Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[N:11]=1.[F:20][C:21]([F:40])([F:39])[CH2:22][N:23]=[C:24]([NH2:38])[NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]=C=S)[N:30]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]>CO.CC(C)=O>[F:19][C:2]([F:1])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][NH:6][C:7]([NH:11][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:29]2[N:30]=[C:26]([NH:25][C:24]([NH2:38])=[N:23][CH2:22][C:21]([F:20])([F:39])[F:40])[S:27][CH:28]=2)=[S:8])[N:11]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]\[C:44]([OH:46])=[O:45]
Reactant: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCCCN=C=S)cs1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: NC(=NCC(F)(F)F)Nc1nc(CCCCNNC(=S)NNCCCCc2csc(NC(N)=NCC(F)(F)F)n2)cs1
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)thiazole (0.12 g.) and 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-[4-isothiocyanatobutyl]thiazole (0.12 g.) in methanol (3 ml.) was allowed to stand at room temperature overnight. The mixture was then evaporated to dryness and purified by preparative thin layer chromatography using methanol/chloroform/ammonia 85:15:1 v/v/v as developing solvent. The appropriate band was extracted with chloroform/ethanol 1:1 v/v (200 ml.) and the resulting solution evaporated to give a brown gum. This was treated in acetone with excess maleic acid to give 1,3-di[4-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)butylamino]thiourea containing 2.25 equivalents of maleic acid. The n.m.r. spectrum in d6 dimethylsulphoxide containing tetramethylsilane as internal standard (δ=0) included the following resonances (δ): 1.5 (multiplet, 8H); 3.3 (multiplet, 4H); 4.1 (quartet, 4H); 6.5 (singlet, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:22])=O>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=C(O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Yield: 100.4 %

Procedure:
2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoic acid (0.46 g) and thionyl chloride (0.36 g) were added in 1,2-dichloroethane (10 ml), two drops of DMF were added and the mixture was refluxed by heating for 3 hours. After cooling, the solvent was distilled off to obtain the desired 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoyl chloride (0.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH2:15][CH2:16][CH3:17])[C:6]([N+:18]([O-])=O)=[CH:5][CH:4]=1>C(O)C>[NH2:18][C:6]1[C:7]([N:9]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]2[CH2:15][CH2:16][CH3:17])=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CCCc1nc(C)cn1-c1nc(OC)ccc1[N+](=O)[O-]
Solvent: CCO
Product: CCCc1nc(C)cn1-c1nc(OC)ccc1N
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared of 138.2 g 6-methoxy-2-(4-methyl-2-propyl-imidazol-1-yl)-3-nitro-pyridine and 900 ml ethyl alcohol 4 g palladium-charcoal were added. The reaction mixture was heated to 40° C. and then hydrogenated under pressure (10 to 15 bar). At room temperature the catalyst was filtrated off and the filtrate was evaporated. To the solid residue 150 ml methyl tert.-butyl ether (MTBE) were added. After stirring for 30 minutes the product was collected by filtration, washed with 50 ml MTBE for 2 times and dried in a dry box with vacuum (40° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C.C1(C)C=CC=CC=1>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:11][CH:10]=1)[NH2:12])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
19.8 grams of 4-trifluoromethylanthranilic acid are dissolved in 350 ml of anhydrous ethanol and 300 ml of dry toluene. To this solution is added 21.8 grams of anhydrous p-toluenesulfonic acid. The solution is refluxed under an extractor containing a thimble of anhydrous magnesium sulfate for 2 weeks with periodic replacement of the drying agent. The solvent is then removed on a rotary evaporator. The residue is treated with 200 ml of 2N sodium hydroxide. The resultant mixture is extracted thrice with combined 75 ml portions of diethylether. The combined extracts are washed with 2N sodium hydroxide, then distilled water and finally brine. The organic solution is dried over anhydrous potassium carbonate. The drying agent is filtered off, and the solvent is removed on a rotary evaporator. The resultant oil is chromatographed on a filter column of silica gel with chloroform as the eluant. The first fractions contain 4-trifluoromethylanthranilic acid ethyl ester, which is recovered by crystallization. Melting Point: 42°-43° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[N:29]=[C:28]([C:30](OCC)=[O:31])[CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[N:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: CCOC(=O)c1cccc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3cccc(CO)n3)cs2)cc1OCC
Reaction time: 2 h
Yield: 21 %

