Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[CH2:31]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[CH2:31]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A mixture of 3,4-dichlorophenyl-acetic acid (0.31 g, 1.5 mmol) and CDI (0.26 g, 1.6 mmol) in DMF (20 mL) was stirred at 70° C. under N2. After 4 h, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.47 g, 1.5 mmol) was added. The mixture was cooled to 40° C. and was stirred at this temperature for an additional 16 h. Water (30 mL) was added resulting in precipitation of the product. The solid precipitate was filtered, washed with water (50 mL) and dried in vacuo providing 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a yellow solid (0.24 g, 34% yield); mp 191-193° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4. 4.17 (98.19%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.45 (m, 1H), 2.57-2.73 (m, 1H), 2.86-2.98 (m, 1H), 3.54 (s, 2H), 4.45-5.14 (m, 4H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.24 (dd, 1H, J=8.4, J=6.3), 7.29-7.47 (m, 2H), 7.48-7.59 (m, 2H), 7.67 (d, 1H, J=7.8), 8.72 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.0, 42.3, 47.1, 51.6, 122.1, 123.0, 127.1, 129.1, 129.5, 130.3, 130.4, 130.6, 131.1, 137.3, 142.3, 143.6, 168.0, 169.4, 170.9, 172.8; LCMS: MH=461, 463; Anal. Calcd for C22H19Cl2N3O4+0.5H2O: C, 56.30; H, 4.30; N, 8.95. Found: C, 56.19; H, 3.91; N, 8.56.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:21][O:20][C:19]3[CH:22]=[C:23]4[C:27](=[CH:28][C:18]1=3)[CH2:26][CH2:25][O:24]4)[C:5](=[O:17])[N:6]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][O:13]1.O.[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=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>[CH3:30][N:31]([CH3:41])[C:32]1[N:33]=[CH:34][C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]2=4)[CH2:26][CH2:25][O:24]5)[C:5](=[O:17])[N:6]3[CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:36][CH:37]=1
Reactant: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: CN(C)c1ccc(B(O)O)cn1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)CCO5)C(=O)N3C[C@H]2CCCO2)cn1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A stirred solution of 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.125 g, 0.3 mmol), 2-(dimethylamino)pyridine 5-boronic acid hydrate (0.08 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 2 M sodium carbonate (1 mL) in N,N-dimethylformamide (4 mL) was heated with stirring at 150° C. for 15 min in a microwave reactor. The solution was poured into distilled water (15 mL) and washed with ethyl acetate (75 mL). The ethyl acetate layer was washed with brine (3×25 mL), dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (gradient: 30% to 60%) to afford 4′-[6-(dimethylamino)pyridin-3-yl]-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.11 g, 73%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ7.53 (d, J=2.4 Hz, 1H), 7.33 (dd, J=7.8 Hz, 1H), 7.18 (dd, J=7.4, 4.7 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.71 (ddd, J=8.8, 2.4, 0.9 Hz, 1H), 6.51 (d, J=5.6 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 6.12 (d, J=0.9 Hz, 1H), 4.59-4.41 (m, 3H), 4.33 (dd, J=9.4, 3.1 Hz, 1H), 4.23-4.08 (m, 1H), 3.89-3.55 (m, 4H), 3.09-2.86 (m, 2H), 2.95 (s, 6H), 2.05-1.69 (m, 3H), 1.67-1.51 (m, 1H); MS (ES+) m/z 484.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[CH:10]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>FC(F)(F)C(O)=O>[F:15][C:14]1[C:9]([CH:8]2[C:21]3[C:4](=[C:3]([O:2][CH3:1])[C:24]([O:25][CH3:26])=[CH:23][CH:22]=3)[CH2:5][NH:6][CH2:7]2)=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=1
Reactant: COc1cc(F)c(C(O)CNCc2cccc(OC)c2OC)cc1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3c2ccc(OC)c3OC)cc1OC
Yield: 98.9 %

Procedure:
α-[[(2,3-dimethoxybenzyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (1.0 g) was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto under ice cooling, conc. sulfuric acid (0.25 ml), the mixture was stirred for 40 minutes. 0.72 g of sodium acetate was added to the reaction mixture, and the mixture was concentrated. To the residue was added chloroform and water, and the mixture was basified by addition of conc. aqueous ammonia under ice cooling. After separating procedure, the chloroform layter was collected, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, 0.94 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline was obtained as a syrupy matter.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH:26]=[O:27])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCNC1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NC1CCCN(c2ccccc2C=O)C1
Yield: 16.9 %

Procedure:
Using N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (67.2 mg, 0.200 mmol) and 2-fluorobenzaldehyde (0.211 mL, 2.00 mmol), the same procedure was followed as in Step 6c of Example 6 to give 14.9 mg (17%) of the desired compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:44]=[CH:43][O:42][C:41]=2[CH3:45])O1>>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([C:40]1[CH:44]=[CH:43][O:42][C:41]=1[CH3:45])[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]
