Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:21]([O:23]CC)=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCO.[K+].[Br-]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc2c(OCc3ccccc3)cc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 13 (8.67 g, 26.2 mmol) in 260 mL of THF--CH3OH--H2O (3:1:1) was treated with LiOH--H2O (5.49 g, 131 mmol, 5 equiv) and the mixture was stirred at 25° C. for 25 h. The solution was acidified with the addition of 10% aqueous HCl (pH<1) and the product partially precipitated. The product was collected by filtration and the remaining aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford a combined 14 (7.94 g, 7.94 g theoretical, 100%): mp 235° C. (white powder, EtOH); 1H NMR (DMSO-d6, 400 MHz) δ8.73 (d, 1H, J=1.1 Hz), 8.34 (d, 1H, J=8.9 Hz), 8.32 (s, 1H), 7.88 (dd, 1H, J=1.5, 8.9 Hz), 7.63 (s, 1H), 7.57-7.34 (m, 5H), 5.38 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ167.3, 153.8, 136.6, 135.5, 132.3, 130.3, 128.6, 128.3, 128.1, 127.6, 126.4, 123.4, 121.9, 118.8, 110.0, 107.5, 70.0; IR (KBr) vmax 3000 (br), 2227, 1687, 1577, 1499, 1419, 1343, 1283, 1250, 1105, 996, 915, 836, 740 cm-1 ; FABHRMS (NBA) m/z 304.0964 (M+ +H, C19H13NO3 requires 304.0974).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:47])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[F:46])[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:31][C:30]1[S:29][C:28]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=2[F:46])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:47])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(-c3ccc(F)cc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(F)cc3F)sc2N)c1N1CCC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
To a stirred mixture of [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester (46.0 mg, 0.067 mmol) in anhydrous DCM (4.0 mL) at −10° C. under N2 was added dropwise 1.0 M boron tribromide in DCM (0.22 mL, 0.22 mmol, 3.3 eq.). The reaction mixture was stirred at ambient temperature for 4 h and then cooled to −20° C. Additional 1.0 M Boron tribromide in DCM (0.11 mL, 0.11 mmol, 1.65 eq.) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aq. NaHCO3 solution and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via reverse phase HPLC to afford 200 (12.7 mg, 42.1%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.33 (dd, J=15.5, 8.8 Hz, 1H), 7.47-7.36 (m, 4H), 7.29 (dd, J=11.6, 5.3 Hz, 1H), 3.66 (s, 3H), 3.26-3.14 (m, 3H), 3.14-3.05 (m, 3H), 2.03-1.89 (m, 2H), 1.88-1.77 (m, 1H), 1.76-1.56 (m, 3H); MS (ESI) m/z: 448.1 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CC#N>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:12]([O:14][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:11][CH2:10][CH2:9][C:8]=2[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.10 g, 3.74 mmol), NaI (841 mg, 5.61 mmol) and triethylamine (1.56 mL, 11.22 mmol) in CH3CN (15 mL), is added trimethylsilyl chloride (0.707 mL, 5.61 mmol) via syringe. The reaction mixture is stirred at room temperature for 15 h., 30 mL of ethyl acetate/hexanes (1:1 with a few drops of triethylamine) is added to dilute the solution. Saturated sodium bicarbonate solution (20 mL) is added. The layers are separated and the aqueous phase is extracted with ethyl acetate/hexanes (1:1) (3×10 mL). The combined organic layers are dried (Na2SO4) and evaporated to provide 4-trimethylsilanyloxy-6,7-dihydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1.3 g, 100%) as a viscous red oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]1[O:33]C(C)(C)[O:31][C:30](=O)[CH:29]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:30](=[O:31])[CH2:29][C:28]([C:24]1[S:25][CH:26]=[CH:27][C:23]=1[Cl:22])=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1sccc1Cl

Procedure:
Prepared from (2-amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G17) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) according to the general procedure K. Obtained as an amorphous brown solid (145 mg).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:19][CH:18]=1)[CH3:16].[OH-].[Na+]>CS(O)(=O)=O.CO>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][CH2:24][CH2:25][C:26]2=[O:28])[CH3:16]
Reactant: CCOC(=O)CCNc1ccc(CC)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Product: CCc1ccc2c(c1)C(=O)CCN2
Temperature: 25 °C
Yield: 28 %

