Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+].Cl>C(OCC)C>[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:21][CH2:22][C:23]([C:2]3[Se:1][CH:5]=[CH:4][CH:3]=3)([OH:26])[CH2:24][CH2:25]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Reactant: c1cc[se]c1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC1CCC(C2CCC(O)(c3ccc[se]3)CC2)CC1
Temperature: -50 °C
Reaction time: 18 h

Procedure:
25.0 g (0.19 mol) of selenophene are initially introduced in 250 ml of diethyl ether, and 130 ml (0.21 mol, 15% soln. in hexane) of n-BuLi are added. The mixture is warmed under reflux for 25 min and subsequently cooled to −50° C. A solution of 46.7 g (0.21 mol) of 4′-propylbicyclohexyl-4-one in 70 ml of diethyl ether is metered in, and the mixture is slowly warmed to RT. After 18 h, sat. ammonium chloride soln. and 2 N hydrochloric acid are added, and the organic phase is separated off. The aqueous phase is extracted with diethyl ether, and the combined organic phase is washed with 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=3:1→2:1). Further purification is carried out by recrystallisation from n-heptane. 4′-Propyl-4-selenophen-2-ylbicyclohexyl-4-ol is obtained as a yellow-brown solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][N:8]([CH3:12])[CH2:9][CH2:10][NH2:11])[CH:4]=[C:3]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=1.C(#N)C.[CH3:22][N:23]([CH3:78])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34](N(CCCCN4C5C(=NC=CC=5)N=C4)[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]>O>[CH3:78][N:23]([CH3:22])[C@H:24]1[CH2:75][C@@H:74]([CH3:76])[O:73][CH:26]([O:27][C@@H:28]2[C@@H:44]([CH3:45])[C:43](=[O:46])[C@@H:42]([CH3:47])[C:41](=[O:48])[O:40][C@H:39]([CH2:49][CH3:50])[C@:38]3([CH2:51][CH3:52])[C@H:34]([N:11]([CH2:10][CH2:9][N:8]([CH2:7][C:5]4[CH:4]=[C:3]([C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:2]=[N:1][CH:6]=4)[CH3:12])[C:36](=[O:53])[O:37]3)[C@@H:33]([CH3:67])[C:32](=[O:68])[C@H:31]([CH3:69])[CH2:30][C@@:29]2([O:71][CH3:72])[CH3:70])[C@@H:25]1[OH:77]
Reactant: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCn3cnc4ncccc43)C(=O)O[C@]12CC
Reactant: CN(CCN)Cc1cncc(-c2cccnc2)c1
Solvent: O
Solvent: CC#N
Product: CC[C@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](OC2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCN(C)Cc3cncc(-c4cccnc4)c3)C(=O)O[C@]12CC
Yield: 27 %

Procedure:
C12 ethyl, C9, C10, C11 enone, 3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-[3,3′]Bipyridinyl-5-ylmethyl-N1-methyl-ethane-1,2-diamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{2-[(3,3′-bipyridin-5-ylmethyl)(methyl)amino]ethyl }-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (27% yield) as a white solid. MH+(852.50).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Li+].[OH-].Cl>C1COCC1>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCCCCCN(CCc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCN(CCc1ccccc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-(4-{2-[hexyl(2-phenylethyl)amino]-2-oxoethoxy}phenyl)propanoate (0.081 g, 0.17 mmol) in THF (8.6 mL) was added 4.3 mL of a 0.10 M LiOH solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 2M HCl and extracted with ethyl acetate (3×25 mL). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.073 g (96%) of a colourless oil.
Reaction SMILES: C(OC([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:16]1[N:25]=[C:24]3[C:19]([C:20](=[O:39])[C:21]([C:34]([O:36]CC)=[O:35])=[CH:22][N:23]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:18][C:17]=1[F:40])[CH2:10]2)=O)(C)(C)C.[ClH:41]>C(OCC)(=O)C>[ClH:41].[NH2:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:16]1[N:25]=[C:24]3[C:19]([C:20](=[O:39])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:18][C:17]=1[F:40])[CH2:10]2
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC4CC4(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC12CC1CCN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3-c1ccc(F)cc1F)C2
Yield: 62 %