Reactant: Cc1occc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(-c4ccoc4C)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 191 from methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate and 4,4,5,5-tetramethyl-2-(2-methyl-3-furanyl)-1,3,2-dioxaborolane and was isolated as a pale yellow solid (10 mg, 49%) after reverse phase chromatography: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.58-8.46 (m, 1 H), 7.62-7.53 (m, 1 H), 7.46-7.33 (m, 2 H), 7.32-7.24 (m, 1 H), 7.24-7.05 (m, 2 H), 6.62 (t, J=1.9 Hz, 1 H), 5.37 (s, 1 H), 3.71 (d, J=1.2 Hz, 3 H), 2.51 (d, J=2.3 Hz, 3 H), 2.37 (d, J=1.2 Hz, 3 H), 2.33 (d, J=2.0 Hz, 3 H), 1.09 (d, J=4.5 Hz, 9 H); LC/MS (m/z) ES+=474 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH:20]=[CH:21][CH3:22]>>[CH2:17]([NH:23][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH3:22]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC=CCCCN
Product: CC=CCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 85° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and hex-4-enylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[CH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:22][N:30]=[C:28]([C:27]5[CH:32]=[CH:33][C:24]([NH2:23])=[N:25][CH:26]=5)[N:29]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (114 mg, 52%). MS (ISP) 440.2 [(M+H)+]; mp 254° C.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:13]1(=[O:17])[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:15](=[O:16])[NH:14]1
Reactant: [H][H]
Reactant: O=C1NC(=O)[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)C2CNCC12
Reaction time: 48 h
Yield: 68.6 %

Procedure:
A degassed solution of cis-5-(benzyl)tetrahydropyrrolo[3,4-c]pyrrole-1,3-(2H,3H)-dione (250 mg, 1.30 mmol) in methanol (50 mL) was treated with Pd/C (25 mg) and a hydrogen balloon was attached. The mixture was stirred for 48 h before filtering through celite and removal of the solvents in vacuo gave the title compound as a brown solid (125 mg, 88%). δH (DMSO-d6) 11.01 (1H, s) 3.12 (4H, d, J 10.4 Hz), 2.75 (2H, m). LCMS RT 0.19 minutes, (ES+) 141 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.[C:19](Cl)([Cl:21])=[S:20]>O.C(Cl)(Cl)Cl>[Cl:21][C:19]([O:3][C:4]1[CH:18]=[CH:17][C:7]([C:8]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[S:20]
Reactant: O=C(Sc1ccccc1)c1ccc(O)cc1
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(Sc1ccccc1)c1ccc(OC(=S)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.55 g in 150 ml of water was added dropwise with vigorous stirring to a solution of 8.8 g of S-phenyl 4-(hydroxy)thiobenzoate and 3.70 ml of thiophosgene in 250 ml of chloroform, the temperature being kept below 10° C. The mixture was stirred at room temperature for 2 hours and the organic layer separated. The organic layer was washed successively with water and brine, dried over calcium chloride, and evaporated to dryness in vacuo to give 11.57 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[O:11]=[C:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].Cl[Sn](Cl)(Cl)Cl.[OH-].[K+]>O.C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]([OH:11])[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)Cc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1ccc(C(O)C(=O)O)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
To a dry 3-necked round-bottom flask under argon atmosphere equipped with a dropping funnel, septum and magnetic stir bar was added 12.6 mL (80 mmol) of isobutylbenzene, 12.3 mL (80 mmol) of diethyl ketomalonate (DEOM) and 40 mL of CH2Cl2. The flask was cooled with stirring to 0° C. followed by the dropwise addition of 11.7 mL (100 mmol) of SnCl4. The yellow reaction mixture was allowed to warm slowly to room temperature and after 3 hours the reaction was quenched by pouring the suspension into a mixture of 50 g of ice and 50 mL of 5% aqueous HCl and extracted with ether (3×100 mL). The ether layers were combined and washed with water (2×50 mL), 25 mL of brine, dried over MgSO4 and concentrated. The crude diester was diluted with 120 mL of H2O and 18 g (320 mmol) of KOH was added. The orange reaction mixture was stirred at 90° C. for 1.5 h, and washed with 2×30 mL of ether. Decarboxylation was effected by adjusting the pH to 1 with concentrated HCl and warming to 90° C. for 45 minutes. The pH of the solution was monitored and additional HCl was added as needed to maintain the pH of the solution below 2. The two phase system was extracted with 3×75 mL of ether and the combined ether layers were washed with 25 mL of H2O, 25 mL of brine, dried over MgSO4 and concentrated leaving 12.3 g (73.8%) of a white solid which was not purified, but directly resolved into individual enantiomers.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1)[C:2]#[N:3].[NH2:23][OH:24]>CCO>[OH:24]/[N:23]=[C:2](\[NH2:3])/[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: NO
Reactant: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Solvent: CCO
