Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:12]=1)[C:8]#[N:9].Cl>CCO>[NH2:14][CH2:13][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([Br:4])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cc(Br)cc(CN)c1

Procedure:
Hydrazine hydrate (85%, 1.31 g) was added to a suspension of 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 10.3 mmol) in EtOH (60 mL). The mixture was refluxed for 3 h. Then, at room temperature, 2 N HCl (20 mL) was added (pH=3), and the mixture was filtered and the solid was rinsed with water (20 mL×2). The filtrate was evaporated to about 50 mL and filtered again. After addition of NaHCO3 (pH=9), the filtrate was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. It was recrystallized from MeOH-Et2O yielding the product (1.40 g, 55%) as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.92 (m, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 4.11 (s, 2H); 13C NMR (400 MHz, D2O): δ 137.1, 135.9, 135.8, 131.7, 123.0, 117.7, 113.8, 42.0; MS: m/z 209.0 (M+-HCl); HPLC: retention time: 9.313 min; purity: 98.4%.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][S:2][CH3:1])=[CH:7][CH:6]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1ccc(Br)cc1
Temperature: 60 °C

Procedure:
Sodium thiomethoxide (1.0 g, 14.3 mmol) and 4-bromobenzyl bromide (2.65 g, 10.6 mmol) were combined with anhyd THF (50 mL) and the reaction mixture was stirred at 60° C. After 3h the reaction mixture was concentrated in vacuo and the residue was washed into a separatory funnel with EtOAc and water. The organic layer was separated, dried (anhyd MgSO4), and concentrated in vacuo to yield 1-bromo-4-methylthiomethyl-benzene. To a solution of this crude thioether in DCM (100 mL) was added 3-chloroperoxybenzoic acid (77%, 4.0 g) portionwise. After stirring overnight the reaction mixture was poured into a separatory funnel, washed with 1 N NaOH, dried (Na2SO4), and concentrated in vacuo. The residue was crystallized from EtOAc-Hex to afford 1-bromo-4-methanesulfonylmethyl-benzene (2.02 g, 76%) as light tan needles: 1H-NMR (CDCl3) δ 7.56 (2H, d, J=8 Hz), 7.29 (2H, d, J=8 Hz), 4.20 (2H, s), 2.78 (3H, s); MS (ESI) m/z 249 and 251, both [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:23][C@@H:24]([C:27]([OH:29])=[O:28])[CH2:25][OH:26])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[C:1]1([CH:7]([O:29][C:27](=[O:28])[C@@H:24]([CH2:25][OH:26])[NH:23][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of approximately 214 g of diphenyldiazomethane in 1 l of methylene chloride is added dropwise at 22°, while cooling, to a solution of 236.7 g of the resulting crude (2R)-BOC-serine in 700 ml of methylene chloride and the mixture is stirred for 11/2 hours at 20°. The mixture is concentrated by evaporation in vacuo, the residue is taken up in ethyl acetate and washed at 0° with a phosphate buffer of a pH of 2.0 then of a pH of 7.0. The dried organic phase yields a crystalline residue on concentration by evaporation which is digested in hexane and, after filtering, (2R)-N-BOC-serine diphenylmethyl ester is obtained; m.p. 116°-117° (corrected).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:14](=[O:20])[C:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:30]1([C:38]3[C:33](=[N:34][CH:35]=[CH:36][CH:37]=3)[N:32](COCC[Si](C)(C)C)[C:31]1=[O:47])[CH2:29]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C@H:10]2[N:15]([CH2:16][C:17]([NH:25][C:26]3[CH:27]=[C:28]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:30]3([C:38]5[C:33](=[N:34][CH:35]=[CH:36][CH:37]=5)[NH:32][C:31]3=[O:47])[CH2:29]4)=[O:19])[C:14](=[O:20])[C:13]([CH2:21][CH3:22])([CH2:23][CH3:24])[NH:12][CH2:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetic acid hydrochloride (43 mg, 0.119 mmol, described in Intermediate 29), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (30 mg, 0.119 mmol, described in Intermediate 9), HOBT (27 mg, 0.179 mmol), and EDC (34 mg, 0.179 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=560 (M+1). HRMS: m/z=560.2469; calculated m/z=560.2468 for C31H32F2N5O3.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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(O)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1ccc(Br)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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
A mixture of 4-bromobenzaldehyde (10.0 g), 4-fluorophenylboronic acid (11.3 g), tetrakis(triphenylphosphine)palladium(0) (3.12 g), sodium carbonate (28.6 g), toluene (150 mL), ethanol (70.0 mL) and water (70.0 mL) was stirred at 100° C. for 12 hours. After cooling the reaction mixture to room temperature, water was added and extraction with toluene was conducted twice. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10) and after adding n-hexane to the residue, the mixture was stirred. The precipitate was recovered by filtration and dried under reduced pressure to give the titled compound as a colorless solid (10.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C.CC(N(C)C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:6]2[C:5]([O:9][CH3:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cnc(Cl)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cnc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2,4-dichloro-5-methoxy-pyrimidine (0.80 g, 4.47 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 6.70 mmol, 1.5 equiv) and triethylamine (0.93 mL, 0.68 g, 6.70 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.43 g (93%) of the title compound. 1H NMR (400 MHz, CDCl3): δ1.28-1.49 (m, 2H), 1.40 (s, 9H), 1.93-1.98 (m, 2H), 2.85-2.92 (m, 2H), 3.80 (s, 3H), 3.97-4.02 (m, 2H), 4.06-4.12 (m, 1H), 5.22 (d, J=8.0 Hz, 1H), 7.46 (s, 1H). MS (ISP): 343.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:12]([NH:14][NH2:15])=O)([CH3:8])[CH3:7].[OH-].[Na+]>C(O)C>[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([C:12]2[N:2]([CH3:1])[C:3](=[O:4])[NH:15][N:14]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Reactant: CN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n[nH]c1=O
Temperature: 25 °C
Yield: 29.6 %

