Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[CH2:1]([Cl:26])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Arachidonic acid (2.0 g, 6.6 mmol) was dissolved in benzene (20 ml). To this solution, oxalyl chloride (5.4 ml, 7.9 mmol) was added and the mixture was stirred at room temperature in a nitrogen atmosphere for 2.5 hours. Subsequently, the mixture was concentrated under reduced pressure to obtain arachidonyl chloride as an oily product. Meanwhile, L-ascorbic acid (1.4 g, 7.9 mmol) was added to a mixture of N-methylpyrrolidone (15 ml) and 4N-HCl/dioxane (2.4 ml) and the mixture was chilled on ice. To this solution, the arachidonyl chloride in methylene chloride (approx. 2 ml) was added, and the mixture was stirred overnight while chilled on ice. Upon completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water (twice), was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant=methanol/methylene chloride (1% to 20% methanol gradient)) and was dried under reduced pressure to give the desired product as a paste (2.7 g, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:29])([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-].C1CCCCC=1>[Pd].CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([CH3:28])([CH3:29])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2cccc[n+]2[O-])c(F)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CC(C)O
Product: CCOC(=O)CC(C)(C)Cc1ccc(OCCCNc2ccccn2)c(F)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of the product of STEP 7 (640 mg, 1.6 mmol), 10% Pd/C (400 mg, 0.36 mmol), cyclohexene (4.0 ml, 39.5 mmol), and 2-propanol (20 ml) was heated at reflux for 6 h. The reaction was allowed to cool to room temperature. An additional 10% Pd/C (250 mg, 0.23 mmol) and cyclohexene (2.0 ml, 19.8 mmol) were added. After 18 h of refluxing, the reaction was cooled to room temperature, filtered through a short column of Celite®, and washed with 100 ml 2-propanol. The filtrate was concentrated to give 380 mg oil. The NMR spectra were consistent for the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[C:6]1[CH2:21][CH2:22][CH3:23].[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH:16]([OH:20])[CH:17]([CH3:18])[CH3:19])=[C:6]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1c(C(=O)C(C)C)c2ccc(C#N)cc2n1Cc1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(C(O)C(C)C)c2ccc(C#N)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.8 %

Procedure:
To a solution of 1-(2-chlorobenzyl)-3-isobutyryl-2-propylindole-6-carbonitrile (70 mg) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added sodium borohydride (21 mg) at 25° C. After stirred at 25° C. for 2 hours, the reaction mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized from diisopropyl ether to give 1-(2-chlorobenzyl)-3-(1-hydroxy-2-methylpropyl)-2-propylindole-6-carbonitrile (28 mg) as pale yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=3)[O:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCOc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCOc1cccc(CCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.5 %

Procedure:
To a solution of methyl 3-(3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)propanoate (155 mg) in MeOH (2.0 mL) was added 1M NaOH aqueous solution (0.482 mL) at ambient temperature and the mixture was stirred at ambient temperature for overnight. The mixture was acidified to pH=3 with 1M HCl aqueous solution and extracted with chloroform (4.0 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:MeOH=9:1) to afford 3-(3-{3-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]propyl}phenoxy)propanoic acid (27.8 mg) as white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].Br[CH:8]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9]1.Cl.[CH2:17]([OH:20])[CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][O:20][CH:8]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9]1
Reactant: BrC1Cc2ccccc21
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: OCCOC1Cc2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 56.1 g of potassium t-butoxide, 150 ml of ethylene glycol was dropwise added in a stream of nitrogen to dissolve potassium t-butoxide completely. To the solution, 45.3 g of 1-bromobenzocyclobutene (synthesized according to a method of DeCamp et al., J. Org. Chem., 1981, 46, 3918) was dropwise added. After the addition was completed, the mixture was heated to 80° C., and stirred for 8 hours. The mixture was cooled to room temperature, and poured into ice-cold water. After adjusting pH to 6 with hydrochloric acid, an organic phase was extracted with ethyl acetate. After the solvent was distilled away, the residue was purified in a silica gel chromatography to obtain 20.6 g of 1-(2′-hydroxyethoxy)-benzocyclobutene.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.F[C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2>CS(C)=O>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:15]2[C:16]([CH3:35])=[N:17][C:18]3[C:23](=[C:22]([C:25]4[NH:33][C:32]5[CH2:31][CH2:30][NH:29][C:28](=[O:34])[C:27]=5[CH:26]=4)[CH:21]=[CH:20][CH:19]=3)[N:24]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 85 °C
Yield: 32.7 %