Product: Cc1ccc(N/C(N)=N/O)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NH2OH (50 wt % in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1 H), 9.46 (dd, J=6.8, 0.8 Hz, 1 H), 8.54 (s, 1 H), 8.34 (s, 1 H), 7.76 (dd, J=7.2, 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.52-7.43 (m, 2 H), 7.18-7.06 (m, 2 H), 2.13 (s, 3 H). MS m/z 325.1 (M+1)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1ccc(C)cc1B(O)O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 70.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.10 mmol) was treated with (2-methoxy-5-methylphenyl)boronic acid (42 mg, 0.25 mmol), sodium carbonate (26 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (8 mg, 0.11 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 45 mg (70% yield) of the title compound. Purity 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19].I[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH2:26][CH2:27][CH3:28])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=[C:6]1[CH3:19]
Reactant: CCCI
Reactant: COC(=O)c1cc(C)c2nc(C)n(Cc3ccc(O)cc3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(Cn2c(C)nc3c(C)cc(C(=O)OC)nc32)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of methyl 3-(2-chloro-4-hydroxybenzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (500 mg), 1-iodopropane (295 mg), potassium carbonate (300 mg) and N,N-dimethylformamide (5.0 ml) was stirred at 60° C. for 3 hr. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed twice with water and once with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was powdered from diethyl ether to give methyl 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (490 mg) as a pale-yellow powder.
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][S:17][C:18](=[O:20])[CH3:19])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.C[Si](Cl)(C)C.[I-].[Na+].C(#N)C>O>[C:18]([S:17][CH2:16][CH:15]([CH3:21])[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:23])=[O:5])=[O:22])(=[O:20])[CH3:19]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCC1
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
N-(3-Acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester (80.1 g, 0.23 mol), trimethylsilyl chloride (37.9 g, 0.35 mol), and sodium iodide (52.5 g, 0.35 mol) were added to acetonitrile (300 ml), and the reaction mixture was stirred at 45° C.-50° C. for 30 minutes. Water (50 ml) was then added and the mixture was concentrated. The residue was dissolved in saturated aqueous sodium bicarbonate (400 ml) and was washed with ethyl acetate (3×400 ml). The aqueous portion was separated, acidified (conc. hydrochloric acid), and extracted with ethyl acetate. The organic extracts were combined, dried over Na2SO4 and MgSO4, filtered and concentrated yielding the crude desired product as a brown oil (60 g, 90%). When this material was eluted through a high pressure liquid chromatography column with ethyl acetate/hexane/acetic acid (60:40:2) a slightly yellow oil was obtained. This compound was characterized as its DCHA salt which was prepared by adjusting to pH 9 an acetonitrile solution of the compound with DCHA. The salt was obtained as a white crystalline solid, m.p, 172°-174° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)NC(=O)C1CCC(O)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CC(C)NC(=O)C1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from 4-hydroxy-N-isopropylcyclohexanecarboxamide (Example 45c) and 2-amino-6-fluorobenzonitrile as an off-white solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.47-1.57 (m, 4H), 1.67-1.77 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 1H), 3.75-3.84 (m, 1H), 4.57 (brs, 1H), 5.93 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([O:20]C)=[O:19])=[O:10])=[C:7]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>O1CCCC1>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([OH:20])=[O:19])=[O:10])=[C:7]([O:24][CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnccc1NC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2C(=O)Nc2ccncc2C(=O)O)CC1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a stirring solution of methyl 4-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzoylamino]pyridine-3-carboxylate (0.192 g, 0.376 mmol) in tetrahydrofuran (4 mL) was added water (1 mL), followed by a 1 M solution of LiOH in water (0.4 mL, 0.4 mmol). After stirring overnight, the solution was partially concentrated in vacuo and then diluted with water and washed with diethyl ether. The pH of the aq phase was then adjusted to 4-5 by the addition of citric acid. The resulting precipitate was dried in vacuo to give the title compound (0.15 g, 80%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:12]1[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[C:11]1=[O:22]
Reactant: CN1N=C(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1N=C(c2ccccc2)C2(CCCNC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of a racemic mixture of 3-Methyl-4-oxo-1-phenyl-2,3,7-triaza-spiro[4.5]dec-1-ene-7-carboxylic acid tert-butyl ester (110 mg, 0.32 mmol) in DCM (5 ml) was added TFA (0.5 ml). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was applied to a 1 g SCX-2 cartridge. The impurities were eluted with 1:1 DCM:MeOH, followed by 0.05M ammonia in 1:1 DCM:MeOH. The product was eluted with 1M ammonia in 1:1 DCM:MeOH and the clean fractions were concentrated in vacuo to afford the title compound. No further purification was performed on the title compound.