Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([O:20]CC3C=CC=CC=3)[C:10]([O:12]CC3C=CC=CC=3)=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:28]([NH:30][N:31]1[CH2:35][CH2:34][N:33]([S:36]([NH:39][C:40]([N:42]2[CH2:45][CH:44]([NH:46]C(=O)OCC3C=CC=CC=3)[C:43]2=[O:57])=[O:41])(=[O:38])=[O:37])[C:32]1=[O:58])=[O:29].CN([Si](C)(C)C)C(=O)C(F)(F)F.[NH2:71][C:72]1[S:73][CH:74]=[C:75](/[C:77](=[N:81]/[O:82][C:83]([CH3:101])([CH3:100])[C:84]([O:86][CH:87]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)=[O:85])/[C:78]([OH:80])=O)[N:76]=1>CN(C)C=O.[Pd]>[NH2:71][C:72]1[S:73][CH:74]=[C:75]([C:77](=[N:81][O:82][C:83]([CH3:101])([CH3:100])[C:84]([O:86][CH:87]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)=[O:85])[C:78]([NH:46][CH:44]2[CH2:45][N:42]([C:40]([NH:39][S:36]([N:33]3[CH2:34][CH2:35][N:31]([NH:30][C:28]([C:3]4[C:2](=[O:1])[N:7]5[CH:8]=[C:9]([OH:20])[C:10]([OH:12])=[CH:11][C:6]5=[N:5][CH:4]=4)=[O:29])[C:32]3=[O:58])(=[O:37])=[O:38])=[O:41])[C:43]2=[O:57])=[O:80])[N:76]=1
Reactant: O=C(NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cnc4cc(OCc5ccccc5)c(OCc5ccccc5)cn4c3=O)C2=O)C1=O)OCc1ccccc1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3cnc4cc(O)c(O)cn4c3=O)C2=O)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of [1-[[[[3-[[[4-oxo-7,8-bis(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidin-3-yl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.35 g, 1.66 mmol) in 65 ml of N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (1.66 g, 8.33 mmol) was added. After 20 minutes 0.45 g of palladium on carbon was added, and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration, and to the filtrate (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1-benzotriazole ester (0.83 g, 1.5 mmol) was added. After stirring overnight, the solvent was distilled off, and the residue triturated with 20 ml of water. The resulting solid was filtered off with suction and dried in vacuo. Yield of crude product: 1.28 g.
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([C:14]([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5]4[NH:9][CH:8]=[CH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:19]=[CH:18][CH:17]=2)=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cccc(Nc2ncnc3cc[nH]c23)c1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), 4-benzylpiperidine (158 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethyl acetate containing tetrahydrofuran. The extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The precipitate was collected by filtration to give the title compound (201 mg) as a pale-brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:39]1[CH:48]=[N:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:39]3[CH:48]=[N:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:36])([F:37])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1cnc2ccccc2n1
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cnc4ccccc4n3)C[C@H]1C(=O)N2
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To (2S,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1e, 19 mg, 0.036 mmol) was added 2-hydroxyquinoxaline (8.06 mg, 0.055 mmol) followed by tetrahydrofuran (357 μl). Triphenylphosphine (15.23 mg, 0.058 mmol) was added and the solution was cooled to 0° C. DIAD (10.5 μl, 0.054 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 min and at room temperature for 20 hr. The reaction mixture was diluted with dichloromethane and filtered through Celite. The solvent was evaporated under reduced pressure and the residue was purified by prep-TLC (dichloromethane/ethyl acetate=3/2, 2×) to provide the title compound (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (14.6 mg, 61.8% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:33]=[N:32][O:31][CH:35]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: OB(O)c1cnoc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cnoc5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), isoxazol-4-boronic acid (73 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (127 mg, 44%) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (59 mg, 0.59 mmol), acetic acid (0.053 mL, 0.89 mmol) and sodium triacetoxyborohydride (313 mg, 1.5 mmol) in THF (8 mL). MS (LC-MS): 372.0 [M]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[C:9]([O:12][C:13](=O)C)(=O)[CH3:10].C([O-])(=O)C.[Pb+2].C([O-])(=O)C.COCC=O>O1CCCC1>[CH3:13][O:12][CH2:9][CH:10]=[C:5]1[C:6](=[O:7])[O:8][C:1]([CH3:2])=[N:4]1
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: COCC=O
Agent: [Pb+2]
Solvent: C1CCOC1
Product: COCC=C1N=C(C)OC1=O

