Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH2:20])[N:17]([CH3:19])[N:18]=[C:11]12.[CH3:21][CH2:22][CH2:23][C:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([NH:20][CH:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][CH3:21])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: CCCC(=O)CCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC(CCC)Nc1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (45.7 mg) and 4-heptanone (24 mL) were dissolved and stirred in 3 mL of dichloroethane. After 15 min, 44.5 mg of sodium triacetoxyborohydride was added. The reaction mixture was stirred at 60° C. during the day and at room temperature over night during 3 d. During this period, an additional 109μL of 4-heptanone and an additional 104 mg of sodium triacetoxyborohydride were added to drive the reaction to completion. The reaction mixture was then partitioned between ethyl acetate and water. The ethyl acetate was dried with magnesium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 11 mg of [7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl](1-propylbutyl)amine as a crystalline film, ms m/z 389 (MH+).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:13]1([C:16]2[C:17]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O>[C:7]([C:6]1[CH:9]=[C:2]([N:36]([C:17]2[C:16]([CH:13]3[CH2:15][CH2:14]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:37]([CH3:40])(=[O:38])=[O:39])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])#[N:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: N#Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C#N)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzonitrile (1.280 mL, 11.18 mmol), 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (3.0 g, 7.45 mmol) and K2CO3 (3.09 g, 22.36 mmol) in 1,2-dimethoxyethane (30 mL) and water (7.5 mL) in a seal tube was heated to 80° C. overnight. It was cooled down to room temperature, diluted with EtOAc, filtered and the off-white solid was washed with water and then dried in vacuo to give crude desired product as a yellow solid (80% purity, 3.9 g, 76%). LCMS (m/z, ES+)=549 (M+H+)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)(=[O:30])=[O:29])[CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)(=[O:30])=[O:29])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: O=S(=O)(c1cccnc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3cccnc3)s2)CC1)C(F)(F)F
Yield: 49 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 46(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light brown crystalline solid (yield 49%). MS (m/e): 605.2 (M+H+, 100%).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[F:37][C:17]1[CH:18]=[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)[C:20]([F:22])=[CH:21][C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:14])=[O:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2cnc(Cl)cc2-c2cncnc2)cc1F
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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cncnc2)cc1F
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
10 mg (0.02 mmol) of tert-butyl((4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.6 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.4 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [OH:1]C1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.[C:18]1(=[O:24])[O:23][CH:21]([CH3:22])[CH2:20][O:19]1>>[C:18](=[O:19])([OH:24])[OH:23].[OH:1][CH2:22][CH:21]([CH2:20][OH:19])[OH:23]
Reactant: CC1COC(=O)O1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: O=C(O)O
Product: OCC(O)CO
Yield: 4.1 %

Procedure:
A 2 liter Hoppes Reactor equipped with a vacuum line, and distillation apparatus was charged with 750 grams of bisphenol A obtained from Shell Chemical, 674 grams of propylene carbonate obtained as JEFFSOL PC from Huntsman Chemicals, 20.8 grams of glycerine carbonate obtained as JEFFSOL GC from Huntsman Chemicals and 1.5 grams of potassium carbonate. The mixture was heated to 180° C. over a 3 hour period with stirring and maintained at that temperature for an additional 4 hours. The reactor was then charged with 385.5 grams of fumaric acid (resin grade) from Bartek Ingredients Ink Company, 1.5 grams of butylstannoic acid obtained as FASCAT 4100 from Elf Atochem, and 220 milligrams of hydroquinone. The temperature was then raised to 190° C. over a 2 hour period, and the pressure was then reduced from 760 Torr to 6.5 Torr over a 3 hour period, wherein water was collected in the distillation receiver. The resin, copoly(propoxylated bisphenol A co-fumarate)-copoly(glycerinoxylated bisphenol A co-fumarate), was then discharged through the bottom drain valve, and exhibited a glass transition temperature (onset) of 60.2° C. determined by using the DuPont differential scanning calorimeter and obtained during the second heating cycle of the resin at a heating rate of 10° C. per minute. The melt index of this resin was found to be 13.6 grams per 10 minutes using a 2.16 kilograms weight at a temperature of 117° C. The softening point of this resin determined using the Mettler softening point apparatus was found to be 116° C. The weight average molecular weight was found to be 20,700 grams/mole and the number average molecular weight was found to be 4,600 grams as measured by the gel permeation chromatography and using tetrahydrofuran as the solvent and polystyrene as the standard. The acid number of this resin product was 27 milligrams of KOH per gram of sample.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[C:8]2[I:24])[NH2:4].CCN(CC)CC.[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=O.O>C1COCC1>[I:24][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]3[N:4]=[C:34]([C:33]([Cl:38])([Cl:37])[Cl:32])[O:1][N:2]=3)[CH:6]=2)[N:10]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(N)=NO)ccc32)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a suspension of N′-hydroxy-3-iodo-1-tosyl-1H-indole-5-carboximidamide (950 mg, 2.09 mmol) in dry THF (10 mL) was added Et3N (1.4 mL, 10.10 mmol) and O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) (1.6 g, 4.18 mmol) at 0° C. Trichloroacetyl chloride (0.48 mL, 2.51 mmol) was added portion wise at 0° C. and the reaction was stirred for 16 h at RT. The mixture was treated with H2O (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was further with basic alumina chromatography (eluent: 5% EtOAc in petroleum ether) to afford 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (250 mg, 20.8%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 8.21 (d, J=8.8 z, 1H), 8.10 (t, J=1.2 Hz, 1H), 7.99-7.95 (m, 3H), 7.44 (d, J=8.4 Hz, 1H), 2.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].C(O)CCC>CS(C)=O>[CH2:12]([NH:16][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCN
Solvent: CS(C)=O
Solvent: CCCCO
Product: CCCCNc1nc(N)c2nc[nH]c2n1
Temperature: 170 °C
Yield: 83 %

