Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.CN(C)C=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Yield: 92.9 %

Procedure:
A mixture of N-(6-nitrobenzothiazol-2-yl)benzamide (3.77 g, 12.6 mmol), palladium on charcoal (2 g, 10% Pd, 1.88 mmol Pd), dimethyl formamide (80 mL) and ethyl acetate (20 mL) was hydrogenated (1 bar) for 2 h at 60° C. The palladium was removed by filtration through a pad of celite. After concentration to 20 mL, water was added and the resulting precipitate was separated by filtration to obtain N-(6-aminobenzothiazol-2-yl)-benzamide (3.15 g, 11.7 mmol, 93%) as a grey solid. LC/ESI-MS: m/z=270 [M+H]+; m/z=268 [M−H]−; Rt=2.27 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=3)=[CH:10][N:9]([CH:19]([CH3:21])[CH3:20])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].C1C[O:36][CH2:35][CH2:34]1>>[C:29]([N:18]([C:14]1[N:13]=[C:12]([C:11]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8][N:9]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)[CH:17]=[CH:16][N:15]=1)[C:35](=[O:36])[CH3:34])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Reactant: CC(C)n1cc(-c2ccnc(N)n2)c(-c2ccc(Cl)s2)n1
Solvent: CCN(CC)CC
Product: CC(=O)N(C(C)=O)c1nccc(-c2cn(C(C)C)nc2-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-amine (1 eq, 1.9 mmol) and triethylamine (4 eq, 7.5 mmol) in 10 mL THF was added acetyl chloride (2 eq, 3.8 mmol). The mixture was then stirred at room temperature overnight and the solvent was evaporated. The residue was purified by chromatography on silica gel (heptane:ethyl acetate) to afford 220 mg of N-acetyl-N-{4-[3-(5-chloro-2-thienyl)-1-isopropyl-1H-pyrazol-4-yl]pyrimidin-2-yl}acetamide (27% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2([O:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]2=[O:14])[C:2]1=[O:15].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:12]1[CH:11]=[CH:10][C:8]2[O:9][C:3]3([C:6](=[O:14])[C:7]=2[CH:13]=1)[CH2:4][CH2:5][O:1][C:2]3=[O:15])([O-:23])=[O:22]
Reactant: O=C1OCCC12Oc1ccccc1C2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1OCCC12Oc1ccc([N+](=O)[O-])cc1C2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.408 g. of 4',5'-dihydrospiro[benzo[b]furan-2(3H), 3'(2'H)-furan]-2',3-dione in 3 ml. of concentrated sulfuric acid was added a mixture of 0.35 ml. of nitric acid (d=1.42) and 0.36 ml. of concentrated sulfuric acid, dropwise under ice-cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-water and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from ethyl acetate. By the above procedure there was obtained colorless needles of 4',5'-dihydro-5-nitrospiro[benzo[b]furan-2(3H),3'(2'H)-furan]-2',3-dione. m.p. 199°-200° C.