Procedure:
A flask equipped with a mechanical stirrer, reflux condenser, dropping funnel, and drying tube was charged with 38.5 g (0.33 mol) of N-acetylglycine (2), 134 g (1.3 mol) of acetic anhydride, 54 g (0.166 mol) of lead acetate, and 450 ml of tetrahydrofuran (THF). The mixture was heated with stirring at reflux temperature for 1 hr. A solution consisting of 37 g (0.5 mol) of methoxyacetaldehyde (1) and 220 ml of THF was then added dropwise over a 21/2 hr period. The resultant mixture was heated with stirring at reflux temperature for an additional 4 hrs. The reaction was allowed to cool, diluted with 1 l. of ether, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the dark brown fluid residue was distilled under reduced pressure. The fraction boiling at 60°-83°/0.5 mm consisted mainly of 4-(2-methoxyethylidene)-2-methyl-5-oxazolone (3): NMR (CDCl3) δ 6.5 (m, 1H, --CH2CH=), 4.35 (m, 2H, --CH2CH--), 3.3 (s, 3H, CH3O--), 2.2 ##STR5##
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:30])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3C)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[N+:12]([O-])=O.[ClH:15].O>C(O)C.[Pd]>[ClH:15].[ClH:15].[NH2:12][C:3]1[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])=[N:5][N:6]([CH3:7])[C:2]=1[NH2:1]
Reactant: Cn1nc(C(C)(C)C)c([N+](=O)[O-])c1N
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(N)c1N
Reaction time: 3 h

Procedure:
A suspension of 8.5 g (0.035 mol) of 5-amino-1-methyl-4-nitro-3-tert-butylpyrazole and 1.5 g of 5% by weight palladium-on-charcoal containing 50% water in 200 cm3 of ethanol was placed in a hydrogenator. After stirring for 3 hours under a hydrogen pressure of 10 bar, at a temperature of 75° C., the reaction medium was poured into a solution, precooled to 0° C., of 60 cm3 of ethanol and 20 cm3 of 12N hydrochloric acid. The solution was clarified by filtration on a sinter funnel and then evaporated to dryness under reduced pressure. The brown solid obtained was taken up, at reflux, in 35 cm3 of 5N hydrochloric ethanol and 11 cm3 of water and then cooled to room temperature. The white crystals obtained were filtered off on a sinter funnel and then dried under vacuum at room temperature. 4.9 g of the expected product were obtained in the form of white crystals, the melting point of which was 260° C. The elemental analysis for C8H10N4.2HCl was:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[CH3:23][N:24]([CH3:38])[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:21][CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[OH:22])=[O:36])=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(C(=O)O)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CN(C)c1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 4-dimethylaminonaphthalenecarboxylic acid (89 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (149 mg, 70%).
Reaction SMILES: C([N:3](CC)CC)C.[CH3:8][C:9](C)([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10](O)=O.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[CH3:8][C:9]([NH2:3])([CH3:10])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc(CC(C)(C)C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CC(C)(C)N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 46.2 %

Procedure:
Triethylamine (16.8 g, 166 mmol) and 2,2-dimethyl-3-(4-methoxyphenyl)propionic acid (32.6 g, 157 mmol) were dissolved in 30 mL of water and enough acetone to maintain solubility at 0° C. A solution of ethyl chloroformate (20.1 g, 185 mmol) in acetone (100 mL) was then added dropwise. An aqueous solution (95 mL) of sodium azide (12.9 g, 198 mmol) was then added dropwise and the resulting reaction mixture stirred 45 minutes at room temperature. The intermediate acyl azide was then extracted into toluene (200 mL). The organic extract was washed with water, dried over anhydrous magnesium sulfate, and heated at 100° C. until the evolution of nitrogen ceased (˜45 min). The toluene was removed under vacuum and replaced with benzyl alcohol. The solution was then heated at 100° C. for 16 hours. The excess benzyl alcohol was removed under vacuum. The resulting benzyl carbamate was dissolved in absolute ethanol (200 mL) and reduced in the presence of palladium hydroxide (2 g) under 90 p.s.i. hydrogen for 4 hours at room temperature. The reaction was filtered and concentrated to a yellow oil. Vacuum distillation afforded 13.0 g of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 180 (M+1, 1), 164 (5), 121 (25), 91 (5), 78 (19), 58 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1>CN(C=O)C>[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38]([NH:1][C:2]3[CH:3]=[C:4]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=5)[N:13]=4)[CH:5]=[CH:6][CH:7]=3)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1
Reactant: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5cnccc45)c3)ccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(3-aminophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 5) (0.032 g, 0.12 mmol), DMF (2.0 mL), pyridine (0.015 mL, 0.180 mmol), and isoquinoline-5-sulfonyl chloride hydrochloride (0.0395 g, 0.150 mmol, Toronto Research Chemicals, Ottawa, Ontario). The mixture was stirred at 25° C. for 5 h then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) to afford the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 459 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.03 (s, 1H), 10.91 (s, 1H), 9.50 (s, 1H), 8.75 (d, J=6.5 Hz, 1H), 8.58 (d, J=6.0 Hz, 1H), 8.53 (d, J=7.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.25 (s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: COCCO
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1ncccc1C(=O)O
Temperature: 0 °C
Yield: 81 %

