Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1)[CH:13]=O.[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24](=[O:26])/[CH:25]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:17]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:10]([O:9][CH3:8])[CH:11]=1)[CH3:29]
Reactant: CCOC(C)=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a THF (15 mL) solution of sodium hydride (814 mg) triethylphosphonoacetic acid (4.1 mL) was added at 0° C., and the reaction solution was agitated at 0° C. for 30 minutes and at room temperature for 1 hour. After cooling the reaction solution at 0° C., the THF (5 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.0 g) synthesized in Example 1 was added dropwise to the reaction solution. The reaction solution was further agitated at 0° C. for 30 minutes and then at room temperature for 2 hours. Ethyl acetate and water was added to the reaction solution, and the organic layer was separated and washed with a saturated ammonium chloride solution. After drying with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By re-crystallizing the obtained solid using a mixed solution of hexane and ethyl acetate, the 4.55 g (86%) title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH:16]1[CH2:21][N:22]1[C:27](=[O:28])[C:26]([OH:29])=[C:25]2[C:30](=[O:42])[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:32][CH2:33][N:24]2[C:23]1=[O:43])C1C=CC=CC=1>C(O)C.[Pd]>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:31]2[CH2:32][CH2:33][N:24]3[C:23](=[O:43])[N:22]([CH2:21][CH:16]4[CH2:17][O:18][CH2:19][CH2:20][NH:15]4)[C:27](=[O:28])[C:26]([OH:29])=[C:25]3[C:30]2=[O:42])=[CH:40][CH:39]=1
Reactant: O=C1c2c(O)c(=O)n(CC3COCCN3Cc3ccccc3)c(=O)n2CCN1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2c(O)c(=O)n(CC3COCCN3)c(=O)n2CCN1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
7-[(4-Benzylmorpholin-3-yl)methyl]-2-(4-fluorobenzyl)-9-hydroxy-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione TFA salt (921 mg, 1.86 mmol, from Example 16) was dissolved in degassed ethanol (10 mL) under nitrogen and 10% palladium on carbon (92 mg) was added. The flask was evacuated and purged with hydrogen three times using a vacuum line and a hydrogen gas balloon. The reaction was stirred overnight under a hydrogen gas atmosphere. The reaction was filtered through a thin pad of celite, washing with degassed ethanol. The filtrate was concentrated to a yellow solid which was triturated with methanol. The solids were collected by vacuum filtration to give the desired product as a white powder. 1H NMR (400 MHz, d6 DMSO) δ 11.9 (s, 1H), 8.96 (bs, 2H), 7.39 (m, 2H), 7.22 (m, 2H), 4.72 (s, 2H), 4.13 (m, 1H), 3.84-4.02 (m, 5H), 3.52-3.70 (m, 5H), 3.27 (m, 1H), and 3.05 (m, 1H). HRMS (FT-ICR C19H21FN4O5+H)=405.1572; calculated 405.1569.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[S:35])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: Cc1cnn(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) was added 2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reaction mixture was stirred for 1 hr at room temperature, transferred onto a chromatography column and eluted with a gradient of gradient EtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was triturated with diethyl ether to afford title compound 258a (31 mg, 15% yield) as a white solid. Characterization of 258a is provided in the table 23.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>C(Cl)Cl>[CH:43]1([C:46]([N:23]2[CH2:22][CH2:21][CH:20]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:32]=[CH:33][CH:34]=[CH:35][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)=[O:19])[CH2:25][CH2:24]2)=[O:47])[CH2:45][CH2:44]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCNCC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ylmethanone (47 mg, 0.10 mmol) and NEt3 (27 μL, 0.20 mmol) in DCM (5 mL) was added cyclopropane carbonyl chloride (10 μL, 0.12 mmol) and the resulting mixture stirred at r.t. for 3 h. The reaction mixture was quenched with H2O and extracted with DCM. The combined organic phases were dried (MgSO4) and concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 30-70%) affording 864 (13 mg, 25%). LCMS (method I): RT 4.06 min, [M+H]+ 543.3. 1H NMR (CDCl3, 400 MHz): δ 8.07-8.06 (1 H, m), 7.89-7.82 (1 H, m), 7.40-7.30 (2 H, m), 4.70-4.56 (3 H, m), 4.39-4.28 (1 H, m), 4.13 (3 H, s), 3.93-3.90 (6 H, m), 3.52-3.27 (3 H, m), 2.94-2.80 (1 H, m), 2.08-1.97 (2 H, m), 1.97-1.57 (4 H, m), 1.50 (3 H, t, J=7.40 Hz), 1.04-0.98 (2 H, m), 0.79-0.78 (2 H, m)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:9][Mg]Br>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH3:9])=[CH:3][CH:2]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccncc1
Solvent: C1CCOC1
Product: CC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.9 %

Procedure:
4-Pyridinecarbaldehyde (1.00 ml, 10.5 mmol) in tetrahydrofuran (10 mL) was mixed with methylmagnesium bromide (0.97 M in tetrahydrofuran, 19.5 mL, 18.9 mmol) under cooling with ice and stirred at room temperature for 5 hours. After quenching by adding water under cooling with ice, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (283 mg, 22% yield).