Procedure:
Methyl isocyanate (1.02 g, 18 mmol) is added dropwise to a solution of the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (2.35 g, 8.9 mmol) in absolute ethanol (100 ml). The reaction mixture is stirred at room temperature, concentrated, and poured into ice water. The precipitate (1.2 g) is collected by filtration and dissolved in two equivalents of 1N NaOH. The reaction mixture is refluxed for three hours, and then is cooled and neutralized. The product is extracted into ethyl acetate. Pure 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one (0.8 g, 30%) is obtained by recrystallization from methanol, mp 308°-312° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.CC([O-])(C)C.[K+].[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.CCOC(C)=O>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[CH:18][N:19]=[C:20]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:21]=1
Reactant: Nc1ccc(O)nc1
Reactant: Clc1cc(Cl)ncn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2cc(Cl)ncn2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
Add 5-aminopyridin-2-ol (500 mg, 4.545 mmol), t-BuOK (555 mg, 4.545 mmol) in DMF (20 mL), stir at 25° C. for 30 min. Cool to 0° C., add slowly 4,6-dichloropyrimidine (614 mg, 4.13 mmol). Stir the reaction under N2 for 1 hr. TLC (EtOAc:PE=1:1) shows the reaction is complete. Cool the mixture to 0° C., add water (20 mL), extract with EtOAc (20 mL×2). Combine the organic layers; wash with brine, dry over anhydrous Na2SO4. Filter and concentrate under reduced pressure to give crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (650 mg, 70.8%). MS: (M+1): 223.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=1[C:24](Cl)=[O:25].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:24](=[O:25])[C:23]3[C:22]([F:21])=[CH:30][CH:29]=[CH:28][C:27]=3[F:31])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
570 mg of C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3) was dissolved in 8 ml of dichloromethane and cooled to 0° C. 441 mg of triethylamine was added, followed by dropwise addition of a solution of 385 mg of 2,6-difluorobenzoyl chloride in 2 ml of dichloromethane. The reaction mixture was stirred at ambient temperature for 1 hour. Water was added and the reaction mixture was extracted twice with dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. 1095 mg of crude material was obtained as a pale brown sticky oil. This residue was purified by chromatography on silica gel with cyclohexane/ethyl acetate (3:1) as a eluent. Thus, 742 mg of N-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluoro-benzamide was obtained as a yellow sticky oil. 1H-NMR (CDCl3): 8.47 ppm (s, 1H), 7.86 ppm (s, 1H), 7.33 ppm (m, 1H), 6.90 ppm (t, 2H), 6.30 ppm (s, 1H, broad), 3.71 ppm (d, 2H), 1.09 ppm (m, 4H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@H:22]([CH3:26])[CH:23]1[O:25][CH2:24]1)[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.O>C(OCC)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@:15]([OH:27])([C@H:22]([CH3:26])[C@@H:23]([OH:25])[CH3:24])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@H](C1CO1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@H](O)[C@@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 1 h
Yield: 76.9 %

