Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>N1C=CC=CC=1.C(Cl)Cl>[C:31]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)=[CH:26][CH:25]=1)(=[O:32])[CH2:30][CH2:29][CH3:28]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Oc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)OC(=O)CCC)o2)cc1
Reaction time: 23 h
Yield: 142.1 %

Procedure:
To a solution of 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (example 8) (200 mg, 0.52 mmol) in pyridine (1.0 mL) and CH2Cl2 (7.0 mL) was added n-butyryl chloride (0.16 mL, 1.56 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (10 mL). The mixture was partitioned between H2O (25 mL) and CH2Cl2 (30 mL). The aqueous layer was extracted with CH2Cl2 (20 mL). The combined organic extracts were washed with NaHCO3 (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange viscous oil, which was purified by flash chromatography over silica gel (15-25% EtOAc in hexanes) to provide the title compound as a colourless solid (194 mg, 71%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.00 (dm, J=8.8 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (dm, J=8.8 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.57 (pentet, J=5.9 Hz, 1H), 5.18 (d, J=8.0 Hz, 1H), 5.02 (dd, J=5.7, 8.0 Hz, 1H), 2.55 (t, J=7.4 Hz, 2H), 2.32 (dt, J=2.6, 7.4 Hz, 2H), 2.30 (s, 3H), 1.77 (sextet, J=7.4 Hz, 2H), 1.63 (sextet, J=7.4 Hz, 2H), 1.36 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.4 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[S:24][C:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:12](=[O:23])[CH:11]=3)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[S:24][C:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[CH:5]=1)=[N:14][N:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:12](=[O:23])[CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)CCc1cc(=O)n(-c3ccc(C)cc3)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nc3c(cc2=O)CCc2sc(C(C)O)cc2-3)cc1
Yield: 49.7 %

Procedure:
To a suspension of 600 mg of 8-acetyl-5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in 100 ml of methanol was added 70 mg of sodium borohydride with stirring under ice-cooling. The mixture was stirred for 3 hours and poured into ice-cold water and then extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :20 g) column using a mixed solvent of chloroform and methanol (98:2) as an eluent. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 300 mg of 8-(1-hydroxyethyl)-5,6-dihydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a pale yellow powder, melting at 146°-148° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([O:7][C:8]2[CH:13]=[C:12]([C:14]3([O:32][C@H:31]([CH2:33][O:34]C(=O)C)[C@@H:26]([O:27]C(=O)C)[C@H:21]([O:22]C(=O)C)[C@H:16]3[O:17]C(=O)C)[OH:15])[CH:11]=[C:10]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=3)[C:9]=2[CH3:47])[CH2:6][CH2:5][CH2:4]1.Cl>CO.C1COCC1>[CH:3]1([O:7][C:8]2[CH:13]=[C:12]([C:14]3([O:32][C@H:31]([CH2:33][OH:34])[C@@H:26]([OH:27])[C@H:21]([OH:22])[C@H:16]3[OH:17])[OH:15])[CH:11]=[C:10]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH3:46])=[CH:41][CH:40]=3)[C:9]=2[CH3:47])[CH2:6][CH2:5][CH2:4]1
Reactant: CCc1ccc(Cc2cc(C3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC3CCC3)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc(C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC3CCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (0.15 mL, 4 mol/L) is added to 1-cyclobutoxy-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzene (80 mg) dissolved in methanol (1 mL) and THF (0.5 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->6:1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][Al](C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:4]1[N:3]=[C:2]([CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 70 °C
Yield: 44.4 %