Procedure:
2-chloroadenine (1) (1.60 g, 9.44 mmol) was divided among three microwave vials (10-20 mL), each containing Butylamine (4 mL), 1-Butanol (10 mL,), and DMSO (1 mL). Each vial was heated to 170° C. for 90 minutes. After reaction completion the solvent was removed by rotary evaporation and the product was purified on flash column eluting 10% methanol in ethylacetate. Evaporation of solvent gave 1.62 g (83%) of 64 as an off white solid. 1H NMR (300 MHz, DMSO) δ 0.877 (t, 3H), 1.29 (m, 2H), 1.45 (m, 2H), 3.17 (t, 2H), 6.49 (s, 2H), 7.61 (s, 1H), 12.1 (s, 1H). LCMS: m/z for C9H14N6++H observed 207.2 at 1.40 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:59][NH:60][C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:59][N:60]([C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1)[C:21]([C:19]1[N:20]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]3)[CH2:15][CH2:14]2)[S:17][CH:18]=1)=[O:22]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazin yl]-4-thiazolecarboxylic acid (200 mg, 0.5 mmol) (i.e. the product of Example 30, Step D) was suspended in 5 mL of dry dichloromethane and treated with triethylamine (150 μl, 1.08 mmol) to give a homogeneous solution. To this reaction mixture was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 210 mg, 0.55 mmol) followed by (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (106 mg, 0.60 mmol) (i.e. the product of Example 6, Step A). The reaction mixture was stirred at ambient temperature for 3 h, passed through a Varian Chem Elut™ CE1010 column pretreated with 5 mL of 20% aqueous citric acid solution. The column was flushed with three column volumes of dichloromethane, concentrated and purified by silica gel chromatography eluting with ethyl acetate to give 223 mg of the title product, the compound of present invention as white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[H][H]>[Pd].C(O)C.C(#N)C.O>[N:3]1[CH:2]=[CH:7][C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: O
Solvent: CCO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccncc1
Reaction time: 16 h

Procedure:
A mixture of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (165 mg, 0.363 mmol) and 10% palladium on carbon (77 mg) in ethanol (10 mL) was placed under 1 atmosphere of hydrogen (balloon). After 16 hours, diatamacous earth (300 mg) was added and the mixture and the solution was filtered through diatamacous earth and concentrated to afford an oil. The crude material was dissolved in a 4:1 mixture of acetonitrile in water and purified by reversed-phase HPLC. The desired fractions from the column were concentrated to remove the acetonitrile, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[N:13]([O-])=O.[Na+].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>C1COCC1.O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:13]=[N:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[C:20]([CH3:24])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N)ccc1N=Nc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
For their studies, p-Methylsulfonylaniline (1.42 g, 8.3 mmol) was sequentially treated with HCl (15 ml of a 6M solution, 9 mmol) and sodium nitrite (0.66 g, 9.12 mmol) while the temperature was maintained between 0–5° C. The reagents were allowed to dissolve and the resulting solution was allowed to stir for an about 15 minutes. The resulting diazonium compound was then treated with m-toluidine (0.9 g, 8.4 mmol) in THF, and allowed to stir for about 15 minutes to 1 h. To the resulting red-orange mixture was added sodium acetate NaOAc) (2 g, 2 mmol) or water and allowed to stir for about 16 h. The precipitated orange solid was filtered, sequentially washed with water/ethanol and hexanes, and dried under vacuum and recrystallized from EtOAc/Hexane to give 1.96 g (73.3%) of Compound 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].O1CCCC1.O1CCCC1.B.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1OC
Reaction time: 1.5 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate (0.1 g, 0.5 mmol) and tetrahydrofuran (2 mL). Cool in an ice bath. Add a solution of borane tetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol). After 1.5 hours, again add a solution of borane tetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol). After 2 hours, add a 1 M aqueous solution of hydrochloric acid (2 mL) and stir. After 15 minutes, dilute the reaction mixture with ethyl acetate. Separate the layers, extract the aqueous layer three times with ethyl acetate and combine the organic layers. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-hydroxymethylbenzoate: Rf=0.32 (silica gel, ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=O.Cl.[NH2:23][OH:24].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[N:23][OH:24]
Reactant: NO
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1SC(c1ccccc1)C(C=NO)=C2Cl