Procedure:
A solution of the compound of step A (300 mg, 0.54 mmol) in ethyl acetate (6 ml) and 3N hydrochloric acid (6 ml) was heated to reflux overnight. Solvents were removed in vacuo, and the residue was recrystallized from methanol-acetonitrile to give the title product as a white solid, mp 192° C. (decomp.) (155.5 mg, 0.338 mmol, 62% yield).
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O1CCOCC1>[O:1]([CH:8]([C:9]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccccc1)c1nnc(N)s1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A 1,000 milliliter, 3-neck flask equipped with a Claisen adaptor, paddle stirrer, thermometer, addition funnel and condenser, was charged with 100 grams (0.602 moles) of 2-phenoxypropanoic acid, (54.8 grams, 0.602 mole) of thiosemicarbazide and 300 ml. of dioxane. The slurry was heated to 85° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 was slowly added (for 70 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 105 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous residue to which 400 ml of water was added and the residue emulsified. A 50 percent solution of NaOH was added until the pH of the solution was 10, and a solid precipitate formed. The solid precipitate was filtered off, washed with water, air dried, then dried in a vacuum oven at 60° C. to a granular grey solid which was recrystallized from H2O/ethanol mixture, filtered and then dried in a vacuum oven at 60° C. to white needles of 5-(1-phenoxyethyl)-2-amino- 1,3,4-thiadiazole. (Melting point 157°-167° C.).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.[OH-].[Na+]>C(Cl)Cl.O>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([O:17][C@H:14]2[CH2:15][CH2:16][C@@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Agent: CN(C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](OC(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.24 g (0.001 mol) of cis-4-(4-dimethylaminomethylphenyl)-cyclohexanol, 0.34 ml (0.0025 mol) of triethylamine and 0.12 g (0.001 mol) of dimethylaminopyridine are dissolved in 20 ml of methylene chloride, mixed with 0.175 g (0.001 mol) of 4-chlorobenzoylchloride and stirred for 12 hours at ambient temperature. The reaction mixture is combined with water and adjusted to pH 12-13 using sodium hydroxide solution. The methylene chloride phase is separated off, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated saline solution, dried and evaporated down in vacuo. The residue is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/ethyl acetate=45:1) White crystals. Melting point: 96-97° C. Yield: 0.27 g (73% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([O:14]CC)=[O:13])[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCOC(=O)Cn1ncc2c(-c3ccco3)nc(N)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccco2)c2cnn(CC(=O)O)c2n1
Yield: 94.9 %

Procedure:
A solution of ethyl 6-amino-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidin-1-ylacetate (350 mg, 1.22 mmol) in MeOH (2 mL) was treated with NaOH (1-M, 1 mL, 1 mmol), refluxed for 15 min, cooled, acidified and filtered to give the title compound (300 mg, 95%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[OH:27][CH2:28][CH2:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14]([C:16]4[CH:17]=[N:18][C:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[N:20][CH:21]=4)=[O:15])=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1cnc(N2CCCC2)nc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(OCCO)cc3)nc2c1)c1cnc(N2CCCC2)nc1

Procedure:
Compound 243 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-2-(pyrrolidin-1-yl)pyrimidine-5-carboxamide and 4-(2-hydroxyethoxy)benzaldehyde. [M+H]+ calcd for C24H24N6O3: 445.20; found: 444.87.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([C:4](=[O:20])[CH:5]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[CH3:22][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:3][C:2]([CH3:21])([C:4]([CH3:22])([OH:20])[CH:5]([N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:1]
Reactant: CC(C)(C)C(=O)C(CCOc1ccccc1)n1cncn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(C)(O)C(CCOc1ccccc1)n1cncn1
Reaction time: 24 h

