Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.O.[Si:9]([O:16][C@@H:17]1[C@@H:22]([O:23][CH3:24])[C@@H:21]([CH3:25])[CH2:20][O:19][C@H:18]1[CH2:26][O:27][Si](C(C)(C)C)(C)C)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1>[C:12]([Si:9]([CH3:11])([CH3:10])[O:16][C@@H:17]1[C@@H:22]([O:23][CH3:24])[C@@H:21]([CH3:25])[CH2:20][O:19][C@H:18]1[CH2:26][OH:27])([CH3:13])([CH3:15])[CH3:14]
Reactant: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)OC[C@@H]1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)OC[C@@H]1C
Temperature: 5 °C
Reaction time: 0.42 h
Yield: 82.6 %

Procedure:
A mixture of trifluoroacetic acid (3.28 ml) and water (6.43 ml) was added to a vigorously, stirred solution of (2S,3R,4S,5S)-3-(tert-butyldimethylsilyloxy)-2-[(tert-butyldimethylsilyloxy)methyl]-4-methoxy-5-methyltetrahydro-2H-pyran (1.0 g, 2.48 mmole) in dry THF (6.43 ml) at 5° C. After vigorous stirring for 25 min at 5° C., the reaction mixture was carefully quenched by the addition of cold saturated aqueous sodium bicarbonate (30 ml). The resulting emulsion was partitioned between ether (50 ml) and water (50 ml). The ether layer was washed with water (20 ml×2), dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using AcOEt:n-hexane (2:8) as an eluent to give (2S,3R,4S,5S)-[3-(tert-butyldimethyl-silyloxy)-4-methoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol (0.595 g, 83% yield) as a colorless oil; EI-MS: m/z 290 (M+); 1H-NMR (CDCl3)d: 0.87 (9H,s), 0.97 (3H,d,J=7 Hz), 1.92 (1H,br.s), 2.2 (1H,m), 3.14 (2H,m), 3.28 (3H,s), 3.56 (1H,t,J=9 Hz), 3.57 (1H,dd,J=3 & 11.5 Hz), 3.65 (1H,br,dd,J=6 & 11 Hz), 3.78 (1H,dd,J=2 & 11.5 Hz), 3.84 (1H,br.dd,J=2 & 11 Hz).
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1>C(O)C.C(OCC)C.[Pd]>[CH3:12][S:9]([NH:8][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:36])[CH2:20][N:21]([CH2:23][CH2:24][N:25]2[N:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:35])[CH3:22])=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
N-[2-(4-{N-Benzylmethanesulphonamido}phenyl)-2-hydroxyethyl]-N-methyl-2-(phthalazin-1-on-2yl)ethylamine (0.4 g--as solvate from part D) in ethanol (50 ml) containing 5% Pd/C (0.1 g) was stirred under a hydrogen atmosphere (50 p.s.i.) at 50° for 18 hours. The reaction mixture was then filtered and the ethanol removed. The residue was dissolved in methylene chloride and washed three times with sodium bicarbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). The appropriate fractions were combined and evaporated to give an oil which solidified after stirring for 14 hours in diethyl ether, filtration giving the title compound, 0.11 g, m.p. 134°-137°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.CCN(CC)CC.[CH3:41][C:42](OC(C)=O)=[O:43]>CN(C1C=CN=CC=1)C.C1COCC1>[C:42]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:43])[CH3:41]
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 0.462 g, 1 mmol), DMAP (0.012 g, 0.1 mmol), and Et3N (0.1 g, 1.05 mmol) in 50 ml of THF, was added Ac2O (0.204 g, 2 mmol). The reaction mixture was stirred at room temperature overnight. The yellow solid precipitated was filtered and redissolved in 50% ethanol in water (50 mL). The clear solution was then adjusted to pH1, and the solid formed was filtered and washed with water to give 0.31 g (62%) the title compound as a red solid, mp 218–220° C. 1H-NMR (300 MHz, DMSO-d6) δ 12.26 (br, 1H), 11.15 (s, 1H), 8.32 (s, 1H), 8.25 (d, J=8 Hz, 2H), 8.04–8.09 (m, 3H), 7.83 (d, J=15 Hz, 1H), 7.49 (d, J=7 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.02–7.07 (m, 1H), 6.93–6.97(m, 2H), 6.82 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.94 (s, 3H). HRMS (EI) Calcd for C27H24N2O6S: 504.1335 ([M]+); Found: 504.1365.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]1[CH2:25][C:26](O)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:30]([CH3:33])C=O.C(N)CCN.O[N:40]1[C:44]2C=CC=C[C:43]=2[N:42]=[N:41]1>O.ClCCCl>[N:40]([CH2:44][CH2:43][CH2:33][NH:30][C:26](=[O:27])[CH2:25][CH:12]1[CH:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[N+:41]=[N-:42]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CC(=O)O
Reactant: On1nnc2ccccc21
Agent: NCCCN
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCCN(C(=O)OCc2ccccc2)C1CC(=O)NCCCN=[N+]=[N-]

Procedure:
The compound 25 (784 mg), dimethylformamide (8 mL), propane-1,3-diamine (300 mg), 1-hydroxybenzotriazole (297 mg) and 1,2-dichloroethane (575 mg) were stirred at room temperature for overnight. The reaction solution was added water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=66:34→0:100) to obtain the title compound (797 mg) having the following physical properties.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15](C)[CH:14]=3)[CH2:9]2)[CH:4]=1>C(O)C.[Pd]>[ClH:1].[Cl-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH2:4]1
Reactant: Cc1cc(N2CCC(n3cc[n+](C)c3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: C[NH+]1C=CN(C2CCN(c3ccc(N)cc3)C2)C1
Product: Cl