Procedure:
Prepared according to Example 131 using (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (189 mg, 1.012 mmol) and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 100 mg, 0.337 mmol) in DMSO (1.5 mL) and heating to 85° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided (S)-tert-butyl-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)pyrrolidine-1-carboxylate (51 mg, 32.8%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.90-7.96 (1H, m) 7.63-7.69 (1H, m) 7.42 (1H, t, J=1.00 Hz) 7.11 (1H, s) 4.65-4.80 (1H, m) 3.87-4.03 (1H, m) 3.57-3.68 (3H, m) 3.49-3.55 (1H, m) 3.40-3.49 (1H, m) 2.94-3.03 (1H, m) 2.61 (3H, s) 2.35-2.49 (2H, m) 2.19-2.34 (1H, m) 1.45-1.54 (9H, m). m/z (ESI, +ve) 463.2 (M+H)+.
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11][CH2:10][O:9]1.[Cl:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.C(OCC)(=O)C.O>[Cl:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:24]=1[C:25]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][C:8]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][O:9]1)=[O:26]
Reactant: CCCOc1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)C1(Cc2ccc(OC)c(C[NH3+])c2)CCCO1
Agent: CCOP(=O)(C#N)OCC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)NCc2cc(CC3(C(=O)O)CCCO3)ccc2OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
To a solution of 0.091 g of methyl 2-[3-(ammoniomethyl)-4-methoxybenzyl]tetrahydro-2-furancarboxylate chloride and 0.074 g of 2-chloro-4-propoxybenzoic acid in 2.5 ml of N,N-dimethylformamide were added 0.119 μl of triethylamine and 0.119 μl of diethyl cyanophosphonate, and the mixture was stirred at room temperature for 4 hours. 10 ml of water and 10 ml of ethyl acetate were added, and the organic layer was evaporated. The residue was dissolved in 2.5 ml of ethanol, 0.3 ml of 5N sodium hydroxide was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and 5 ml of ethyl acetate, 2.5 ml of water and 0.5 ml of 5N hydrochloric acid were added. The organic layer was concentrated, and the residue was purified by HPLC, to give 0.081 g of the title compound as a white solid.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[C:32]([CH3:37])=[N:33][O:34][C:35]=4[CH3:36])[CH2:28][CH2:27][C:26]([C:38](O)=[O:39])=[CH:25][C:24]=3[CH:41]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:46][N:47]([CH2:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1)[CH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[C:32]([CH3:37])=[N:33][O:34][C:35]=4[CH3:36])[CH2:28][CH2:27][C:26]([C:38]([NH:59][C:58]4[CH:60]=[CH:61][C:55]([CH2:54][N:47]([CH3:46])[CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)=[CH:56][CH:57]=4)=[O:39])=[CH:25][C:24]=3[CH:41]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2c(C)noc2C)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2c(C)noc2C)cc1
Reaction time: 1 h
Yield: 22.8 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(3,5-dimethylisoxazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (140 mg) in tetrahydrofuran (1 ml). Then, thionyl chloride (102 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this mixture was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (75 mg) and triethylamine (690 mg) in tetrahydrofuran (25 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-1-[(3,5-dimethylisoxazol-4-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 71) (45 mg) as yellow amorphous.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][CH2:33][CH2:34][NH:35][C:36]([C:38]1[CH:39]=[C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:41](=[O:51])[N:42]2[C:47]=1[C:46]1[S:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43]2)=O>O1CCCC1>[O:32]1[CH2:33][CH2:34][N:35]=[C:36]1[C:38]1[CH:39]=[C:40]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:41](=[O:51])[N:42]2[C:47]=1[C:46]1[S:48][CH:49]=[CH:50][C:45]=1[CH2:44][CH2:43]2
Reactant: O=C(NCCO)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c(-c2ccccc2)cc(C2=NCCO2)c2n1CCc1ccsc1-2
Reaction time: 24 h