Procedure:
A solution of phosphorus pentoxide (11.14 g) in methane sulfonic acid (114 mL) was heated to 130°. The mixture was stirred at 130° for one hour until all the phosphorus pentoxide had dissolved. The mixture was allowed to cool for 15 minutes, and ethyl N-(4-ethylphenyl)-beta-alaninate (11.14 g of mono and di-ester mixture) was added. The mixture was heated to 130° for 1.5 hours, and the mixture was allowed to cool to room temperature. The mixture was cooled in an ice bath, and 50% sodium hydroxide was added until the pH reached 8. The gummy dark solids were dissolved in MeOH, and added to the mixture. Solids began to crash out, so they were filtered off with celite. The liquids were combined, and were partitioned between dichloromethane and water, and the organics were extracted three times with dichloromethane. The combined organics were washed with brine, dried with sodium sulfate, filtered, and concentrated. The product was chromatographed using a 30% ethyl acetate in heptane solvent solution. 4.10 g of the title product were recovered. (28% yield through first two steps) MS (ESI+) for C11H13NO m/z 176.00 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([CH:34]([CH3:36])[CH3:35])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: COc1ccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)nc1C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)nc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (86 mg, 171 μmol) in dichloromethane (2.7 mL) was added trifluoroacetic acid (391 mg, 264 μL, 3.43 mmol) and stirred at room temperature for 16 h. The reaction mixture was then diluted with dichloromethane, concentrated in vacuo, and purified by chromatography (silica, 0 to 12% of a 99.5:0.5 methanol:NH4OH solution in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxamide (51 mg, 127 μmol, 74%) as a yellow solid. 1H NMR (400 MHz, METHANOL-d6) δ ppm 8.08 (s, 1H), 7.42 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 4.35 (m, 1H), 4.12 (dd, J=12.1, 3.4 Hz, 1H), 4.07 (d, J=12.6 Hz, 1H), 3.89 (s, 1H), 3.88 (s, 3H), 3.80 (d, J=12.8 Hz, 1H), 3.65 (m, 1H), 3.52 (m, 1H), 2.12 (m, 1H), 1.96 (d, J=13.1 Hz, 1H), 1.32 (d, J=5.8 Hz, 6H); MS (EI/CI) m/z: 402.3 [M+H].
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:48]1[C:56]2[C:51](=[CH:52][C:53](O)=[CH:54][CH:55]=2)[CH:50]=[N:49]1>O1CCCC1>[CH:1]1([O:6][C:53]2[CH:52]=[C:51]3[C:56](=[CH:55][CH:54]=2)[NH:48][N:49]=[CH:50]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc2[nH]ncc2cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
Cyclopentanol (0.068 ml, 0.745 mmol), triphenylphosphine (221 mg, 0.820 mmol) and dibenzyl azodicarboxylate (267 mg, 0.895 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was heated to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure and a 1M-aqueous sodium hydroxide solution (4 ml) and chloroform (3 ml) were added to the resulting residue. After removing the aqueous layer, water (2 ml) was added to the residue. The aqueous layer was removed and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol, hexane/ethyl acetate) to obtain 5-(cyclopentyloxy)-1H-indazole (24 mg, 16%).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:4]([OH:6])=[O:5].[H][H]>[Rh].O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH:2]([C:1]([OH:18])=[O:17])[CH2:16][CH:12]1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Product: O=C(O)C1CC(C(=O)O)C(C(=O)O)CC1C(=O)O
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A 5 L-capacity Hastelloy (HC22) autoclave was charged with 552 g of pyromellitic acid, 200 g of a catalyst prepared by supporting rhodium on activated carbon (available from N.E. Chemcat Corp.) and 1656 g of water, and while stirring the contents of the autoclave, an interior of the reaction vessel was replaced with a nitrogen gas. Then, the interior of the reaction vessel was replaced with a hydrogen gas until a hydrogen pressure in the reaction vessel reached 5.0 MPa and an inside temperature of the reaction vessel was raised up to 60° C. The contents of the autoclave were reacted for 2 hours while maintaining a hydrogen pressure in the autoclave at 5.0 MPa. The hydrogen gas in the reaction vessel was replaced with a nitrogen gas, and the obtained reaction solution was withdrawn from the autoclave. The thus obtained reaction solution was subjected to hot filtration to separate the catalyst therefrom. The resulting filtrate was concentrated by evaporating water therefrom under reduced pressure using a rotary evaporator to precipitate crystals, and the resulting slurry was subjected to solid-liquid separation at room temperature to separate the precipitated crystals therefrom. The thus obtained crystals were dried to obtain 481 g of 1,2,4,5-cyclohexane tetracarboxylic acid (yield: 85.0%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9](Cl)([CH3:11])[CH3:10].NC(N)=[S:18].C(O)C.[OH-].[Na+]>CCOCC.O>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][CH:5]([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([SH:18])([CH3:11])[CH3:10]
Reactant: COC(CC(C)CCCC(C)(C)Cl)OC
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: COC(CC(C)CCCC(C)(C)S)OC