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[NH2:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=[O:19]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]2[CH:29]=[CH:30][CH:31]=[CH:32][C:16]=2[NH:15][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: O=C(O)CCCC(=O)N1CCOCC1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)CCCC(=O)N2CCOCC2)cc1

Procedure:
Using the procedure described in Example 161, 5-oxo-5-morpholinopentanoic acid (166 mg, 0.826 mmol) and 2-amino-N-(4-methoxyphenyl)benzamide yielded, after recrystallization from ethyl acetate/hexanes, 220 mg (63%) of the title compound as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH2:24]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: C=O
Reactant: Cc1cc(N)ncc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C)c(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To 1,1-dimethylethyl (2S)-4-[(6-amino-4-methyl-3-pyridinyl)methyl]-2-methyl-1-piperazinecarboxylate (D100) (0.067 g, 0.21 mmol) in dry MeOH (4 mL) under an argon atmosphere was added paraformaldehyde (0.019 g, 0.63 mmol) and sodium methoxide (0.057 g, 1.00 mmol). The mixture was stirred at 50° C. overnight then sodium borohydride (0.024 g, 0.63 mmol) was added and the reaction stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3 and stirred for 0.5 h. The aqueous phase was extracted with DCM (3×5 mL) and the combined organics were dried and concentrated to give a crude colourless oil. Column chromatography eluting with 0-10% MeOH/DCM gave the crude title compound as a colourless oil (0.037 g) which was used in the next step without further purification. MS (ES): MH+ 335.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:32][O:33][CH2:34]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][O:26][CH2:32][O:33][CH3:34])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: COCBr
Product: COCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as indicated in Example 10 above, with the compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and bromomethyl methyl ether.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[N:30]3[CH2:35][CH2:34][S:33][CH2:32][CH2:31]3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2N2CCSCC2)cn1)c1ccc(Cl)s1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg, 0.16 mmol) and thiomorpholine (1 mL) in DMSO (1 mL) was heated at 150° C. for 3 days. The mixture was purified by HPLC to give the title compound (25 mg). MS 512.0 and 514.0 (M+H, Cl pattern).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27]([SH:29])[CH3:28]>C(C(C)=O)C(C)C>[CH2:27]([S:29][C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:28]
Reactant: CCS
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)c1c(SCC)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 69.7 %

Procedure:
A mixture of 3.0 g (0.009 mol) of product of Example 9, 1.55 g (0.011 mol) of K2CO3 and 3.5 ml (0.047 mol) of ethanethiol in 15 ml of methyl isobutyl ketone was stirred at reflux for 60 hours. The reaction mixture was concentrated. The residue was taken up in ether, washed with 10% NaOH and water, dried (MgSO4) and concentrated in vacuo to 2.98 g of dark oil which was purified by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent affording 2.18 g (69.8%) of product as a tan solid; mp 36°-37.5° C. Anal. Calc'd. for C12H11F6N1O2S1 : C, 41.50; H, 3.19; N, 4.03. Found: C, 41.45; H, 3.22; N, 4.01.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C.CN(C1C=CN=CC=1)C.O.C(OCC)(=O)C>[Si:21]([O:20][CH2:19][C:4]1[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([I:1])[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(I)cc(Nc2nccc(C(F)(F)F)n2)c1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a flask containing the product of Step 2 (2.79 g, 7.06 mmol) in DMF (71 mL) were added tert-butyldimethylsilyl chloride (1.60 g, 10.59 mmol), imidazole (0.96 g, 14.12 mmol) and DMAP (86 mg, 0.71 mmol). After two hours, The reaction was diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Column chromatography on silica gel was used for purification to yield N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-iodophenyl]-4-(trifluoromethyl)pyrimidin-2-amine (3.46 g, 6.79 mmol, 96% yield). MS ESI: [M+H]+ m/z 510.0.