Procedure:
A solution of 6.0 g of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-6-phenoxy-hexan-3-one in 50 ml of tetrahydrofuran is added dropwise to a solution of 5.4 g of methyl-magnesium bromide in 28 ml of tetrahydrofuran, and after the slight exothermic reaction has subsided the mixture is left to stand for 24 hours at room temperature. It is then poured into 1,000 ml of 10% strength aqueous ammonium chloride solution and the batch is extracted twice with 200 ml of methylene chloride at a time. The organic phase is washed and dried over magnesium sulfate, and the methylene chloride is evaporated off under reduced pressure. 10 ml of diisopropyl ether are added to the residue, and 1.5 g of white crystals, of melting point 118°-120° C., are isolated from this mixture.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)C=Cc1ccc(Br)s1
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: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.250 g (1.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 61.9 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of degassed DME and stirred for 10 min at room temperature. 0.251 g (1.6 mmol) of 4-chlorophenylboronic acid and 1 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The reaction mixture was heated to 95° C. for 4 h, and then stirred at room temperature for 16 h. Solids were removed by filtration and the resulting solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated aqueous sodium hydrogencarbonate solution, and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 0.12 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][CH2:14][NH:15][CH:16]([CH3:20])[CH2:17][C:18]#[N:19].O.[OH-].[Na+]>C(OCC)C>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][CH2:13][CH2:14][NH:15][CH:16]([CH3:20])[CH2:17][CH2:18][NH2:19]
Reactant: CC(CC#N)NCCCC1OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CCN)NCCCC1OCCO1
Temperature: 35 °C

Procedure:
In a 1.5 liter sulfonating flask, 10.7 g (0.282 mol) of lithium aluminium hydride are suspended in 620 ml of diethyl ether. Then 55.9 g (0.282 mol) of 3-(3-[1,3]dioxolan-2-yl-propylamino)butyronitrile in solution in 210 ml of diethyl ether are slowly added dropwise. The mixture is subsequently heated at 35° C. for three hours. After cooling to 0° C., 10.7 g of water, 10.7 g of 10% strength NaOH and then a further 32.1 g of water are carefully added dropwise. The reaction solution is filtered over Hyflo and concentrated under reduced pressure. This gives 49.86 g of 3-{3-([1,3]dioxolan-2-yl)propylamino}-1-aminobutane as a reddish liquid which is used without further purification in the next stage.
Reaction SMILES: [N:1]([CH2:4][CH:5]([S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:6][C@@H:7]([NH:52]C(OC(C)(C)C)=O)[C:8]([O:10][C@H:11]1[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[O:13][C@H:12]1[CH2:27][O:28][P:29]([O:32][C@H:33]1[CH2:37][C@H:36]([N:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][C:39]2=[O:45])[O:35][C@@H:34]1[CH2:46][O:47][P:48]([OH:51])([OH:50])=[O:49])([OH:31])=[O:30])=[O:9])=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[NH2:52][C@H:7]([CH2:6][CH:5]([S:60][S:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:4][N:1]=[N+:2]=[N-:3])[C:8]([O:10][C@H:11]1[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[O:13][C@H:12]1[CH2:27][O:28][P:29]([O:32][C@H:33]1[CH2:37][C@H:36]([N:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][C:39]2=[O:45])[O:35][C@@H:34]1[CH2:46][O:47][P:48]([OH:51])([OH:50])=[O:49])([OH:31])=[O:30])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(CN=[N+]=[N-])SSC(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
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSC(CN=[N+]=[N-])C[C@@H](N)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
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
The aforementioned crude product of (2S)-(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 5-azide-2-((tert-butoxycarbonyl)amino)-4-(tert-butyldisulfanyl)pentanoate (Compound 42) (53 mg) was suspended by adding dichloromethane (2 ml) thereto, after which trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(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-amino-5-azido-4-(tert-butyldisulfanyl)pentanoate (Orn(N3) (4-SStBu)-pdCpA) (Compound 43) (24 mg, 31% in two steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:35].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:35])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([C:29]([F:32])([F:31])[F:30])=[C:24]([F:33])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)c(F)c1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP12), chlorination of 8-[2-(3,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (500 mg; 0.854 mmol) and purification by FC (DCM/MeOH=100/3) gave the product 1-chloro-8-[2-(3,5-difluoro-4-trifluoromethyl-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (179 mg; 42%). LC-MS: tR=1.05 min.; [M+H]+=494.37 g/mol.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].S1[C:10]2[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:13]=[CH:14][C:9]=2NC1.Cl[C:33]1C=CC=C(C(OO)=O)C=1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[O:5]=[S:2]1[C:1]2[CH:13]=[C:12]([CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[C:29]4[C:24](=[C:25]([O:30][CH3:31])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[CH3:18])[CH:11]=[CH:10][C:9]=2[CH2:14][CH2:33]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)SCN2
Agent: CS(=O)(=O)O
Product: COc1cccc2c1CCC[C@H]2CN(C)CCc1ccc2c(c1)S(=O)CC2