Procedure:
A mixture of 10 g. of 1,1-dimethoxy-7-chloro-3,7-dimethyloctane, one equivalent of thiourea and 100 ml. of 95% ethanol is refluxed for about 24 hours. Then a solution of 1.5 equivalents of sodium hydroxide in 50 ml. of water is added and the mixture refluxed for about 2 hours. After cooling to about room temperature, the solution is carefully acidified and ether is added. The organic layer is separated, washed with water, dried over calcium sulfate and evaporated to give 1,1-dimethoxy-7-mercapto-3,7-dimethyloctane which is purified by distillation.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[C:5]([CH3:23])[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[C:5]([CH3:23])[NH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(C)c(CN3CC(c4cc(F)cc(F)c4F)CC3=O)c2C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1n[nH]c(C)c1CN1CC(c2cc(F)cc(F)c2F)CC1=O
Temperature: 85 °C
Yield: 14 %

Procedure:
In a 100 ml flask fitted with a magnetic stirrer and a reflux condenser under inert atmosphere, 1-({3,5-dimethyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-4-yl}methyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x61 (0.83 g, 1.7 mmol) is dissolved in THF (40 ml). A 1 M solution of tetrabutylammonium fluoride in THF (1.7 ml, 1.7 mmol) is added and the mixture is heated at 85° C. for 48 h. The solvent is evaporated and the residue is dissolved in water. The aqueous phase is extracted six times with diethylether and the combined organic phases are dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by preparative chromatography on silicagel and recrystallized from AcOEt to give 77 mg of 1-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 167.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]([NH2:15])=[O:14])[CH2:11][S:10][CH2:9]1)=O)(C)(C)C.[ClH:16].O1CCOCC1>>[ClH:16].[S:10]1[CH2:11][C@@H:12]([C:13]([NH2:15])=[O:14])[NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CSC[C@@H]1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(4S)-3(tert-Butyloxycarbonyl)thiazolidine-4-carboxamide (8.6 g, 37.1 mmol) was dissolved in 4M HCl/dioxan (50 ml). The mixture was stirred for 1 hour at room temperature then the solvent was evaporated in vacuo to give a white solid identified as (4R)-thiazolidinecarboxamide hydrochloride (6.2 g, 36.8 mmol, 99%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4C(O)=O)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C(Br)C(C1C=CC([C:48]2[NH:49][C:50]3N(CC4CCCCC4)C(=O)N(CC4CCCCC4)C(=O)[C:55]=3[N:56]=2)=CC=1)Br)C>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:23][CH:24]=[C:25](/[CH:11]=[CH:15]/[C:16]([N:49]5[CH:50]=[CH:55][N:56]=[CH:48]5)=[O:17])[CH:26]=4)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:9]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h

