Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].Cl.[NH2:24][OH:25]>CO>[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=[N:24][OH:25])[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCN1CC[C@]2(c3cccc(OC)c3)CC(=NO)CC[C@H]2C1
Yield: 96.6 %

Procedure:
0.5 g (1.54 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.456 g (6.56 mmol) of hydroxylamine hydrochloride and 0.64 g of KHCO3 in 10 ml of MeOH were refluxed for 45 min. The precipitate was filtered, the solvent was removed in vacuo and the residue taken up in H2O. The pH was adjusted to 8 with conc. NH4OH, the aqueous layer was extracted with CH2Cl2. The organic layer was dried, the solvent removed in vacuo, obtaining 0.45 g of the title compound which was used as such in the subsequent step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH3:13])[C:4]=2[CH:3]=1.[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]3[N:10]=[CH:11][N:12]([CH3:13])[C:4]=3[CH:3]=2)=[CH:21][C:20]=1[C:28]([F:29])([F:30])[F:31]
Reactant: OCCCOc1ccc(B(O)O)cc1C(F)(F)F
Reactant: Cn1cnc2c(C#N)nc(Cl)cc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (6 g), 4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenylboronic acid (12.3 g), tris(dibenzylideneacetone)dipalladium (1.42 g), tricyclohexylphosphoine (1.05) and tribasic potassium phosphate (13.2 g) in dioxane (60 ml) and water (24 ml) was heated at 100° C. under N2 for 4 hours. The mixture was then diluted with ethyl acetate (400 ml) organic layer separated and solvent removed under reduced pressure, to the residue was then added methanol (50 ml), product crystalised out and collected by filtration (7.7 g).
Reaction SMILES: C1CCC([N:7]=[C:8]=[N:9]C2CCCCC2)CC1.ON1C(=O)CCC1=O.[CH2:24]([O:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)[C:28](O)=[O:29])[CH3:25].C(N(C(C)C)CC)(C)C.N#CN>C(#N)C.C(O)(=O)C>[C:8]([NH:9][C:28](=[O:29])[CH:27]([O:26][CH2:24][CH3:25])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][S:48]([CH3:51])(=[O:50])=[O:49])=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)#[N:7]
Reactant: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)NC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
DCC (0.444 g; 2.15 mmole) and N-hydroxy-succinimide (0.247 g; 2.15 mmole) were added to a solution of 2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid (described in Example 2) (0.8 g; 1.96 mmole) in acetonitrile (20 ml) at 0° C. After stirring at room temperature overnight a precipitate was filtered off and diisopropylethylamine (1 ml; 5.88 mmole) and cyanamide (0.165 g; 3.92 mmole) were added. After stirring overnight the reaction mixture was poured onto potassium hydrogen sulfate (1M, 20 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated. Chromatography of the crude product on silica gel using ethyl acetate:heptane; acetic acid (10:10:1) as eluant gave 0.755 g (yield 89%) of N-cyano-2-ethoxy-3-[4-(2-{4-methanesulfonyloxy-phenyl}ethoxy)phenyl]propanoic amide.