Procedure:
To a pressure vessel, a degassed solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (3.0 g, 14.4 mmol) (R. J. Rousseau and R. K. Robins J. Heterocyclic Chem. 2, 1965, 196) and tetrakis(triphenylphosphine)palladium(0) (1.67 g, 1.44 mmol) in DMF (45 mL) was stirred at room temperature. To this mixture was added dropwise a solution of trimethylaluminium (7.93 mL, 15.8 mmol, 2M in toluene). The resulting mixture was sealed and heated at 70° C. for 3 hours. The reaction mixture was poured into ice/water (800 mL). The organic material was extracted with EtOAc (5×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using EtOAc:Hexane gradient (1:9) to (3:7) to afford the desired compound as a yellow solid (1.20 g, 45%), HPLC: 99% (220 nm), LCMS (+ESI, M+H+) m/z 188, IR (KBr, cm−1) 3431, 3310, 3172, 1653, 1506, 1264; 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.57 (br s, 2H), 2.63 (s, 3H);.
Reaction SMILES: C([N:3]=[C:4]([NH:21][CH2:22][CH2:23][S:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[CH3:31])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:19]C)=[N:16][C:17]#N)#N.Cl>>[CH3:31][C:30]1[NH:29][CH:28]=[N:27][C:26]=1[CH2:25][S:24][CH2:23][CH2:22][N:21]=[C:4]([NH2:3])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH2:19])=[N:16][CH3:17]
Reactant: CNC(=NC#N)NCCCCCCCCNC(=NC#N)NCCSCc1nc[nH]c1C
Agent: Cl
Product: CN=C(N)NCCCCCCCCNC(N)=NCCSCc1nc[nH]c1C

Procedure:
The product of Example 20 was heated under reflux with an excess of 12 N hydrochloric acid for 10 hours and evaporated to low volume. This solution was basified by the addition of a basic polyamine polystyrene ion-exchange resin cross-linked with 2% divinylbenzene (OH- form) and the solution was evaporated to dryness to give 1-[N'-(2-((5-methyl-4-imidazolyl)methylthio)ethyl)guanidino]-8-[N'-methylguanidino]octane. To this product was added an excess of hydrochloric acid and the solution evaporated to dryness to give the trihydrochloride which was a glass: nmr:- (100 MHz. D2O) 1.4 (m,(CH2)6), 2.32(s,CH3), 2.76(m,(CH2S)), 2.84(s,(NHCH3), 3.19(m(2xNCH2)), 3.42(m,NCH2), 3.89(s,CH2S), 8.59(s,Imid2-H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2nccn2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 85 %

Procedure:
The title compound is prepared from imidazo[1,2-a]pyridine-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 85% of theory; LC (method 3): tR=1.81 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.C(NC(C)C)(C)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[C:16]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cc(Br)co1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: O=Cc1cc(C#Cc2ccccc2)co1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.6 %

Procedure:
A solid mixture of 4-bromo-2-furaldehyde (1.50 g, 8.57 mmol), PdCl2(PhCN)2 (197 mg, 0.514 mmol) and CuI (65.0 mg, 0.343 mmol) was flushed under an argon stream for 1 minute (min). A solution of HP(t-butyl)3BF4 (298 mg, 1.03 mmol) and diisopropylamine (1.80 mL, 12.9 mmol) in dioxane (9 mL) was added to the solid mixture followed by phenylacetylene (1.13 mL, 10.3 mmol). The reaction was allowed to stir at room temperature (rt) under an atmosphere of argon for 15 hours (h) before being filtered through a plug of silica gel with ethyl acetate (EtOAc). The solution was then concentrated in vacuo and chromatographed over silica gel to give 4-phenylethynyl-furan-2-carbaldehyde as a colorless oil (1.54 g, 92%). Rf=0.35 (1:9 heptane/EtOAc); 1H NMR (400 MHz, CDCl3) δ ppm 9.68 (d, J=0.5 Hz, 1 H) 7.90 (s, 1 H) 7.48-7.55 (m, 2 H) 7.35-7.40 (m, 3 H) 7.33 (d, J=0.7 Hz, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:37])[CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=2)=[CH:18][CH:17]=1)(C)(C)C.[C:40](N1C=CN=C1)(N1C=CN=C1)=[O:41]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:37][C:40](=[O:41])[N:24]([C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)[CH2:23]2)=[CH:18][CH:17]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(NCC(O)c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(N2CC(c3ccc(C(=O)Nc4ccccc4N)cc3)OC2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added 1,1′-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirred at room temperature for 16 h. DCM was removed under reduced pressure, AcOEt and a solution of sat. NH4Cl were added and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (Hexane/AcOEt: 30/70) to afford the desired compound (80 mg, 0.14 mmol, 58% yield). 1H NMR (DMSO) δ (ppm): 9.39 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J=8.4 Hz, 1H), 4.24 (t, J=8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[C:17]([C:19](=[O:31])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:16]=[CH:15][C:14]=1[NH2:32])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([NH:20][C:19]([C:17]2[CH:18]=[C:13]3[C:14](=[CH:15][CH:16]=2)[NH:32][C:11]([CH2:10][CH2:9][CH2:8][NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:12]3)=[O:31])[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCNC(=O)OC(C)(C)C)c2)cc1OC
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccc3[nH]c(CCCNC(=O)OC(C)(C)C)cc3c2)cc1OC
Temperature: 80 °C