Procedure:
200 mg of lithium aluminum hydride was added, at 0° C., to a solution of 1.92 g of 2-(3,4-diethoxyphenyl)-4-(2-ethoxycarbonyl-6-pyridyl)thiazole in 150 ml of tetrahydrofuran. The mixture was stirred in an argon atmosphere for 2 hours. The reaction mixture was mixed with 1 ml of a saturated sodium sulfate slution. The resulting mixture was stirred at 0° C. for 30 minutes and filtered through Celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-n-hexane to obtain 360 mg of 2-(3,4-diethoxyphenyl)-4-(2-hydroxymethyl-6-pyridyl)thiazole.
Reaction SMILES: Cl[C:2]1([CH3:12])[CH:11]2[CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9][CH2:8][O:7]1.CC([O-])(C)C.[K+]>CS(C)=O>[CH2:12]=[C:2]1[CH:11]2[CH:3]1[CH2:4][CH2:5][C:6]12[O:7][CH2:8][CH2:9][O:10]1
Reactant: CC1(Cl)C2CCC3(OCCO3)C21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1C2CCC3(OCCO3)C12
Temperature: 60 °C

Procedure:
To a solution of (±)-6-chloro-6-methyl-spiro[bicyclo[3.1.0]hexane-2,2′-[1,3]dioxolane] (2.50 g, 13.25 mmol) in DMSO (40 mL) was added a solution of KOtBu (15.9 mL of 1.0M in THF). The solution heated at 60° C. overnight. After cooling down the reaction mixture to rt, the product was extracted into n-Hexane. Solvent was removed under reduced pressure. SiO2 column chromatography (14–25% EtOAc/n-hexane) gave the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 5.55 (s, 1H), 5.42 (t, 1H, J=1.0 Hz), 4.08–3.91 (m, 4H), 2.07–1.97 (m, 2H), 1.90–1.84 (m, 2H), 1.65–1.54 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH:5]=1.Br[C:18]1[N:34]=[C:21]2[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[Cl:33])=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O-]C1C=CC=CC=1.[Na+]>ClCCl.O1CCOCC1>[Cl:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[C:22]1[C:21]2[N:20]([N:19]=[C:18]([NH:16][CH:13]3[CH2:14][CH2:15][N:10]([C:6]4[CH:5]=[C:4]([CH3:3])[N:9]=[CH:8][N:7]=4)[CH2:11][CH2:12]3)[N:34]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(-c2cccn3nc(Br)nc23)c(Cl)c1
Reactant: Cc1cc(N2CCC(N)CC2)ncn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)cc5Cl)cccn4n3)CC2)ncn1
Temperature: 130 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
1-(6-Methylpyrimidin-4-yl)piperidin-4-amine dihydrochloride (133 mg, 0.5 mmol) was suspended in dichloromethane (15 mL) and then extracted with aqueous sodium hydroxide (2 M, 10 mL). The aqueous layer was extracted with dichloromethane (15 mL) and the organic layers were combined, dried over sodium sulfate and evaporated carefully. After addition of 2-bromo-8-(2-chloro-4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (180 mg, 0.55 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.1 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(o) chloroform adduct (21 mg, 0.02 mmol) and sodium phenoxide (87 mg, 0.75 mmol) in dry 1,4-dioxane (4 mL) the reaction mixture was stirred under an argon atmosphere for 60 minutes at 130° C. in the microwave. Concentration and purification of the residue by chromatography (SiO2, heptane:ethyl acetate 3:1 to 0:1) afforded the title compound as yellow foam (97 mg, 44%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].[Cl-].[Na+]>C(Cl)Cl>[C:28]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 Grams of 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril and 3.06 ml of triethylamine were dispersed in 40 ml of methylene chloride, then under ice-cooling conditions, 0.78 ml of acetyl chloride was added dropwise thereto, and stirred at room temperature for 4 hours. The reaction mixture was poured into an aqueous solution saturated with sodium chloride, then extracted with chloroform. The extract was dried with anhydrous sodium carbonate, the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =10:1), then recrystallized from methanol-diethyl ether to yield 0.3 g of 6-(4-acetylamino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.1/4-hydrate. White powdery substance. Melting point: 228° C.-229° C. (decomp.).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([CH3:43])=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cnc(Br)cn1
Product: Cc1cnc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-methylpyrazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.257 min, m/z=388; 1H NMR (CDCl3) 1.07 (s, 3H), 1.12 (s, 3H), 1.49 (d, 3H), 2.01-2.13 (m, 4H), 2.28-2.39 (m, 1H), 2.57 (s, 3H), 2.80 (m, 1H), 5.68 (m, 1H), 7.02 (d, 2H), 7.21-7.33 (m, 5H), 7.67 (d, 2H), 8.41 (s, 1H), 8.76 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[CH2:4][C:5]2([CH2:17][CH3:18])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[C:6]=12.[C:20]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:21]=1.O.C([O-])([O-])=O.[Cs+].[Cs+].C(B(CC)CC)C>CN(C=O)C.O1CCCC1>[CH2:20]([C:2]1[C:3](=[O:19])[CH2:4][C:5]2([CH2:17][CH3:18])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[C:6]=12)[CH3:21]
Reactant: CCC12CCc3cc(OC)ccc3C1=C(Br)C(=O)C2
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Agent: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCC1=C2c3ccc(OC)cc3CCC2(CC)CC1=O
Temperature: 60 °C