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][C:4]1([CH3:9])[O:7][C:6](=[O:8])[CH2:5]1>O>[OH:7][C:4]([CH3:9])([CH3:3])[CH2:5][C:6]([O-:1])=[O:8].[Na+:2]
Reactant: CC1(C)CC(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)CC(=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium hydroxide (127.3 g; 3.15 mol) in water (1.5 l) was cooled to 0° C. Then, crude 4,4-dimethyloxetan-2-one (=β-isovalerolactone; 336.7 g; 3 mol; obtained by reacting ketene with acetone) was added dropwise in the course of approximately 2¼ h with vigorous stirring, with the temperature being kept from 1.5 to 2° C. The reaction mixture was stirred for a further 15 min at 0° C. and then heated for a further 40 min at 22° C. Then 415 g of water were distilled off at 300 mbar in the course of approximately 3 h. In this manner 1533 g of a solution containing approximately 27.5% by weight of sodium 3-hydroxy-3-methylbutyrate were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=O.Cl.[CH2:26](NCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1)[CH3:27].CN(C)CCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1.CN(C)CCCCC1C=CC(S(C2SC(S(N)(=O)=O)=CC=2)(=O)=O)=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:24])[CH:3]([CH2:26][CH3:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CCNCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reactant: CN(C)C(=O)Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CN(C)CCCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: CN(C)CCCc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(Cc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(4-dimethylcarbamoylmethylphenylsulfonyl)thiophene-2-sulfonamide (1.35 g) was dissolved in 30 ml of tetrahydrofuran under a nitrogen atmosphere. Borane tetrahydrofuran complex (8 ml of 1 molar solution) was added and the mixture was stirred at room temperature for 3 hours. Hydrochloric acid (20 ml of 6N) was then added cautiously and the mixture was heated on a steam bath, boiling off tetrahydrofuran. The acidic solution was cooled to room temperature and extracted with chloroform. The aqueous phase was separated and its pH adjusted to pH 8.5 before extracting it with ethyl acetate. The ethyl acetate phase was dried over sodium sulfate and concentrated under vacuum to give a residue of an oily solid. This was chromatographed on silica gel to give a pure product, m.p. 169°-172° C. N.M.R. (DMSO, d6) δ: 2.17 (6H, s), 2.50 (2H, T, J=6 Hz), 2.82 (2H, T, J=6 Hz), 7.55 (2H, d, J=9 Hz), 7.60 (1H, d, J=4 Hz), 7.87 (1H, d, J=4 Hz), 7.94 (2H, d, J=9 Hz), 8.04 (2H, broad s). Anal Calc'd for C14H18N2O4S3 : C, 44.90; H, 4.84; N, 7.48. Found: C, 44.54; H, 4.89; N, 7.60. The following compounds where also made by similar procedures: 5-[4-(2-ethylaminoethyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 174-177). 5-[4-(3-methylaminopropyl)phenylsulfonyl]thiophene-2-sulfonmide (m.p. 178°-179.5° C.), 5-[4-(3-dimethylaminopropyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 163°-164.5° C.), and 5-[4-(4-dimethylaminobutyl)phenylsulfonyl]thiophene-2-sulfonamide (m.p. 186°-189° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])[CH2:13][CH2:12]1.C(N)(C)(C)C>[Cu]I.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.CN(C=O)C>[OH:9][CH2:8][C:4]1[N:3]=[C:2]([C:21]#[C:20][CH2:19][CH2:18][C:17]([N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[O:22])[CH:7]=[CH:6][CH:5]=1