Procedure:
The product from Example 54 is treated with one equivalent of m-chloroperbenzoic acid to yield the title compound.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]C)=[O:19].Cl>CN(C)C=O.O>[C:18]([CH2:17][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mole) and potassium carbonate (0.634 mole) in dimethylformamide (900 ml) is added methyl bromoacetate (0.634 mole) and the mixture is stirred vigorously overnight under nitrogen. The mixture is filtered, washed with ether and evaporated to dryness, in vacuo to afford a colorless solid. The solid residue is treated with water (300 ml) and 4 N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2 N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered, and then pricipitated by the addition of 4 N hydrochloric acid (70 ml) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 358.3 %

Procedure:
4-Hydroxybenzyl cyanide (2.5 g, 18.77 mmol), benzyl bromide (3.8 g, 22:5 mmol) and potassium carbonate (45 mmol) were combined in acetone (50 mL) and heated to reflux for 8 h. The reaction was allowed to cool to rt, diluted with ethyl acetate and filtered to remove the solids. The organic layer was concentrated in vacuo to give an oil. The crude benzyl ether was purified by chromatography on silica gel eluting hexane:ethyl acetate (90:10, v:v) to give 4-benzyloxybenzyl cyanide (4.0 g, 95%) which solidified. MS (M+NH4)+=241.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])=[N:26][C:27]=3[F:28])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O>CO>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][NH:29][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[C:27]([F:28])[N:26]=1
Reactant: COc1ncnc2c1c(Cc1ccc(NCc3ccccc3Cl)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ncnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c12
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To [5-(7-benzenesulfonyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(2-chloro-benzyl)-amine (45, 0.30 g, 0.558 mmol) in 15 mL of methanol, potassium hydroxide (0.50 g, 8.9 mmol) was added. The reaction was stirred at 45° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate to provide the desired compound (P-0090, 0.176 g). MS (ESI) [M+H+]+=397.9.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([O-:3])[NH2:2].[C:6]1([C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:15][OH:16])[CH2:13]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:15][O:16][S:1](=[O:4])(=[O:3])[NH2:2])[CH2:13][O:4][S:1](=[O:3])(=[O:5])[NH2:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NS(=O)(=O)[O-]
Reactant: OCC(CO)(c1ccccc1)c1ccccc1
Product: NS(=O)(=O)OCC(COS(N)(=O)=O)(c1ccccc1)c1ccccc1

Procedure:
2,2-Diphenyl-1,3-bis-O-sulfamyl-1,3-propanediol is prepared in an identical manner as the sulfamate reported in Example 1 except for the use of 2,2-diphenyl-1,3-propanediol (87.7 g., 0.385 mol.) as the alkanediol.