Procedure:
A 500 mL round bottom flask was charged with {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-carbamic acid tert-butyl ester (3.0 g, 6.62 mmol), dichlorobis(benzonitrile)palladium (II) (0.514 g, 1.34 mmol), and dimethylformamide (80 mL) and the resulting mixture heated to 80° C. for 24 h. The resulting mixture was then concentrated in-vacuo and the residue via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 100:0-90:10 CH2Cl2:MeOH) to yield tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propylcarbamate. MS (ES+) 454 (M+1); HPLC: Kromasil C18 column (50×2 mm; 3.5μ), gradient 1{tilde over (0)}90% (MeCN+0.16% TFA) in (water+0.2% TFA) over 4 min, tR=3.78 min.
Reaction SMILES: O1CCCOB1[C:7]1[CH:37]=[CH:36][C:10]([C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][S:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([N+:33]([O-:35])=[O:34])[CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:9][CH:8]=1.[F:38][C:39]([F:56])([F:55])[C:40]1[C:49](Cl)=[CH:48][C:47]2[C:42](=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:44]=[CH:45][CH:46]=2)[N:41]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[F:55][C:39]([F:38])([F:56])[C:40]1[CH:49]=[C:48]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][S:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:19]([N+:33]([O-:35])=[O:34])[CH:18]=3)(=[O:15])=[O:16])=[O:12])=[CH:36][CH:37]=2)[C:47]2[C:42](=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=[CH:45][CH:46]=2)[N:41]=1
Reactant: FC(F)(F)c1nc2c(C(F)(F)F)cccc2cc1Cl
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(B2OCCCO2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(-c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)cc1
Temperature: 85 °C

Procedure:
A solution of Example 214D (100 mg, 0.15 mmol) and 2,8-bistrifluoromethyl-3-chloroquinoline (100 mg, 0.343 mmol) in dioxane (2 mL) was treated with Pd2(dba)3 (10 mg, 0.011 mmol), P(t-Bu)3 (20 mg, 0.1 mmol) and Cs2CO3 (150 mg, 0.50 mmol), purged with argon, sealed, and heated to 85° C. for 18 hours. The mixture was concentrated and the concentrate was dissolved in 1:1 DMSO/methanol (1 mL) and filtered. The filtrate was purified by preparative HPLC (using a Nova-Pak HR C-18 column and a solvent system varying in gradient from 10-95% acetonitrile/water containing 0.1% TFA) to provide the desired product. MS (ESI(+)) m/e 721 (M+H)+, m/e 719 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 8.80 (t, 1H), 8.67 (d, 1H), 8.41 (d, 1H), 8.14 (d, 1H), 8.12 (d, 2H), 8.08 (s, 1H), 7.97 (dd, 1H), 7.91 (t, 1H), 7.77 (d, 2H), 7.38 (dt, 2H), 7.28 (td, 2H), 7.24 (d, 1H), 7.17 (tt, 1H), 3.69 (q, 2H), 3.31 (t, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]([CH3:32])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:19]=1[O:35][CH3:36])=[O:16])=O)(C)(C)C.[ClH:41]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:41].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:40]=[CH:39][CH:38]=[CH:37][C:14]=1[C:15]([NH:17][C:18]1[CH:34]=[CH:33][C:21]([C:22]([N:24]([CH3:32])[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:23])=[CH:20][C:19]=1[O:35][CH3:36])=[O:16]
Reactant: COc1cc(C(=O)N(C)c2ccc(O)cc2)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C)c2ccc(O)cc2)ccc1NC(=O)c1ccccc1OCCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-[(3-tert-butoxycarbonylaminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-(4-hydroxyphenyl)benzamide (50 mg) in chloroform (3.0 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (1.0 ml) and the mixture was stirred at ambient temperature for 2 hours. The resulting mixture was evaporated in vacuo and the residue was solidified with diethyl ether. Diethyl ether was removed in vacuo to give 4-[2-[(3-aminoprop-1-yl)oxy]benzoyl]amino-3-methoxy-N-methyl-N-(4-hydroxyphenyl)benzamide hydrochloride (40 mg).
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:25][C:26](OC(C)=O)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([C:10]3([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:3][C:4]=2[CH2:5]1)(=[O:27])[CH3:25]
Reactant: O=C(O)c1ccc(C2(c3nc4c(s3)CNCC4)CCOCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(C3(c4ccc(C(=O)O)cc4)CCOCC3)sc2C1