Reactant: OCc1cccc(Br)n1
Reactant: C#CCCC(=O)N1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CCC#Cc2cccc(CO)n2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a 50 mL round-bottom flask, 484 mg of 2-bromopyridine-6-methanol, 510 mg of 1-(4-methylpiperazin-1-yl)pent-4-yn-1-one, 20 mg of BHT, 162 mg of copper(I) iodide, 118 mg of tetrakis(triphenylphosphine)palladium (0), 375 mg of t-butylamine and 7.5 mL of DMF were added, and the mixture was stirred under argon atmosphere at 80° C. for 6 hours. The DMF was removed under reduced pressure, then saturated aqueous sodium bicarbonate was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=600:20:1) to give 540 mg of 5-(6-hydroxymethylpyridin-2-yl)-1-(4-methylpiperazin-1-yl)pent-4-yn-1-one as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>O>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: O
Product: C[C@H](O)c1ccccc1
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. Acetophenone (0.500 g; 0.004 moles) I(a) was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 24 hr at 15–20° C. Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (360 mg). Pure 1-phenyl-(1S)-ethan-1-ol II(a) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:14])([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])[C:4](=[O:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:22]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[O:22]([C:29]1[CH:30]=[C:31]([NH:32][CH2:11][CH2:10][C:9](=[O:12])[C:8]([N:5]2[C:4](=[O:15])[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:2]([CH3:1])[O:7][CH2:6]2)([CH3:13])[CH3:14])[CH:33]=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: C=CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CCNc2cccc(Oc3ccccc3)c2)CO1
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methylpent-1-en-3-one (50 mg), 3-phenoxyaniline (30 mg) and pyridine (0.2 ml) was heated at 40° C. for 1 hour then stirred overnight at 20° C. and at 40° C. for 4 hours. After evaporation the residue was purified by silica gel column chromatography eluting with isohexane/ethyl acetate to give 5-(3-phenoxyphenyl)amino-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpentan-3-one (Compound 1082, 69 mg), NMR 1.4(s,6H), 1.9(s,3H), 2.8(m,2H), 3.4(m,2H), 5.3(s,2H), 6.3-6.4(m,3H), 6.9-7.4(m,11H).
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([N+:29]([O-])=O)[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[H][H]>CO.[Pd]>[NH2:29][C:27]1[CH:28]=[C:23]([C:21]2[C:20]([CH3:34])=[CH:19][CH:18]=[C:17]([NH:16][C:14]([C:11]3([C:9]4[CH:8]=[CH:7][C:5]5[O:6][C:2]([F:1])([F:35])[O:3][C:4]=5[CH:10]=4)[CH2:12][CH2:13]3)=[O:15])[N:22]=2)[CH:24]=[N:25][C:26]=1[O:32][CH3:33]
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1N
Yield: 77.8 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-5′-nitro-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (71 mg, 0.15 mmol) in methanol (10 mL) was added Pd/C (15 mg, 0.015 mmol) The reaction was stirred at room temperature under a balloon of hydrogen for one hour before being filtered and evaporated to yield the product (53 mg, 77%). ESI-MS m/z calc. 454.15. found 455.1 (M+1)+. Retention time 1.75 minutes.
