Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K:1].[S:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)([OH:5])(=[O:4])=[O:3].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19].C(OC(=O)C)(=O)C>C(O)(=O)C>[S:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:16](=[O:21])[CH2:17][C:18](=[O:19])[NH:15][C:13]2=[O:14])=[CH:10][CH:11]=1)([OH:5])(=[O:4])=[O:3].[K:1]
Reactant: O=C(O)CC(=O)O
Reactant: NC(=O)Nc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(c2ccc(S(=O)(=O)O)cc2)C(=O)N1
Temperature: 95 °C
Yield: 91.1 %

Procedure:
A mixture of 29.9 g of N-(4-sulfophenyl)urea potassium salt, 15 g of malonic acid and 200 ml of glacial acetic acid was heated to 60° to 70° C with stirring and 300 ml of acetic anhydride was added dropwise to the mixture. After about 50 ml of the acetic anhydride had been added, the mixture dissolved. After all of the acetic anhydride (300 ml) was added, the temperature of the reaction solution increased to 95° C. The reaction solution was stirred for 4 hours and then condensed under reduced pressure so as to precipitate crystals. 700 ml of ethanol was added to the condensed solution and the crystals were completely precipitated. The precipitated crystals were collected by filtration, washed thoroughly with ethanol and dried by heating under reduced pressure to obtain 34.5 g of crystals. The obtained crystals were recrystallized using a 90% methanol aqueous solution and, thereby, 29.3 g of white crystals was obtained. Melting point: above 300° C. Elemental Analysis:
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1/[CH:4]=[N:5]/[S@@:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7].[CH3:20][Mg]Br.CCOC(C)=O.CCCCCCC>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:3]=1[C@@H:4]([NH:5][S@@:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[O:7])[CH3:20]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)(F)F)cc1F
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide (7.3 g, 24.7 mmol) in CH2Cl2 (247 mL) cooled to 0° C. (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol) in Et2O. Reaction mixture allowed to stir for 30 min at 0° C., then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0° C. then quenched with the slow addition of a saturated solution of NH4Cl. Aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 40 to 100%) provided (R)—N—((S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (4.68 g, 15.0 mmol, 61% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCL3) δ 1.22 (s, 9H) 1.60 (d, J=6.80 Hz, 3H) 3.38 (d, J=4.01 Hz, 1H) 4.87-4.97 (m, 1H) 7.33 (d, J=10.32 Hz, 1H) 7.39-7.45 (m, 1H) 7.49-7.55 (m, 1H). LCMS m/z 312.0 (M+H)+, Rt 0.92 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH:31]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (60.0 mg, 0.155 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (95.6 mg, 0.309 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), potassium carbonate (64.1 mg, 0.464 mmol) and 4:1 dioxane/H2O (10 mL) was heated to 90° C. for 2 h. The solution was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in dioxane, and 4M HCl in dioxane (1 mL) was added. The solution was heated to 40° C. for 2 h. The material was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.3 Hz, 3 H), 2.65-2.73 (m, 2 H), 3.45 (t, J=6.1 Hz, 2 H), 3.76-3.86 (m, 2 H), 5.28 (d, J=7.3 Hz, 1 H), 5.95 (dt, J=3.3, 1.7 Hz, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.34 (d, J=2.3 Hz, 1 H), 7.36-7.50 (m, 2 H), 8.26 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 390.00 (100) [MH+]. HPLC: tR=2.48 min (ZQ3, polar—5 min).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C(O)(=O)C.O>CCO>[CH:24]1([NH:27][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:26][CH2:25]1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NC1CC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=C(NC1CC1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 46.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.11 mmol) and cyclopropylamine (0.080 mL, 1.1 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.1 mL) and water (3 mL) were added. The resulting suspension was filtered and the solid isolated was dried under high vacuum to afford 17 mg of the title compound. MS: (+) m/z 336.00 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[N+:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[C-:18].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:18]=[N:17][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncoc1-c1cc(OC)c(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of ethyl isocyanoacetate and subsequently with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at room temperature for 48 hours. After distillation of the solvent, the residue is extracted with ethyl acetate/water. The crude product obtained after evaporation is chromatographed on a 20-fold amount of silica gel with ethyl acetate. After recrystallization from ethyl acetate/hexane there is obtained ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazolecarboxylate in the form of yellow crystals of m.p. 109°-110°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C@@H:6]1[CH2:10][O:9]C(C)(C)[O:7]1>C(O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][C@@H:6]([OH:7])[CH2:10][OH:9]
Reactant: COc1ccccc1C[C@@H]1COC(C)(C)O1
Solvent: CCO
Product: COc1ccccc1C[C@@H](O)CO
Reaction time: 2 h
Yield: 89.8 %