Procedure:
53 mg (1.40 mmole) of lithium aluminum hydride were added, under an atmosphere of nitrogen, to a solution of 207 mg (0.70 mmole) of (2R*,3R*)-2-(2,4-difluorophenyl)-4,5-epoxy-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2-pentanol [about a 3:1 mixture of isomers at the C4 position, prepared as described in Preparation 3] in 4 ml of diethyl ether, whilst ice-cooling and stirring. Ten minutes later the reaction mixture was heated under reflux, and this was continued for 1 hour. At the end of this time, the mixture was cooled, and 1 ml of water was slowly added, after which the mixture was stirred for 10 minutes. The insoluble materials were removed by filtration using a Celite filter aid, after which the residue was washed with ethyl acetate. The combined filtrate and washings were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting oily residue was subjected to column chromatography through silica gel, using a 5:5:1 by volume mixture of ethyl acetate, chloroform and hexane as the eluent, to afford 160 mg of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:15]=[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NCC(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (2.00 g, 11.1 mmol, described in Intermediate 25), 2-bromoacetophenone (2.44 g, 12.2 mmol), and NaHCO3 (2.34 g, 27.9 mmol) in DMF (20 mL) was stirred at ambient temperature for 5 h. H2O (25 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[C:43]([S:47][S:48][C:49]([N:51]([CH3:66])[C@@H:52]([CH2:59][S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:53](OCC#N)=[O:54])=[O:50])([CH3:46])([CH3:45])[CH3:44].FC(F)(F)C(O)=O>O.O1CCCC1>[C:43]([S:47][S:48][C:49]([N:51]([CH3:66])[C@@H:52]([CH2:59][S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:53]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:54])=[O:50])([CH3:46])([CH3:45])[CH3:44]
Reactant: CN(C(=O)SSC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C(=O)SSC(C)(C)C)[C@@H](CSSC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.2 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (77 mg, 0.121 mmol) in water (2.40 ml) and a solution of (R)-cyanomethyl 2-((tert-butyldisulfanecarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 21-G) (198 mg, 0.483 mmol) in tetrahydrofuran (1.21 ml) were added to buffer A (46 ml), and the mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (0.967 ml) was then added, after which the mixture was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2R)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butyldisulfanecarbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoate (Compound 2m-G) (3.8 mg, 3%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Reaction time: 6.5 h
Yield: 63.3 %

Procedure:
2-(Butyloxy)-8-(methoxy)-9-(tetrahydro-3-furanylmethyl)-9H-purin-6-amine (Isomer 1, 1.54 gm) was suspended in methanol (20 ml) and 4N HCl in dioxan (4 ml) added with stirring to give a clear solution. After 6.5 h, the solvents were evaporated to low volume and water added with stirring, followed by neutralisation with saturated sodium bicarbonate. The resulting off-white solid was filtered, washed with water and dried, yield 1.26 gm. This material was added portionwise to boiling methanol (130 ml), adding a further 20 ml of methanol. The suspension was filtered, and the solid treated with boiling methanol (20 ml) and added to the filtrate. This was reboiled, then allowed to cool with stirring when a white solid crystallised out. This was filtered, washed with methanol and dried, to give the title compound yield 932 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=O)=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[S:8][C:7]=2[CH:35]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.CO>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:17][CH:18]=3)[OH:12])=[C:9]([CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc2c(C(=O)c3ccc(CCC(=O)N4CCCCC4)cc3)c(C3CCCCC3)sc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(O)c3ccc(CCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1
Yield: 31.1 %

Procedure:
353 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinylcarbonyl)ethyl]phenyl]methanone was dissolved in 30 ml of THF, 850 mg of lithium aluminum hydride was added, and the mixture was refluxed with heating for 1 hour. A small quantity of water was added to the reaction mixture, followed by stirring, 1 ml of methanol was added, followed by stirring for 5 minutes, and 5 ml of ethyl acetate was added, followed by stirring for 5 minutes. The mixture was filtered using a super cell, the filtrate was concentrated under reduced pressure, and the resultant crude product was purified by TLC (developing solvent, chloroform:methanol=19:1) to obtain 107 mg of (6-methoxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[3-(1-piperidinyl)propyl]phenyl]methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:21])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C[O:23][C:24](=[O:47])[C@H:25]([C@@H:44]([CH3:46])O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([O:21][C@H:44]([CH3:46])[C@@H:25]([C:24]([OH:47])=[O:23])[NH2:26])[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cc1ccccc1C1(O)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Product: Cc1ccccc1C1(O[C@H](C)[C@H](N)C(=O)O)c2ccccc2-c2ccccc21

Procedure:
from 9-(2-methylphenyl)-9H-fluoren-9-ol (Example 3g) and Nα -(9-fluorenyl methoxycarbonyl )-L-threonine methyl ester;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]Cl)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][NH:27][CH2:25][CH3:26])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CCN
Solvent: CC(=O)N(C)C
Product: CCNC/C=C/[C@H]1CC[C@H](CCN(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester was reacted with ethylamine in N,N-dimethylacetamide at room temperature to yield trans-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 379 (MH+, 1Cl).