Reaction SMILES: [C:1](=O)([O-])[NH2:2].F[C:6](F)(F)C(O)=O.Cl.C([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])(OC(C)(C)C)=O>O1CCOCC1.CCOCC>[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:1](=[NH:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=N)NCCCCCCN
Reaction time: 8 h
Yield: 66 %

Procedure:
To a 0° C. stirred solution of 1.0 g (4.62 mmol) of N-Boc-1,6-diaminohexane in 30 ml ethanol was added 0.86 g (4.62 mmol) of intermediate B. After two hours the solution was concentrated, diluted with water (50 ml), and extracted with ether twice. The aqueous phase was freeze-dried to yield 0.9 g of white sticky solid tert-butyl N-(6-((acetimidoyl) amino)hexyl)carbamate intermediate. A suspension of the carbamate above (0.88 g, 3 mmol) in 15 ml dioxane and 7.5 ml trifluoroactic acid was treated with 10 ml (40 mmol) of 4N hydrochloric acid in dioxane solution with stirring overnight. The mixture was diluted with ether (50 ml) and the solids were isolated by filtration to provide 0.7 g N-(6-aminohexyl)acetamidine as a white solid (66% yield from N-Boc-1,6-diaminohexane). M.P.=163°-164° C. Mass spectrum (CI) 158.1 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (700 mg, 2.1 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (686 mg, 2.1 mmol) and methyliodide (299 mg, 0.13 mL, 2.1 mmol) and the resulting mixture stirred for 30 min. The resulting mixture was then evaporated and extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 2:3) afforded the title compound (354 mg, 49%) which was obtained as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:4]([CH3:6])=O.O.[NH3:14].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O>O1CCOCC1.C(O)C>[OH:1][N:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:4]([CH3:6])[N:14]=[C:19]1[C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: COc1ccccc1C=O
Reactant: CC(=O)C(=NO)c1cccnc1
Reactant: N
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1nc(C)c(-c2cccnc2)n1O
Temperature: 25 °C
Reaction time: 192 h

Procedure:
To a suspension of 1-hydroxyimino-1-(3-pyridyl)acetone (1.5 g) in a mixture of dioxane (30 ml) and ethanol (8 ml) were added conc. ammonia water (40 ml) and 2-methoxybenzaldehyde (1.24 g), and the mixture was stirred at ambient temperature for 8 days. After evaporation, the mixture was triturated with chloroform to give 1-hydroxy-2-(2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.65 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(#N)C.CCOCC>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)c1ccccc1
Reaction time: 24 h

Procedure:
A solution of 16.7 g (100 mmol) of ethyl bromoacetate, 10.7 g (100 mmol) of N-methylaniline, and 12.9 g (100 mmol) of N,N-diisopropylethylamine in 100 mL of acetonitrile was allowed to stand for 24 hr. and then diluted with 200 ml of ether. The amine salt was filtered and the filtrate concentrated, dissolved in 150 ml of CH2Cl2, washed with water, filtered through a plug of sodium sulfate/silica and distilled: 15.5 g (80%), b.p. 132°/12 mm.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:27])=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Reactant: N#Cc1cn[nH]c1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c(C#N)cnn23)ccc1F)S(C)(=O)=O
Yield: 71.1 %

Procedure:
A mixture of 0.036 g (0.33 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 81 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[N:6]=1.[CH3:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20](O)=[C:19]([CH3:25])[CH:18]=2)[N:13]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:10][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][C:20]2[C:19]([CH3:25])=[CH:18][C:17]([C:14]3[N:13]=[C:12]([CH3:11])[O:16][N:15]=3)=[CH:22][C:21]=2[CH3:23])[S:9][N:8]=1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Reactant: Cc1nsc(CCCO)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nsc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)n1
Temperature: 20 °C
Yield: 60.8 %

Procedure:
A mixture of 5-(3-hydroxypropyl)-3-methyl-1,2,4-thiadiazole (66 mg, 0.42 mmol), 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol (94 mg, 0.46 mmol), and DEAD (80 mg, 0.46 mmol) was dissolved in 5 mL of THF. To the above solution was added triphenylphosphine (120 mg, 0.46 mmol) at 0° C. and the mixture was allowed to warm to 20° C. overnight. The solvent was removed in vacuo, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride (3×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, from 1/6 to 1/4) followed by recrystallization from ethyl acetate/hexane to afford 88 mg (61%) of 3-methyl-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-1,2,4-thiadiazole, as a white crystalline solid, m.p. 67°-71° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Clc1nccc2ccccc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3nccc4ccccc34)CC2)cc1
Yield: 18.5 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (150 mg, 0.53 mmol) was reacted with 1-chloroisoquinoline (183 mg, 1.06 mmol), DIEA (0.37 ml, 2.12) and 1,4-dioxane (0.2 ml) at 185° C. to afford the title compound (40 mg), a white solid, in 18% yield.