Procedure:
(R)-4-(2-methoxybenzyl)-2,2-dimethyl-1,3-dioxolane(2.2 g) was dissolved in ethanol (20 ml) and to 6N-aqueoushydrochloric acid solution was added and stirred for 2 hours atroom temperature. After evaporating ethanol in vacuo, water wasadded and extracted with ethyl acetate. After washing with aqueoussaturated sodium bicarbonate solution, it was dried over sodiumsulfate and evaporated in vacuo to give (R)-3-(2- methoxyphenyl)propane-1,2-diol (1.62 g).
Reaction SMILES: S(O)(=O)(=O)C.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](C3C=CC(CC(NCC4C=CC=CC=4)=O)=NC=3)=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.ClCCN1CCOCC1.[Br:47]C1C=CC(O)=CC=1>>[Br:47][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:9]2[CH2:10][CH2:11][O:6][CH2:7][CH2:8]2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Agent: CS(=O)(=O)O
Agent: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
In another aspect the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with methane sulfonic acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate.
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:42])[CH:37](Br)[CH:38]([CH3:40])[CH3:39])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:37]([CH:38]([CH3:40])[CH3:39])[C:36]([O:35][CH2:33][CH3:34])=[O:42])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(C(=O)OCC)C(C)C)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromo-3-methylbutyrate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained. 1H NMR (CDCl3): δ5.26-5.23 (d, 1H); 4.29-4.19 (q, 2H); 2.94-2.77 (m, 3H); 1.82-1.70 (m, 2H); 1.31-1.20 (m, 21H); 1.08-1.05 (d, 3H); 0.97-0.95 (d, 3H) and 0.90-0.85 (t, 3H) ppm.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6]>C(Cl)Cl>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24])[C:2]([C:3]#[C:4][C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:6])=[O:1]
Reactant: COCCOCCOC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Solvent: ClCCl
Product: COCCOCCOC(=O)C#CC(=O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 2 h

Procedure:
A solution of 8.5 g (23 mmol) of 2-(2-methoxyethoxy)-ethyl 4-hydroxy-4-(3,4,5-trimethoxyphenyl)-2-butynoate in 100 ml of methylene chloride was added dropwise at 0° to a suspension of 60 g (0.69 mol) of manqanese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 2 hours, filtered over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 700 g of silica gel (elution agent methylene chloride/ether 4:1) and subsequently crystallized from ether/hexane. There was obtained 2-(2-methoxyethoxy)ethyl 3-(3,4,5-trimethoxybenzoyl)propiolate of melting point 33°-34°.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.[Cu]I.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>[NH2:1][C:2]1[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 23c (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 23e.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]([CH3:17])[N:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:17][N:8]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1cc(-c2ccccn2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)O)cc1-c1ccccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 138.9 %

Procedure:
To a stirred solution of 1-methyl-5-pyridin-2-yl-1H-pyrazole-3-carboxylic acid ethyl ester (655 mg, 2.8 mmol) at r.t. in ethanol (6 ml) under an argon atmosphere was added 1 N NaOH (5.7 ml) in one portion. The mixture was stirred at r.t. for 5 hrs, neutralized by the addition of 1 N HCl and concentrated to leave a light brown solid. This was triturated in a mixture of Et2O (10 ml) and EtOH (1 ml). The suspension was stirred at r.t. for 2 h. The solids was collected by filtration, washed with Et2O and dried to give the title compound (0.79 g, 100% with 73% purity; impurity: NaCl) as light brown solid. MS: M=204.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[S:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:14])=[O:15]
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)N2CCOCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCOCC1
Temperature: 60 °C
Yield: 88.8 %