Reaction SMILES: OC[C:3]([CH2:7]O)([CH2:5][OH:6])[NH2:4].[Cl-].[Cl-].[Ca+2].F[C:13](F)(F)[C:14]([OH:16])=[O:15].FC(F)(F)C(O)=[O:22].C(#N)C>>[NH2:4][C@H:3]([C:5]([OH:6])=[O:22])[CH2:7][CH2:13][C:14]([OH:16])=[O:15]
Reactant: NC(CO)(CO)CO
Reactant: O=C(O)C(F)(F)F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC#N
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
The oligopeptides prepared as described in Example 2 were individually dissolved in PSA digestion buffer (12 mM tris(hydroxymethyl)-aminomethane pH8.0, 25 mM NaCl, 0.5 mM CaCl2) and the solution added to PSA at a molar ration of 100 to 1. The reaction is quenched after various reaction times by the addition of trifluoroacetic acid (TFA) to a final 1% (volume/volume). The quenched reaction was analyzed by HPLC on a reversed-phase C18 column using an aqueous 0.1% TFA/acetonitrile gradient. The results of the assessment are shown in FIG. 2. Other oligopeptides prepared as described in Example 2 were tested in the same assay wherein the reaction was quenched at 4 hours. Those results of the assessment are shown in FIG. 3. The removal of an asparagine residue from the amino terminus of the oligopeptide results in a significant loss of PSA mediated peptide hydrolysis, while the presence of a glutamic acid residue at the carboxyl end of the peptide appears not to be essential to recognition by PSA.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:60][O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:16][S:17][CH2:18][C@H:19]([NH:42][C:43](=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33]([O:38]CC)([O:35]CC)=[O:34])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Si](Br)(C)C>C(Cl)Cl>[C:1]([O:14][C@H:15]([CH2:60][O:61][C:62](=[O:74])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:16][S:17][CH2:18][C@H:19]([NH:42][C:43](=[O:59])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:20](=[O:41])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][P:33](=[O:34])([OH:35])[OH:38])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-1-(diethoxyphosphoryl)-13-oxo-14-palmitamido-3,6,9-trioxa-16-thia-12-azanonadecane-18,19-diyl didodecanoate (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 25° C. overnight and concentrated. The crude mixture was purified by reverse phase high performance liquid chromatography (HPLC) with C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to give the title product as a white solid after lyophilizing. 1H NMR (CDCl3): δ 8.09 (br s, 2H), 5.18 (d, 2H), 4.62-4.70 (m, 2H), 4.36 (d, 2H), 4.13 (dd, 2H), 3.40-3.80 (m, 13H), 2.70-3.05 (m, 8H), 2.27-2.32 (m, 6H), 1.54-1.62 (m, 6H), 1.20-1.32 (m, 56H), 0.88 (t, 9H). LRMS [M+H]=1037.7.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C.[I-].ClC1C=CC=C[N+]=1C.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:6]
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Reactant: c1ccc2c(c1)CCCN2
Agent: C[n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Br)c(C(=O)N2CCCc3ccccc32)c1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-5-cyano-benzoic acid (0.50 g, 2.12 mmol, 1.0 equiv; [CAS RN 845616-12-8]) in dichloromethane (5 mL) was added 1,2,3,4-tetrahydro-quinoline (0.35 g, 330 μL, 2.66 mmol, 1.2 equiv; [CAS RN 635-46-1]), N-ethyldiisopropylamine (1.43 g, 1.88 mL, 11.06 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 2-chloro-1-methylpyridinium iodide (0.68 g, 2.66 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt over the weekend. To the residue was added a sat. solution of NaHCO3 (100 mL) and the solution extracted with dichloromethane (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of toluene/acetone affording 0.35 g (46%) of the title compound as a light yellow solid. MS (ISP): 341.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](O)(=O)[CH3:47]>>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:46]([CH3:47])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: CC(=O)O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C)nc12

Procedure:
A suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) in acetic acid (1 ml) was refluxed for 8 hours. After being evaporated in vacuo, the residue was dissolved chloroform and the solution was washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylamino-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (84 mg) as a powder.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>CCCCCC.C1COCC1.C(OCC)C>[Cl:21][C:15]1[CH:16]=[CH:17][C:18]([B:29]([OH:34])[OH:30])=[CH:19][C:14]=1[N:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(Br)cc1N(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc(Cl)c(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon and at −78° C., 20.2 ml (50.42 mmol) of a 2.5 M solution of n-butyllithium in hexane were slowly added dropwise to a solution of 15 g (38.79 mmol) of N,N-dibenzyl-5-bromo-2-chloroaniline in 350 ml of THF/diethyl ether (1:1). The reaction solution was stirred at −78° C. for 60 min, and 14.3 ml (62.1 mmol) of triisopropyl borate were then added slowly. The reaction solution was subsequently stirred at −78° C. for another 15 min, then slowly warmed to room temperature, and stirring at this temperature was continued overnight. 150 ml of ice-water were then metered in. The organic phase was separated off, and the aqueous phase was then extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulphate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1). This gave 9 g (66% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52]([Mg]Br)#[C:53][CH3:54]>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:51])[C:52]#[C:53][CH3:54])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#C[Mg]Br
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: C1CCOC1
Product: CC#CC(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carbaldehyde 1k (0.2 g, 0.28 mmol, obtained from the synthetic method described in step 10 of example 1) in anhydrous tetrahydrofuran (10 mL) was added dropwise 1-propynylmagnesium bromide (1.1 mL, 0.57 mmol, 0.5 M in tetrahydrofuran) at 0° C. After the addition, the mixture was stirred at room temperature for 4 hours and quenched with 1.5 mL of saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with water (10 mL×2) and then saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=8/1 to give the title compound 5a as colorless oil (145 mg, 69%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm:) 7.45 (m, 1H), 7.37 (m, 2H), 7.32 (m, 8H), 7.28 (m, 2H), 7.16 (m, 3H), 7.07 (d, 2H), 6.88 (m, 2H), 6.74 (m, 2H), 4.90 (m, 1H), 4.85 (m, 1H), 4.81 (m, 1H), 4.57 (m, 1H), 4.37 (t, 1H), 4.29 (m, 1H), 4.23 (m, 1H), 4.17 (m, 1H), 4.09 (m, 1H), 4.02 (m, 2H), 3.96 (m, 3H), 3.84 (d, 1H), 3.73 (d, 1H), 2.35 (d, 1H), 1.84 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[CH3:9][O:10][C:11]1[C:12]([O:43][CH3:44])=[CH:13][C:14]2[N:20](COCC[Si](C)(C)C)[C:19](=O)[C@@H:18]3[CH2:30][C:31]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[CH:32][N:17]3[C:16](=[O:41])[C:15]=2[CH:42]=1.CCO.C1COCC1>O>[CH3:9][O:10][C:11]1[C:12]([O:43][CH3:44])=[CH:13][C:14]2[N:20]=[CH:19][C@@H:18]3[CH2:30][C:31]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[CH:32][N:17]3[C:16](=[O:41])[C:15]=2[CH:42]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OC)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OC)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 40 %

Procedure:
Solid sodium tetraborohydride (NaBH4, 70 mg, 1.88 mmol) was added in one portion to a rapidly stirring solution of 178 (100 mg, 0.2 mmol) in a mixture of anhydrous EtOH (2 mL) and anhydrous THF (4 mL) and left to stir at room temperature for 9 h. The reaction mixture was diluted with water (10 mL) and stirred for 30 minutes with silica gel (2.0 g). The mixture was extracted with EtOAc (3×10 mL). The organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. Filtration and evaporation afforded the crude product (179), which was purified by flash column chromatography eluting with a 50:50 mixture of petroleum ether:EtOAc. Pure fractions were combined and evaporation of the solvent in vacuo afforded the product as a yellow glass (28 mg, 0.08 mmol, 38%). 1H NMR (270 MHz, CDCl3) δ7.89 (d, 1H, J=4.03 Hz, Imine CH), 7.53 (s, 1H, ArH), 7.39 (t, 1H, J=1.83 Hz, H3), 7.33 (d, 2H, J=8.97 Hz, methoxyphenyl ArH), 6.91 (d, 2H, J=8.98 Hz, methoxyphenyl ArH), 6.83 (s, 1H, ArH), 4.44-4.36 (m, 1H, H11a), 3.97 (s, 3H, OMe), 3.94 (s, 3H, OMe), 3.91-3.79 (m, 4H, H1+Suzuki ArOMe), 3.64-3.34 (m, 1H, H1); 13C NMR (67.8 MHz, CDCl3) δ162.7, 161.3, 159.2, 151.8, 147.8, 140.4, 126.3, 126.2, 126.0, 125.9, 123.2, 121.9 114.3, 114.1, 111.6, 109.8, 56.2, 56.1, 55.6, 35.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][C:19](I)=[CH:18][C:17]=3[CH3:27])=[O:14])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:33]#[N:34]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([NH:15][C:16]3[C:21]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][C:19]([C:33]#[N:34])=[CH:18][C:17]=3[CH3:27])=[O:14])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: CNC(=O)c1cc(I)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