Procedure:
4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (40 mg, 0.116 mmol) in pyridine, catalytic amount of 4-dimethylaminopyridine (DMAP), and excess Ac2O were mixed together at room temperature. After the reaction was complete, the mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid. Similar HATU coupling procedure from Example 9 was followed to obtain the title compound. MS found for C26H28N4O3S as (M+H)+477.58. 1H NMR (400 MHz, dmso-d6): δ: 9.53 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.51 (t, J=8.4 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.54 (t, J=7.6 Hz, 1H), 4.84 (s, 2H), 4.61-4.57 (m, 2H), 3.69-3.57 (m, 6H), 2.80-2.29 (m, 6H), 2.05-1.98 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH2:20])=O)=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.N1C=CC=CC=1.O1CCOCC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:20])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1
Reactant: NC(=O)c1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 2.0 g. of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carboxamide, 1.03 g. of anhydrous pyridine and 50 ml. of anhydrous dioxane is chilled in an ice bath. To this is added 1.51 g. of trifluoroacetic anhydride and the mixture is stirred at room temperature overnight. Water is added and the resulting solid is collected by filtration. This solid is dissolved in methylene chloride and passed through a column of hydrous magnesium silicate. The effluent is refluxed with the continued addition of hexane until crystallization is started. Cooling gives the desired solid product which is recovered by filtration, m.p. 168°-169° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])[N:3]=1.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CS(C)=O>N1C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C(N)=O)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Br)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 12) (22 mg, 0.07 mmol) was dissolved in pyridine (1.6 mL) and added to 5-bromo-2-thiophenesulfonyl chloride (27 mg, 0.1 mmol). The reaction mixture was shaken at room temperature for 5 min and then stood overnight at room temperature. DMSO (0.2 mL) was added to the reaction mixture and purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (4.6 mg, 12%) LCMS (System A) RT=1.04 min, ES+ve m/z 521/523 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-7-yl acetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9 g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H), 3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20 (m, 1H), 1.49 (s, 9H), 1.29-1.20 (m, 3H). MS (APCI+) [M+H]+377. The resulting mixture of the diastereomers was purified by chiral separation HPLC (Chiralcel ODH column, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak (RT=3.73 min) gave the tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl)piperazine-1-carboxylate (0.172 g, 29%). MS (APCI+) [M+H]+377.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:6][C@@H:7]1[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]([CH3:20])([CH3:19])[C@H:8]1[OH:21])[CH3:5])#[N:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:21][C@H:8]1[C@H:7]([NH:6][C:4](=[N:3][C:1]#[N:2])[CH3:5])[C:12]2[CH:13]=[C:14]([C:17]#[N:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]1([CH3:20])[CH3:19])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](NC(C)=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A mixture of trans-4-[N-[1-(cyanoimino)ethyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (0.53 g) and acetic anhydride (0.38 g) in dry pyridine (2.65 ml) was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, successively. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl ether and collected by filtration to give trans-3-acetoxy-4-[N-[1-(cyanoimino)-ethyl]amino]-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.55 g).