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][S:28][CH2:29][CH2:30][O:31][C:32]([NH:34][C:35]1[NH:36][C:37](=[O:48])[C:38]2[N:39]=[CH:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=2[N:43]=1)=[O:33]>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:40]=[N:39][C:38]3[C:37](=[O:48])[NH:36][C:35]([NH:34][C:32]([O:31][CH2:30][CH2:29][S:28][CH3:27])=[O:33])=[N:43][C:42]2=3)[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)O)c(=O)[nH]1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CSCCOC(=O)Nc1nc2c(ncn2CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)[nH]1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [2-N-(2-methylthioethoxycarbonyl)-guanin-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.41 (brs, 1H), 11.35 (brs, 1H), 8.35 (m, 1H), 8.25 (m, 1H), 7.82 (d, 0.6H), 7.78 (d, 0.4H), 7.72 (m, 2H), 5.14 (s, 1.2H), 5.03 (s, 0.8H), 4.51 (s, 0.8H), 4.32 (t, 2H), 4.27 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8 H), 4.04 (t, 1.2H), 3.85 (t, 0.8H), 2.75 (t, 2H), 2.12 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[N:48]=[CH:47][C:46]3[C:41](=[C:42]([F:53])[CH:43]=[C:44]([C:49]([CH3:51])([CH3:50])[CH3:52])[CH:45]=3)[C:40]2=[O:54])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[N:14][N:13]([CH:16]([F:18])[F:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1cc(Br)cc(Nc2cnn(C(F)F)n2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cnn(C(F)F)n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Yield: 32.1 %

Procedure:
Following the procedure of Example 152c, and starting with 159c (150 mg, 0.46 mmol, 1.0 eq.) and 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid (116c) (285 mg, 0.69 mmol, 1.5 eq.) afforded 159d as a yellow solid (90 mg, 32%). MS-ESI:[M+H]+ 609.3
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Br:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(OCC)C>[Br:15][CH:16]([CH3:20])[C:17]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][O:4]1)=[O:18]
Reactant: CC(Br)C(=O)Cl
Reactant: OCC1CCCO1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(Br)C(=O)OCC1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a 250 milliliter three-necked flask were added 0.15 mole of 2-(hydroxymethyl)tetrahydrofuran, 0.15 mole of triethylamine, and 100 milliliters of diethylether. The flask was immersed in ice, and 0.15 mole of 2-bromopropanoyl chloride introduced dropwise. The ice bath was removed, and the reaction stirred at ambient temperature for two hours. The mixture was extracted with an equal volume of water, and the organic phase dried over sodium sulfate. Pecanration and solvent removal resulted in 2-tetrahydrofuranylmethyl 2-bromopropanoate in 94% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:30]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][N:24]=3)=[O:31])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)c1cnccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To a mixture of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol), pyrazine-2-carboxylic acid (12 mg, 0.095 mmol), and HATU (36 mg, 0.095 mmol) was added 0.6 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.041 mL, 0.24 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 10 minutes. The reaction mixture was diluted with EtOAc (15 mL), washed with water and brine (5 mL each), concentrated, and purified by reverse-phase column chromatography, eluting with 5 to 65% acetonitrile/water to yield the final product as a yellowish solid (31 mg, 93% yield). MS (apci) m/z=422.2 (M+H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
25 g (185 mmol) 4-isopropyl-aniline were dissolved in to 260 ml conc. sulfuric acid and treated at −5° C. with 17.9 g nitric acid (65%). After stirring the mixture at 0° C. for 0.5 h, the reaction mixture was poured on ice water and the precipitating product collected via filtration and dried. The resulting 23.8 g product were essentially pure and were used for the subsequent step without further purification.
Reaction SMILES: C[O-].[Na+:3].[F:4][C:5]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:6]=1[CH2:7][N:8]1[N:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22].C(O)(C)C>CO>[F:4][C:5]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:6]=1[CH2:7][N:8]1[N:17]=[C:16]([CH2:18][C:19]([O-:21])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:22].[Na+:3]
Reactant: O=C(O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: O=C([O-])Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2ccccc12
Temperature: 25 °C

Procedure:
A solution of sodium methoxide (25 ml. of a 1.0 M solution in methanol) was added to a solution of 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (9.87 g.) in methanol (300 ml.) and the mixture heated to its boling point. Methanol was then allowed to boil off until the volume of the mixture was approximately 100 ml. Isopropanol (150 ml.) was then added, followed by petrol (60-80) until the mixture was just opaque. The mixture was then allowed to cool to room temperature. The solid which formed was separated by filtration, evaporated with toluene (2×400 ml.) and then washed with ether (300 ml.) to give sodium 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate, 6.5 g., m.p. 244°-247° C.