Procedure:
0.94 g of diethyl azodicarboxylate and 0.71 g of triphenylphosphine were added to a solution of 1.0 g of 4,5-dihydro-N-(2-hydroxyethyl) -8-phenyl-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxamide in 27 ml of tetrahydrofuran, whereupon the reaction mixture was stirred for 24 hours. The mixture was then evaporated in vacuo, the residue was treated with water and extracted three times with methylene chloride. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel with acetonitrile/diethyl ether (2:3). By recrystallization from dioxane, there was obtained 4,5-dihydro-10-(2-oxazolin-2-yl)-8 -phenyl-7H-thieno[2,3-a]quinolizin-7-one of m.p. 211°-212°.
Reaction SMILES: [CH:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+]>>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][C:9]([O:8][C:7]2[CH:20]=[CH:21][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:36][CH:37]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(Oc1ccc(C(C)C)cc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccc(C(C)C)cc1)C(=O)OCC
Yield: 90.1 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-(4-isopropylphenoxy)malonate (21.5 g), which is the product of Reference example 5(a), 4-benzyloxybenzyl chloride (19.7 g) and sodium hydride (55% suspension in oil, 3.53 g) and the reaction mixture was treated to afford the desired compound (32.3 g) as a syrup.
Reaction SMILES: O[CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH2:22].[OH-].[Li+:24]>>[OH:22][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13]([O-:15])=[O:14].[Li+:24]
Reactant: O
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]

Procedure:
A lithium hydroxystearate grease thickener was prepared by saponification of a mixture containing about 8% by weight of 12-hydroxystearic acid and 9% by weight of the glyceride thereof, with lithium hydroxide monohydrate (2.5%) in a mineral oil vehicle (about 76%) at about 177° C. and final pressure of about 110 psig in a closed contactor. All percentages were percentages by weight of the total weight of the thickener.
Reaction SMILES: [CH3:1][OH:2].CC1C=CC([S:10]([OH:13])(=[O:12])=[O:11])=CC=1.[CH:14]([Cl:17])([Cl:16])[Cl:15]>>[CH:14]([Cl:17])([Cl:16])[Cl:15].[CH3:1][OH:2].[S:10](=[O:11])(=[O:2])([OH:12])[OH:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)O
Reaction time: 72 h

Procedure:
A colorless solid (yield: 90.9%) was obtained through reaction conducted as in example 54 except that the reactants were replaced by the compound (123) prepared in example 23 (0.5 g), methanol (42.7 mL), chloroform (42.7 mL) and p-toluene sulfonate (4.43 g), the reaction temperature was lowered to room temperature and the reaction time was extended to 72 hours. 1H-NMR data showed that the product consisted of a compound (144) and the compound (123) (content of compound (144): 89.0 mol %).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12](=[O:25])[NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[CH2:16][CH2:15]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH2:10][CH2:11][C:12]([NH:13][C@H:14]1[CH2:19][CH2:18][C@@H:17]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])[CH2:16][CH2:15]1)=[O:25]
Reactant: CC(C)N(C)[C@H]1CC[C@@H](NC(=O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C)[C@H]1CC[C@@H](NC(=O)CN)CC1

Procedure:
Example 1 h, Step 4: cis-{[4-(Isopropyl-methyl-amino)-cyclohexylcarbamoyl]-methyl}-carbamic acid benzyl ester (1.86 g), methanol (20 mL), and 20% Pd(OH)2 (400 mg) were hydrogenated until completion by TLC on a Parr shaker at 50 psi. Filtration through fiberglass filter paper under nitrogen and removal of solvent in vacuo yielded 870 mg of cis-2-amino-N-[4-(isopropyl-methyl-amino)-cyclohexyl]-acetamide. MS found: (M+H)+=227.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[CH2:17][C:18]([OH:20])=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O.C(Cl)Cl.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[CH2:17][C:18]([O:20][CH3:3])=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=O)CC(=O)CC(=O)O)cc1OC
Reactant: C=[N+]=[N-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC(=O)CC(=O)c1ccc(OC)c(OC)c1
Yield: 56 %