Procedure:
Potassium t-butoxide (45.0 g, 0.40 mol) was added portion-wise to ice-cold 2-methoxyethanol (175 ml), and the resulting solution added to a suspension of 2-chloronicotinic acid (30.0 g, 0.19 mol) in 2-methoxyethanol (175 ml). The reaction mixture was heated under reflux for 26 hours, then cooled and concentrated under reduced pressure. The residue was diluted with water (200 ml), the pH of the solution adjusted to 5 using concentrated hydrochloric acid, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried (MgSO4), evaporated under reduced pressure and azeotroped with toluene, to afford the title compound, (30.54 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1.Cl.[CH3:24][O:25][NH2:26]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[N:26][O:25][CH3:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH3:8])[O:4][N:3]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N)no1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccccc1)c1cccc(C(C)c2nc(N)no2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 105.2 %

Procedure:
To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.60 g, 2.0 mmol) in pyridine (10 ml) was added methoxyamine hydrochloride (0.224 g, 2.7 mol). After reflux with stirring for 18 h, the mixture was poured upon ice water, extracted with ethylacetate. The extracts were washed with water, dried and anhydrous sodium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-amino-5-(1-(3-(α-methoxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.678 g, quantitive yield) as oily substance: NMR(CDCl3)δ1.70 (d, 3H), 3.97(s, 3H), 4.24(q, 1H), 4.48(broad singlet, 2H), 7.21-7.58(m, 9H) ppm; IR(neat) 3310, 3220, 1625, 1585, 1410, 1050 cm-1.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:57]=[CH:56][C:12]2[NH:13][C:14]([CH2:16][CH2:17][CH:18]3[CH2:21][CH:20]([N:22]([CH2:24][C@@H:25]4[C@H:29]5[O:30]C(C)(C)[O:32][C@H:28]5[C@H:27]([N:35]5[C:39]6[N:40]=[CH:41][N:42]=[C:43]([NH:44]CC7C=CC(OC)=CC=7OC)[C:38]=6[CH:37]=[CH:36]5)[CH2:26]4)[CH3:23])[CH2:19]3)=[N:15][C:11]=2[CH:10]=1.C([SiH](CC)CC)C>O>[NH2:44][C:43]1[C:38]2[CH:37]=[CH:36][N:35]([C@@H:27]3[CH2:26][C@H:25]([CH2:24][N:22]([CH:20]4[CH2:19][CH:18]([CH2:17][CH2:16][C:14]5[NH:13][C:12]6[CH:56]=[CH:57][C:9]([Br:8])=[CH:10][C:11]=6[N:15]=5)[CH2:21]4)[CH3:23])[C@@H:29]([OH:30])[C@H:28]3[OH:32])[C:39]=2[N:40]=[CH:41][N:42]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Br)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Br)ccc3[nH]2)C1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
Trifluoroacetic Acid (20 ml) added to a mixture of Water (2 ml) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-bromo-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.9 g, 1 mmol) at RT. The reaction mixture was stirred for one hour, Triethylsilane (0.39 ml, 2.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was purified twice by flash chromatography (DCM/7N NH3 in MeOH 87:13). The residue was taken up in MeOH/H2O (5:0.5 ml) and K2CO3 (100 mg) added. The mixture was stirred for 1 hour, then concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 87:13) to give the desired product (0.15 g) as an off-white foam/gum. cyclobutyl)(methyl)amino)methyl)cyclopentane-1,2-diol (0.15 g; 20%) as an off-white foam/gum. MS (ESI+) for C26H32BrN7O2 m/z 554.1 [M+H]+; MS (ESI−) for C26H32BrN7O2 m/z 552.1 [M−H]−; HPLC purity >90% (ret. time, 2.298 min.) 1HNMR (400 MHz, d4-MeOH) δH 8.080 (s, 1H), 7.652 (s, 1H), 7.425-7.403 (m, 1H), 7.342-7.7.312 (m, 1H), 7.232-7.217 (m, 1H), 6.620-6.611 (d, J=3.6 Hz, 1H), 4.358-4.318 (m, 1H), 3.928-3.888 (m, 1H), 3.099-3.039 (m, 0.5H (methine of trans isomer)), 2.898-2.829 (m, 2H), 2.777-2.726 (m, 0.5H (methine of cis isomer)), 2.580-2.529 (m, 1H), 2.453-2.397 (m, 2H), 2.307-2.141 (7H), 2.068-2.017 (m, 1H), 1.955-1.891 (m, 3H), 1.695-1.506 (m, 2H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])O.[Na+]>C(O)C.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1.6 parts of sodium hydroxide was dissolved in ethanol. A solution of 5 parts of p-aminothiophenol in 20 parts of ethanol was added to the solution. The mixture thus obtained was cooled at 0° C. or below. A solution of 3.8 parts of chloroacetic acid and 3.4 parts of sodium hydrogencarbonate in 10 parts of water was added dropwise to the mixture, while the mixture was kept at 0° C. or below. After completion of the addition, the mixture was stirred at 0° C. for 3 hours and then adjusted at pH 3. A solid thus formed was filtered to obtain 5.4 parts of p-aminothiophenoxyacetic acid.