Procedure:
A slurry of (E)-4-[(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid (from part (a) of this example, 0.50 g) in anhydrous N,N-dimethylformamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-Carbonyldiimidazole (Aldrich, 0.211 g) was then added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned a bright yellow and thickened as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-[3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl]-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.32 g). A mixture of this sample (0.32 g), nonaethylene glycol monomethyl ether (from part (a) of example 10, 0.277 g) and anhydrous potassium carbonate (0.170 g) in acetonitrile (10 mL) was refluxed for 20 h. Chloroform (50 mL) was added and the solution was washed with 1N HCl, (20 mL). The organic layer was washed with brine, dried (magnesium sulfate), and eluted from a silica gel column with 10% methanol-chloroform. Evaporation of solvents left yellow waxy solid which was reprecipitated from ethyl acetate-hexanes. The yellow waxy solid precipitate was filtered and dried to (E)-4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid nonaethylene glycol methyl ether ester (0.355 g, 65%); 1H-NMR (DMSO-d6) δ: 8.24 (d, J=8.4, 2,2 CH), 8.06 (d, I=8.6, 2, 2 CH), 4.40 (m, 2, CH2O), 3.90 (d, J=7.3, 2, CH2N), 3.75 (m, 4, CH2N and CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.19 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])#[CH:12].N>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[N:8][CH:9]=2)[CH:12]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1ccc(F)cc1F
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)c(F)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.42 (m, 1H), 7.61 (ddd, J=11.5, 9.1, 2.4 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 8.08 (td, J=8.6, 6.5 Hz, 1H), 9.35 (s, 1H), 9.39 (s, 2H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCBr
Reactant: Oc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromo-3-methylbutane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 89°-92° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]4[CH:26]=[CH:25][S:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.C(OCC)C>[N:28]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:27])[CH:20]=[C:21]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccsc4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccsc3)c2O1
Temperature: 70 °C
Reaction time: 6 h
Yield: 83.4 %

Procedure:
To a solution of (±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.5 g, 10.69 mmol) in dimethylsulfoxide (150 mL) was added sodium azide (3.6 g, 55.38 mmol) and the reaction mixture was heated to 70° C. and allowed to stir for 6 h. The reaction mixture was cooled to room temperature and diluted with water (300 mL) and diethyl ether (200 mL). The aqueous layer was separated and extracted with diethyl ether (200 mL). The combined organic layers were washed with water (3×200 mL), saturated aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent removed in vacuo to afford 2.6 g (83%) of (±)-2-(azidomethyl)-5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran as a white solid. mp 50-52° C.; Anal. calcd. for C13H10ClN3OS: C, 53.52; H, 3.45; N, 14.40. Found: C, 53.50; H, 3.33; N, 14.26.
Reaction SMILES: [C]=O.Cl[C:4]1[C:5]2[N:6]([C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[N:11][N:12]=2)[CH:7]=[CH:8][N:9]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CO.CS(C)=O>[C:22]([O:21][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:6]3[CH:7]=[CH:8][N:9]=[C:4]([C:20]([O:21][CH3:22])=[O:26])[C:5]3=[N:12][N:11]=2)=[CH:14][CH:15]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(Cl)nccn23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1nccn2c(-c3ccc(NC(=O)OC(C)(C)C)cc3)nnc12
Temperature: 75 °C
Yield: 27 %

Procedure:
Carbon monoxide gas was charged into a pressure bottle containing a mixture of tert-butyl 4-(8-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)phenylcarbamate (61C) (714 mg, 2.065 mmol), Pd(OAc)2 (185 mg, 0.826 mmol), dppp (341 mg, 0.826 mmol), Et3N (1.15 mL, 8.26 mmol), DMSO (12 mL) and MeOH (6 mL) until the pressure reached to 30 psi. The bottle was then sealed and heated at 75° C. for 4 h. After cooling to room temperature, the reaction was diluted with EtOAc, washed with water (3×), saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge eluting with a gradient of EtOAc in hexanes to afford 103 mg (17%) of the title compound. HPLC/MS (Method C): retention time=1.72 min, [M+H]+=370.4; 1H NMR (500 MHz, DMSO-d6): δ 9.75 (s, 1H), 8.78 (d, J=4.95 Hz, 1H), 8.04 (d, J=4.95 Hz, 1H), 7.86 (d, J=8.80 Hz, 2H), 7.73 (d, J=8.80 Hz, 2H), 4.02 (s, 3H), 1.47 (s, 9H).