Procedure:
To a cold (−20° C.) solution of 8.9 mL (63.7 mmol) of diisopropylamine in 100 mL of diethyl ether under argon was added 28.1 mL (63.7 mmol; 2.27 M solution in hexanes) of n-BuLi via syringe and the solution was stirred at 0° C. for 45 min. In a separated flask, 3.315 g (25.5 mmol) of freshly distilled ethyl acetoacetate and 50 mL of diethyl ether were added and the solution was cooled to −78° C. To it, the above LDA solution was added via cannula, then 3.84 mL (25.5 mmol) of N,N,N′,N′-tetramethylethylenediamine (TMEDA) (distilled from LiAlH4) was added via syringe, and the solution was stirred at 0° C. for 3 h. To this dianion solution, a solution of 5.0 g (25.5 mmol) of methyl 3,4-dimethoxybenzoate in 50 mL of diethyl ether was added via cannula and the reaction solution was warmed to room temperature and stirred for 40 h. The reaction mixture was filtered through fritted funnel, and the solid (desired product) was saved. The organic filtrate from the above filtration was washed with a solution of 50 mL of 1 N HCl and 50 mL of distilled water, and then with 80 mL of brine, dried (MgSO4), and concentrated to give the desired product, 5-(3,4-dimethoxy-phenyl)-3,5-dioxopentanoic acid. The solid obtained above was dissolved in 80 mL of distilled water and 10 mL of 1 N HCl solution, and washed twice with methylene chloride (100 mL each). The water layer was further acidified with 100 mL of 1 N HCl, extracted twice with methylene chloride (50 mL each). The combined methylene chloride extract was washed with 80 mL of brine, dried (MgSO4), concentrated to give the desired carboxylic acid [5-(3,4-dimethoxyphenyl)-3,5-dioxopentanoic acid]. This acid and the above acid from the filtrate were combined and dissolved in 50 mL of CH2Cl2, cooled over ice-water bath, and a solution of diazomethane in diethyl ether was added dropwise until the carboxylic acid was no longer present. The solution was concentrated on a rotary evaporator and dried under vacuum, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate as eluant to give 3.798 g (56% yield) of pure 13B. 1H NMR δ7.51 (dd, J=8.5 Hz, 2 Hz, 1 H, C5′ H, Ar), 7.45 (d, J=2 Hz, 1 H, C2′ H), 6.9 (d, J=8.5 Hz, 1 H, C6′ H), 6.24 (s, 1 H, ═CH of enol at C4&5), 3.95 (s, 6 H, 2 OMe on Ar ring), 3.77 (s, 3 H, MeO), 3.47 (s, 2 H, CH2); 13C NMR δ186.18 (s, C3 C═O), 184.05 (s, C5═C—O), 168.21 (s, C═O ester), 153.16 (s, C4′Ar), 149.07 (s, C3′Ar), 127.04 (s, Cl′Ar), 121.49 (d, C2′), 110.56 (d, C5′), 109.66 (d, C6′), 96.17 (d, C4═CH), 56.06 (q, OMe), 56.0 (q, OMe), 52.32 (q, OMe of ester), 44.89 (t, CH2); MS.FAB, m/z 281 (M+1), 280 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:24]1[N:32]=[C:31]([Cl:33])[C:30]([F:34])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]>C1COCC1>[Cl:33][C:31]1[C:30]([F:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([Si:8]([CH3:9])([CH3:11])[CH3:10])=[CH:7][C:2]=2[F:1])[N:32]=1
Reactant: C[Si](C)(C)c1ccc(N)c(F)c1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Nc2nc(Cl)c(F)cc2C(=O)O)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-trimethylsilanyl-phenylamine (19.2 g, 105 mmol) in anhydrous THF (50 mL) was added a solution of LHMDS (160 mL, 1 M in hexanes, 160 mmol) dropwise over 45 minutes under a nitrogen atmosphere. After 2 hours at −78° C., a solution of 2,6-dichloro-5-fluoro-nicotinic acid (10.5 g, 50 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at −78° C. for 1 hour then allowed to warm to ambient temperature. After 18 hours stirring at ambient temperature the reaction was quenched with water and adjusted to pH 2 by the addition of concentrated HCl. The solution was extracted with ethyl acetate and the organic layer was isolated, washed with water followed by brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was triturated with methanol and filtered to afford the title compound as a yellow solid (8.7 g, 49%). LCMS (method B): RT=4.92 min, [M+H]+=357.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[N:15][N:16]4[C:21](Cl)=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(N)CCCC1>[Cl:23][C:19]1[CH:20]=[C:21]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:16]2[N:15]=[C:14]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=1
Reactant: COc1ccc(-c2nn3c(Cl)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: NC1CCCC1
Product: COc1ccc(-c2nn3c(NC4CCCC4)cc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 154.6 %

Procedure:
N-Cyclopentyl-4-[5,7-dichloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (80 mg, 0.18 mmol) in cyclopentylamine was treated as described for Example 13 to give 70 mg (80%) of N-{4-[5-chloro-7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine as a solid. 1H NMR (CDCl3): δ 7.96 (d, 1H), 7.85 (s, 1H), 7.54 (d, 2H), 6.98 (d, 2H), 6.27 (d, 1H), 6.08 (d, 1H), 5.97 (d, 1H), 5.13 (d, 1h), 4.35 (m, 1H), 3.95 (m, 1H), 3.87 (s, 3H), 2.2–2.0 (m, 4H), 1.4–1.9 (m, 12H); MS m/z 503 (M+1).