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49]([N:51]3[CH2:55][CH2:54][C@@H:53]([N:56]([CH3:58])[CH3:57])[CH2:52]3)=[O:50])[CH:43]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:6](=[O:7])[NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49]([N:51]4[CH2:55][CH2:54][C@@H:53]([N:56]([CH3:58])[CH3:57])[CH2:52]4)=[O:50])[CH:43]=3)=[CH:33][CH:32]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)c4ccccc34)ccn2)C1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CC[C@@H](N(C)C)C4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of CDI (100 mg, 0.370 mmol) in dry DCM (1.0 mL) was added 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (85 mg, 0.370 mmol), portionwise, over 20 min and the resulting solution maintained at RT for 2.5 hr. A portion of this solution (0.70 mL) was added to a solution of (R)—N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (100 mg, 0.255 mmol) in DCM (1.0 mL) and the mixture was maintained at RT for 18 hr. The reaction was quenched by the addition of MeOH (3.0 mL) and the mixture was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 4 g, [5% NH3 (7M in MeOH) in DCM] in DCM, 0-100%, gradient elution) to afford the title compound, Example 54, as a brown glass (52 mg, 30%); Rt 4.92 min (Method 1 basic); m/z 647 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 1.61 (1H, m), 1.98 (1H, m), 2.12 (6H, s), 2.39 (3H, s), 2.58 (1H, m), 3.03 (1H, m), 3.25 (1H, m), 3.49 (1H, m), 3.58 (1H, m), 6.41 (1H, s), 6.60 (1H, dd), 7.30 (1H, d), 7.37 (2H, d), 7.44-7.47 (3H, overlapping m), 7.56 (1H, m), 7.64 (1H, m), 7.83 (1H, d), 7.95 (1H, d), 8.08 (1H, d), 8.10 (1H, d), 8.70 (1H, s), 8.79 (1H, s), 9.12 (1H, s)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[NH2:30])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[CH2:43]([S:45](Cl)(=[O:47])=[O:46])[CH3:44].CN(C1C=CC=CN=1)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[NH:30][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[NH:30][S:45]([CH2:43][CH3:44])(=[O:47])=[O:46])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Reactant: O=C(Cl)C1CC1
Reactant: CCS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Product: O=C(Nc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12)C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46 %
Yield: 49 %

Procedure:
To a solution of 30 mg (0.075 mmol) 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-ylamine in 2 mL of acetonitrile (CH3CN) was added 0.018 mL (0.225 mmol) of pyridine (pyr), followed by 16 mg (0.2 mmol) of cyclopropylcarbonyl chloride or 19 mg (0.15 mmol) of ethanesulfonyl chloride, and 1 mg of dimethylaminopyridine (DMAP) and the resulting mixture was stirred at 60° C. overnight. Since analysis by LC-MS revealed product formation, the reaction mixture was concentrated to give a residue which was purified via reverse-phase chromatography to afford (after lyophilization) 17 mg (49% yield) of cyclopropanecarboxylic acid [6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-yl]-amide (415) as a yellow solid or 17 mg (46% yield) of ethanesulfonic acid [6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-yl]-amide (421) as a yellow solid as indicated by LC-MS—calcd for C29H30N4O2 [M++H]+: 467.24, found: 467.2; calcd for C27H30N4O3S [M++H]+: 491.2, found: 491.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: C1=COCCC1
Reactant: COc1cc(O)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(OC2CCCCO2)ccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 2-methoxy-4-hydroxy-benzaldehyde (2.40 g, 15.8 mmol) and 3,4-dihydro-2H-pyran (3.6 mL, 39.5 mmol) in 50 mL methylene chloride was added pyridinium p-toluenesulfonate (0.397 g, 1.58 mmol). The reaction mixture was stirred at room temperature overnight at which time the reaction was concentrated to one-half its original volume. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (5% ethyl acetate/hexanes) afforded 2.13 g (58%) of the title compound of Step A. MS 152.9 (M+1-THP)+
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:20].O1CCOCC1.C(OCC)(=O)C>C(Cl)Cl>[ClH:20].[N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][C:13]=1[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C#N)ccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc2c(n1)CCNC2
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
2-Cyano-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (WO00/09480) (3.74 g) was dissolved in methylene chloride (5.0 mL). 4N HCl-dioxane solution (14 mL) was added thereto. The resultant mixture was stirred at room temperature for 65 minutes, and stirred at 40° C. for 40 minutes. 4N HCl-dioxane solution (8 mL) was further added to the reaction mixture, followed by stirring at 45° C. for 75 minutes. Ethyl acetate was added to the reaction mixture, and the precipitated powder was recovered by filtration, to thereby give the title compound (3.20 g) as a colorless powder.