC in dichloromethane-methanol (9:1). The deamination stopped after 72 h and the ratio of synadenol (1, B=adenin-N9-yl): synhypoxanthol (1, B=hypoxanthin-N9-yl) was 7:3 as determined by UV spectrophotometry of the eluted spots. Addition of another two portions of enzyme (30 mg every 24 h) did not improve this ratio. The mixture was lyophilized and the resultant product was sonicated with several portions of dichloromethane-methanol (1:1, first 100 mL and then 40 mL) until no UV absorption was detectable in the solvent. The filtrate and washings were combined and evaporated. The residue was adsorbed on silica gel (4 g) and loaded on a column made of the same material. Chromatography using dichloromethane-methanol (9:1) as an eluent afforded (R)-(−)-synadenol (1, B=adenin-N9-yl), 135 mg, 66.5%), [α]25D−59.10 (c 0.04, MeOH) and elution with dichloromethane-methanol (4:1) gave (S)-(+)-synhypoxanthol (1, B=hypoxanthin-N9-yl), 85 mg, [α]25D 91.8° (c 0.1, MeOH).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[C:8]([CH3:29])=[C:9]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=2)=[O:17])[N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2>N1C=CC=CC=1>[CH3:28][O:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[N+:24]([O-:26])=[O:25])[C:16]([C:9]1[N:10]2[C:15]([CH:14]=[CH:13][CH:12]=[CH:11]2)=[C:7]([NH:6][S:1]([CH3:4])(=[O:3])=[O:2])[C:8]=1[CH3:29])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2c(C)c(NS(C)(=O)=O)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
0.292 ml (3.78 mmol) of mesyl chloride is added to a solution of 350 mg (1.08 mmol) of the compound of Example 29 in 3 ml of pyridine, and the medium is stirred at room temperature for 4 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in 1 N hydrochloric acid and extracted with dichloromethane. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The residue is crystallized from ethanol. 327 mg of yellow crystals are obtained.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.[N:22]1(C#N)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[N:3][C:15]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:16]2
Reactant: N#CN1CCCC1
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (0.270 g, 1.220 mmol) in THF (10 mL) was added tert-butyllithium (1.077 mL, 1.830 mmol) dropwise at −78° C. After stirring for 0.5 h, pyrrolidine-1-carbonitrile (0.135 mL, 1.342 mmol) was added, then the solution was warmed to rt, and stirred for 16 h. The reaction mixture was quenched with MeOH, neutralized with 1.5 mL of 4.0M HCl in dioxane. Extracted product with 20 mL of DCM. The solution was evaporated on rotovap and then placed under high vacuum for 1 h to give 6-methoxy-3-(pyrrolidin-1-yl)isoquinolin-1-ol (298 mg, 100% yield) which was used in the next step without further purification. MS m/z 245.1 (M++1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([CH3:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[C:36]([CH3:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 3.5 h
Yield: 84.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.95 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.42 g) at: room temperature under ice-cooling and the mixture was stirred for 3.5 hours. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.82 g) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C1CNC(=O)C1.[Br:24][Br-]Br>>[Br:24][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C@H:5]2[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC(=O)c1ccc(OC2CCC(C)CC2)cc1
Agent: O=C1CCCN1
Product: C[C@H]1CC[C@@H](Oc2ccc(C(=O)CBr)cc2)CC1
Yield: 104.4 %

Procedure:
2-Bromo-1-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-ethanone (650 mg) was prepared following procedure A using 1-[4-(4-Methyl-cyclohexyloxy)-phenyl]-ethanone (464 mg, 2.0 mmol) and pyrrolidone hydrotribromide (701 mg, 2.2 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[CH:18]=2)=[CH:5][CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:25])[CH2:3][CH2:4][CH2:5][CH:6]1[C:7]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[CH:18]=1
Reactant: CCc1cccc(-c2ccc(C(=O)OC)cc2C2=CCCC2(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(-c2ccc(C(=O)OC)cc2C2CCCC2(C)C)c1
Reaction time: 18 h
Yield: 121.9 %

Procedure:
To a stirred solution of 83.28A (0.410 g, 1 mmol) in MeOH (5 mL) at 23° C. was added palladium on carbon (0.1 g, 1 mmol). The reaction was placed under an atmosphere of hydrogen and stirred for 18 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 83.28B as a colorless oil (0.410 g, 99% yield).