Procedure:
To methyl 4-methoxy-3-(morpholinosulfonyl)benzoate 41 (0.970 g, 3.08 mmol) was added NaOH (0.599 g, 15.0 mmol) (15 mL, 1 M in water) followed by methanol (10 mL). The reaction mixture was heated to 60° C. for 2 h and acidified with 1 M HCl. The organic phase was extracted with EtOAc (5×) and the combined extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated to yield 4-methoxy-3-(morpholinosulfonyl)benzoic acid 42 (0.824 g, 88.9% yield) as a white solid which was used without further purification. Mass spectrum: calculated for C12H15NO6S 301.1. found 302.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]O)[CH:20]=1)(=[O:17])[CH3:16]>>[C:15]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=1)(=[O:17])[CH3:16]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(=O)Oc1cccc(CO)c1
Product: CC(=O)Oc1cccc(COc2ccnn2-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 3-(hydroxymethyl)phenyl acetate according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.24 (3H, s), 5.17 (2H, s), 5.66 (1H, d, J=1.6 Hz), 7.01-7.03 (1H, m), 7.14 (1H, s), 7.20-7.22 (1H, m), 7.32-7.36 (2H, m), 7.49 (1H, d, J=1.6 Hz), 7.97 (1H, s), 8.63 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:27]1[C:35]2[CH2:34][CH2:33][CH2:32][C:31](=[O:36])[C:30]=2[CH:29]=[CH:28]1.[O-]CC.[Na+]>C(O)C>[OH:5][C:4]([C:7]([F:10])([F:8])[F:9])([CH2:3][C:2]([CH3:1])([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)[CH:13]=1)[CH3:11])[CH2:6][N:27]1[C:35]2[CH2:34][CH2:33][CH2:32][C:31](=[O:36])[C:30]=2[CH:29]=[CH:28]1
Reactant: O=C1CCCc2[nH]ccc21
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(-c2cncnc2)cc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 85 °C
Yield: 56.1 %

Procedure:
To a suspension of 5-{7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran-5-yl}pyrimidine (56.0 mg, 0.15 mmol) and 1,5,6,7-tetrahydroindol-4-one (41.6 mg, 0.31 mmol) in 1.0 mL of anhydrous ethanol was added sodium ethoxide solution (0.057 mL, 21 wt. % in ethanol). The reaction mixture was heated at 85° C. for 15 hours. After cooling to room temperature, the reaction mixture was concentrated onto silica gel (for dry loading) and purified by silica gel chromatography (eluted with 40% to 70% ethyl acetate-hexanes) to give 42.0 mg (55% yield) of the title compound as a white solid, m.p. 213° C.-214° C.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][CH2:50][N:49](C(OCC2C=CC=CC=2)=O)[CH2:48]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:63][CH3:64])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{5-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]pentyl}-1-piperidinecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:18]
Reactant: O=C=NCCCCBr
Reactant: COC(=O)c1cscc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1cscc1NC(=O)NCCCCBr

Procedure:
Methyl 4-aminothiophene-3-carboxylate was reacted with one equivalent of 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl] urea as a tan solid, mp 85°-86° C.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C(N([CH2:11][CH3:12])CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:5][CH:11]([CH2:12][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][O:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCC(COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
A solution of 18.1 ml of methanesulphonic acid in 45 ml of ethyl acetate was added dropwise within 2 hours under argon to a solution, cooled to 0-5° C., of 7.96 g of S-1,2,4-butanetriol and 33.5 ml of triethylamine in 90 ml of ethyl acetate. The white suspension was stirred at 0-5° C. for a further 2 hours and thereafter the suspension was filtered and the yellow filtrate was washed in succession with 75 ml of 1N hydrochloric acid, 75 ml of saturated NaHCO3 solution and 75ml of saturated NaCl solution. The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated. 21.79 g of yellow oil were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C(=O)c1ccc(C#N)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
The synthesis of the starting material, 3-tert-butoxycarbonyl-3,9-diaza-spiro[5.5]undecane, was accomplished as described in U.S. Pat. No. 5,451,578. This mateial (1.45 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. under an argon atmosphere. To this solution was added triethylamine (1.67 mL) and 4-dimethylaminopyridine (70 mg) followed by 4-cyanobenzoyl chloride (1.04 g). The mixture was stirred overnight as it warmed to rt. It was cooled to 0° C., and ice cold 1 M HCl (30 mL) was carefully added. The resulting mixture was washed with EtOAc (3×30 mL). Then washing the EtOAc with saturated NaHCO3 and brine followed by drying with MgSO4 and evaporation of the solvent under reduced pressure afforded the title compound (1.62 g, 74%) as a yellow foam. Chromatography on silica gel with hexanes/ethyl acetate (2:1) as eluant gave pure compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].C(=O)=O>O1CCOCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])[C:3]2[N:4]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:5]=1
Reactant: CC(C)CN
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc2c1Cl
Agent: O=C=O
Solvent: C1COCCO1
Product: CC(C)CNc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(N3CCOCC3)cnc12
Temperature: 25 °C

Procedure:
In a sealed tube, a solution of 8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile (30 mg, 0.074 mmol) and isobutylamine (0.044 mL, 0.44 mmol) in dioxane (1 mL) was heated at 110° C. for 14 h. The reaction mixture was cooled to RT, then frozen at −44° C. (dry ice) and lyophilized to give the crude 6-(2,4-dichloro-phenyl)-8-isobutylamino-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-carbonitrile intermediate. HPLC: AtRet=2.77.