To a solution of 1-(3-chloro-2-pyridinyl)-N-[4-iodo-2-methyl-6-[(methylamino)carbonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (i.e. the diamide product of Step A) (410 mg, 0.72 mmol) in tetrahydrofuran (8 mL) was added copper(I) iodide (24 mg, 0.126 mmol), tetrakis(triphenyphosphine)palladium(0) (70 mg, 0.060 mmol) and copper(I) cyanide (640 mg, 7.2 mmol) sequentially at room temperature. The reaction mixture was heated at reflux for 4.5 hours. Thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure and the residual solid was purified by chromatography on silica gel to afford 114 mg of the title compound, a compound of the present invention, as a white solid, melting at 214-216° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].C([O-])(O)=O.[Na+].CO[CH2:40][CH2:41]OC>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:17]=[CH:16][C:15]3[S:14][CH:13]=[N:12][C:40]=3[CH:41]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Reactant: COCCOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1scc(-c2ccc3scnc3c2)c1C(=O)O)c1cc2ccccc2o1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 7 (49 mg, 0.1 mmol) in 1,2-dimethoxyethane (DME, 2 mL) and EtOH (1 mL) was added 37 (31 mg, 0.12 mmol), 0.5 M NaHCO3 (1 mL). The suspension was bubbled with argon for 5 min before adding Pd(PPh3) (38, 12 mg, 0.01 mmol). The reaction mixture was heated at 110° C. for 30 min using microwave initiator. The solid was filtered off and the filtrate was extracted with EtOAc (10 ml×2). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The compound 39 was purified by HPLC. The 39 was dissolved in CH2Cl2 (2 ml) and TFA (0.5 ml) was added. The mixture was stirred for 2 h at r.t. The solvent was removed in vacuo. The residue was treated with MeOH (2 mL) and the solid was collected by centrifuge and washed with MeOH. Compound 40 (20 mg, 48%) was obtained as yellow solid. LC-MS: calcd. for C21H12N2O4S2: 419 (M−1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[NH4+:26]>O1CCOCC1>[I:11][C:10]1[C:3]2[C:2]([NH2:26])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:9]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
Trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (0.89 g, 1.9 nmol) in concentrated ammonium hydroxide (40 mL) and dioxane (40 mL) was heated at 120° C. in a pressure vessel for 18 hours. The mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The water phase was further extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield trans-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.35 g, 0.8 mmol). RP-HPLC (Hypersil C18, 5 μm, 250×4.6 mm; 25%-100% over 15 min with 0.1 M ammnonium acetate, 1 mL/min) Rt 4.01 min. MS: MH+441.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(O[C:42]1(O[Si](C)(C)C)[CH2:44][CH2:43]1)C>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][CH2:36][N:35]4[CH:42]4[CH2:44][CH2:43]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4)ncn3)cccc2s1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CCCN4C4CC4)ncn3)cccc2s1

Procedure:
(2S)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)-phenyl)pyrrolidine-2-carboxamide [Example 69(b)] was reacted with (1-ethoxycyclopropoxy)trimethylsilane (Aldrich) under the conditions of Example 62(c) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 583 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](O)=[O:22])=[CH:16][CH:15]=1>C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:22])[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: Nc1cccnc1NCC1CC1
Reactant: O=C(O)C(=O)c1ccc(Cl)cc1
Agent: C=O
Product: O=c1c(-c2ccc(Cl)cc2)nc2cccnc2n1CC1CC1
Yield: 36.6 %

Procedure:
430 mg (2.63 mM) of N2-(cyclopropylmethyl)pyridine-2,3-diamine and 485.4 mg (2.63 mM) of (4-chlorophenyl)(oxo)acetic acid in 6 ml of methanal were refluxed for 16 h. A solid crystallized. The compound was filtered and washed with methanol to give 300 mg of 2-(4-chlorophenyl)-4-(cyclopropylmethyl)pyrido[2,3-b]pyrazin-3(4H)-one as a beige solid. Yield: 36.5%.