Procedure:
A solution of 1-bromo-3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (120 mg, 0.37 mmol) in DMF (3 mL) was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (61 mg, 0.075 mmol), triphenylarsine (23 mg, 0.075 mmol), water (0.22 mL, 12.2 mmol), Cs2CO3 (244 mg, 0.75 mmol), and triethylborane (0.75 mL of a 1.0M solution in tetrahydrofuran, 0.75 mmol). The resulting mixture was placed under a N2 atmosphere, stirred, and heated in an oil bath at 55-65° C. for 100 minutes. After cooling, the mixture was quenched with saturated aqueous NH4Cl and diluted with CH2Cl2. The organic phase was dried over MgSO4 and filtered through a pad of silica gel, washing through with EtOAc. The filtrate was evaporated under vacuum to remove the solvents. The residue was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with 4:1 hexane-EtOAc. The UV visible product band was extracted with 5% MeOH in CH2Cl2 and the extracts evaporated under vacuum to provide 1,3a-diethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:21]=2)=[CH:14][CH:13]=1>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:29]/[C:25]1[CH:24]=[C:23]2[C:28]([C:20](/[CH:19]=[CH:18]/[C:15]3[CH:14]=[CH:13][N:12]=[CH:17][CH:16]=3)=[N:21][N:22]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])=[CH:27][CH:26]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Solvent: CO
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccc(Br)cc43)cc21
Yield: 76.5 %

Procedure:
The title compound was prepared from 5-bromooxindole (36 mg, 0.171 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (65 mg, 0.171 mmol) as described in Example A57 part B to give, after silica gel column chromatography (Eluent: 98:2 CH2Cl2/MeOH) the title compound as a yellow oil (75 mg, 77%). MS ESI 573.4 [M+H]+, calcd for [C29H29BrN4O2Si+H]+ 573.13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2)[C:29]([CH3:30])=[O:31]
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.1 %