Procedure:
As in example 10 but starting with 1 g 4-chloro-3-formyl-8-methoxy-thioflav-3-ene in 1.5 ml DMF. 220 mg hydroxylamine hydrochloride dissolved in 2 ml DMF are added. After 11/2 hours of reflux, the solution is cooled at room temperature before the addition of 20 ml of water. After extraction with CH2Cl2 a gum is obtained which is purified by column chromatography on silicagel using n-hexane/acetone 9:1 as eluant. Pure 4-chloro-3-hydroxyiminomethyl-8-methoxy-thioflav-3-ene is obtained as a yellow solid. TLC (SiO2, n-hexane/acetone 4:1): Rf =0.15.-NMR (90 MHz, CDCl3): δ(ppm)=3.76 (s, 3H, OCH3), 5.5 [s, 1H, H-C(2)], 6.76-7.69 [m, 3H, H-C(5,6,7)], 7.17 [s, 5H, H-C(2',3',4',5',6')], 8.53 [s, 1H, CH=N], 11.4 [s, 1H, OH].-M.p. 190°-203° C. (n-hexane/toluene).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.CN(C)C=O.[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.CO.O>[C:22]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[CH:1]=[N:2][C:3]2[C:14](=[O:15])[NH:13][C:12]([NH2:16])=[N:11][C:4]1=2)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCCCC(=O)OCCOCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 5 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A mixture of acyclovir prepared according to UK Patent No. 1523865 (3.11 moles), 4-dimethylaminopyridine (4.91 moles) and dimethylformamide (5.6 L) was stirred under nitrogen with heating on steam bath to give a homogeneous solution. On cooling to room temperature valeryl chloride (4.91 moles) was added dropwise while the temperature was maintained at 20°-25° C. Progress of the reaction was monitored by HPLC (Partisil ODS-3, methanol:water 50:50) and the reaction was terminated when the level of residual acyclovir was less than 0.5% (AUC). The mixture was cooled to 5° C., filtered and the cake was washed with dimethylformamide (200 ml). The combined filtrates were diluted with absolute ethanol (1 L), stirred for two hours at ambient temperature and concentrated to a thick oil. Methanol (16 L) was added and the resulting suspension was refluxed for 1.5 hours, cooled to 5° C. and filtered. The crude product was washed with methanol (200 mL) and dried under vacuum to constant weight to give 819 g (85.1% yield) of 9-(2-valeryloxyethoxymethyl) guanine, M.p. 215°-217° C.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2(O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1.[OH-].[NH4+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(C2(O)CCN(C)CC2)c1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C2=CCN(C)CC2)c1
Yield: 97.5 %

Procedure:
To 4.075 liters of 85% phosphoric acid at 60° C. in a 22 liter flask equipped with a condenser, thermometer, and stirrer was added portionwise 1.015 kg (4.35 mol) of 4-(3-methoxyphenyl)-1-methyl-4-piperidinol via a powder funnel. The reaction mixture was stirred for 3 hours at a temperature between 70° C. and 80° C. whereupon 4 liters of water was added and the temperature of the reaction mixture adjusted to approximately 50° C. The mixture was neutralized to pH 8.5 by the addition of 8.5 liters of 28% ammonium hydroxide while maintaining the temperature of the reaction mixture above 50° C. The resulting aqueous solution was extracted at 60° C. with 1.25 liters of hexane three times. The organic extracts were combined and washed twice with 1 liter of water, once with 0.5 liters of saturated sodium chloride solution and dried over 250 g of anhydrous sodium sulfate. Evaporation of the volatiles under reduced pressure provided 862.5 g of 97.9% pure 1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-methylpyridine. Yield 97.7%. mp (hydrobromide salt)=139.5°-141° C.
Reaction SMILES: [O:1]([C@H:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:10][CH2:9][C@H:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:11])[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: C[C@H](CN)Oc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H](CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.9 %

Procedure:
(R)-2-Phenoxy-1-propylamine (0.6 g, 2.9 mmol)(prepared by the method described in example 2) was reacted with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g, 2.4 mmol) in dioxan (20 ml) in the presence of triethylamine (0.5 g, 5.3 mmol). The reaction mixture was stirred at room temperature for 72 h before being filtered and evaporated. The product, following purification by flash chromatography, was treated with saturated methanolic ammonia (30 ml) for 18 h and evaporated to provide a solid residue. This solid was washed thoroughly with dichloromethane to provide the title 2-chloro- N-[(R)-2-phenoxy-1-propyl]adenosine (0.7 g, 65%), mp 175°-177° C., 1H NMR (DMSO-d6)δ 1.39 (3H, d, --CH3), 3.56 (1H, ABX, H-5'a), 3.68 (1H, m, H-5'b), 3.33-3.40 (1H, m, --C--H), 3.83-3.92 (1H, --C--H), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.53 (1H, dd, H-2'), 4.70 (1H, q, --C--H), 5.08, 5.34, 5.50 (3H, 3 br, 2', 3' and 5'-OH), 5.85 (1H, d, H-1'), 6.90 (1H, t, Ar--H), 7.11 (2H, d, Ar--H), 7.28 (2H, t, Ar--H), 8.45 (1H, s, H-8), 8.63 (1H, t, N--H).