Procedure:
To a solution of 14 (200 mg, 1.25 mmol), dimethylaminopyridine (20 mg) and triethylamine (0.94 mL) in THF cooled to 0° C. was added a solution of acetyl chloride (0.30 mL, 4.16 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 3 h. THF was removed in vacuo and ethyl acetate (40 mL) was added. The solution was washed with water (20 mL×2). The solution was dried using sodium sulfate and solvent was removed in vacuo. The residue was dissolved in methanol (5 mL) and 3N NaOH solution(1 mL) was added. The reacted was allowed to proceed overnight. The reaction mixture was evaporated and water (10 mL) was added. The product was extracted with ethyl acetate (30 mL×3) and the solvent was removed in vacuo. The product was crystallized in acetate and washed with ether. 128 mg (50% yield) of grew powder 15 was obtained. mp: 161° C. 1H NMR (DMSO-d6, ppm): 10.84 (s, 1 H, NH), 9.62 (s, 1 H, NH), 7.75 (d, 1 H, J=2.1 Hz, Ar--H), 7.22-7.10 (m, 2 H, Ar--H), 6.20 (s, 1 H, Ar--H), 6.43-6.40 (dd, 1 H, J=2.4, 8.5 Hz, Ar--H), 5 5.18-5.15 (t, 1 H, J=5.5 Hz, OH), 4.57-4.56 (d, 2 H, J=5.4 Hz, CH2OH), 2.01 (s, 3 H, CH3), Anal. (C11H12N2O2), C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:24]N1C(=O)CCC1=O>CC(N(C)C)=O.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:9]([Br:24])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: Nc1ncnc2[nH]c(Br)c(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (302 mg) was dissolved in dimethylacetamide (10 ml) and dichloromethane (50 ml) and then treated with N-bromosuccinimide (178 mg) in dichloromethane (10 ml). The mixture was left stirring ambient temperature for 16 hours. The mixture was evaporated under reduced pressure and the residue was triturated with water to give a solid which was collected by filtration and dried to give 4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine, m.p. 282-283° C.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH:20]O>C(O)(=O)C.[Pd].C(O)C>[C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-:20])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: OO
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Twenty grams of adenosine (commercialized by Sigma-Aldrich Corporation, St. Louis, Mo. USA, Product code: A9251-25G) was dispersed in one liter of acetic acid, admixed with 100 mL of hydrogen peroxide solution, and stirred at ambient temperature for five days. To the resulting solution was added five grams of 5% palladium on carbon, commercialized by Kawaken Fine Chemicals Co., Ltd, Tokyo, Japan, followed by decomposing an excessive amount of hydrogen peroxide, filtering the resultant to remove palladium carbon, drying the resulting solution in vacuo, adding ethanol to unstiffen the formed crystals, and filtering the resultant to obtain a crude crystalline adenosine N1-oxide. The crude crystals were dissolved by heating in two liters of ethanol, filtered, and ice chilled for crystallization, followed by repeating the recrystallization step twice to obtain eight grams of adenosine N1-oxide with a purity of 99.5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=O)[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:29]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([NH:35][S:32]([CH:29]2[CH2:31][CH2:30]2)(=[O:34])=[O:33])=[O:16])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.2 %

Procedure:
A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated to reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) provided the desired product (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9% acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92%). 1H NMR (DMSO-d6) δ 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 minutes, method B), MS m/z 331 (M++H).
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[CH:4]=[O:32])[CH:17]=2)=[CH:24][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.75 g, 1.7 mmol) in THF (10 mL) was added LAH (3.4 mL, 3.4 mmol, 1 M solution in THF) at −60° C. The reaction mixture was stirred at −60° C. for 1 h, was quenched with Na2SO4 solution (2 mL) and was extracted with ethyl acetate (10 mL). The organic layer was separated and washed with water (2 mL) and with brine solution (2 mL) and was dried over anhydrous Na2SO4. Filtration followed by concentration under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzaldehyde (0.6 g, 92%) as an off yellow solid.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:21][C:22]1[CH:30]=[CH:29][C:25](C(O)=O)=[CH:24][CH:23]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:25]1[CH:29]=[CH:30][C:22]([O:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCOc1ccc(C(=O)N[C@@H](C)C#N)cc1
Yield: 29.9 %

Procedure:
General procedure D and E were used to deprotect 1.17 mmols of (S)-tert-butyl 1-cyanoethylcarbamate and couple the resulting amine to 1.17 mmols of 31. After standard purification techniques 0.35 mmols of the title product were recovered. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=8.9, 2H), 6.90 (d, J=8.8, 2H), 6.67 (s, 1H), 5.30-5.05 (m, 1H), 3.98 (t, J=6.6, 2H), 1.85-1.74 (m, 2H), 1.64 (d, J=7.2, 3H), 1.45 (s, 3H), 1.30 (d, J=19.1, 7H), 0.88 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 166.26, 162.49, 129.11, 124.52, 119.58, 114.40, 68.26, 36.25, 31.77, 29.30, 29.19, 29.07, 25.95, 22.63, 19.53, 14.08.