Procedure:
3.2 g (0.01 mole) of derivative (4) in 300 ml of ethanol were hydrogenated in the presence of palladium on charcoal under hydrogen pressure of 9 bars. The catalyst was removed by filtration. The derivative (5) was isolated under chloride form.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:10][CH:9]1[NH:11][C:12]([C:14]1[S:39][C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][C@H:31]3[CH2:34][C@H:33]([NH:35][C:36](=[O:38])[CH3:37])[CH2:32]3)[C:16]=2[C:15]=1[CH3:40])=[O:13])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:10][CH:9]1[NH:11][C:12]([C:14]1[S:39][C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[O:30][C@H:31]3[CH2:32][C@H:33]([NH:35][C:36](=[O:38])[CH3:37])[CH2:34]3)[C:16]=2[C:15]=1[CH3:40])=[O:13]
Reactant: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NC4CC4NC(=O)OC(C)(C)C)c(C)c23)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@H]1C[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NC4CC4N)c(C)c23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.15 g [2-({4-[2-(trans-3-acetylamino-cyclobutoxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carbonyl}amino)-cyclopropyl]-carbamic acid tert-butyl ester in 5 ml dioxane was added 1 M hydrochloric acid solution in Dioxan and was stirred at rt overnight. The reaction mixture was concentrated and the residue was purified by chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].I[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5 mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir at room temperatue for 30 minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to room temperature and stir overnight at room temperature. Cool to 5° C., quench by addition of ice and saturated ammonium chloride solution (5 mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve the residue in ethyl acetate (150 mL), wash the organic phase with water (3×40 mL), dry (Na2SO4), filter and concentrate to afford a yellow oil. Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60% ethyl acetate in hexane. Concentrate the appropriate fractions in vacuo and dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>[Fe]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCC(=O)O)cc1
Agent: [Fe]
Product: CC(C)c1ccc(CCC(=O)CCc2ccc(C(C)C)cc2)cc1
Temperature: 290 °C

Procedure:
3-(4-Isopropylphenyl)propionic acid (0.20 mole) and iron (hydrogen reduced, 6.15 g., 0.11 mole) are heated for 1.5 hours at 195° C. under a nitrogen atmosphere. After that time, the temperature is increased to 290° C. and maintained at that temperature for 3 hours. The cooled reaction mass is extracted well with ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under vacuum to leave the product, 17.3 g. (51%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][OH:14].CCCCCC.C(OCC)(=O)C>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:13][OH:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=O)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: Cc1cccc(C#CC=NO)c1
Yield: 85 %

Procedure:
130 mg of the resulting aldehyde was dissolved in 20 ml of ethanol, and 5 ml of an aqueous solution of 70 mg of hydroxylamine hydrochloride was added. The solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography column: Lobar column, size A, Lichroprep Si 60 (E. Merck Co.); eluting solvent: hexane/ethyl acetate=-10/1] to give 122 mg (yield 85%) of 3-(3-methylphenyl)-2-propynaldehyde oxime as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1cc(F)ccc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cc(F)ccc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,5-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[C@H:4]1[O:31][CH:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(OCC3C=CC=CC=3)=O)=[CH:12][CH:11]=2)[C@H:7]([O:32][C:33](=[O:35])[CH3:34])[C@@H:6]([O:36][C:37](=[O:39])[CH3:38])[C@@H:5]1[O:40][C:41](=[O:43])[CH3:42]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:44])[C@H:4]1[O:31][CH:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[CH:14][CH:15]=2)[C@H:7]([O:32][C:33](=[O:35])[CH3:34])[C@@H:6]([O:36][C:37](=[O:39])[CH3:38])[C@@H:5]1[O:40][C:41](=[O:43])[CH3:42]
Reactant: COC(=O)[C@H]1OC(Oc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1OC(Oc2ccc(CCCCN)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.3 %

Procedure:
Glucuronide 38 (1.5 g, 2.4 mmol) was dissolved in dry methanol (100 mL) and Pd/C (0.62 g, 5%) was added. The reaction mixture was stirred under hydrogen (1 atm) for 2.5 h at room temperature. After this time, the solution was passed through a pad of silica gel and the solvent was evaporated under reduced pressure to give amine 39 (0.94 g, 84%). 1H NMR (300 MHz, CDCl3) δ 1.46 (m, 2H), 1.60 (m, 2H), 2.08 (m, 9H), 2.58 (m, 2H), 2.72 (m, 2H), 3.63 (s, 3H), 4.14 (m, 1H), 5.10 (m, 1H), 5.34 (m, 3H), 6.90 (d, 2H), 7.12 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[C:4]=2[O:3]1.[C:20]([NH:22][C:23]([NH2:25])=[NH:24])#[N:21]>C(OCCOCCO)C>[NH2:25][C:23]1[N:22]=[C:20]([NH2:21])[C:16]2[CH2:17][CH:12]([CH2:11][C:10]3[C:4]4[O:3][C:2]([CH3:19])([CH3:1])[CH2:6][C:5]=4[CH:7]=[CH:8][CH:9]=3)[CH2:13][CH2:14][C:15]=2[N:24]=1
Reactant: CC1(C)Cc2cccc(CC3CCC(=O)CC3)c2O1
Reactant: N#CNC(=N)N
Solvent: CCOCCOCCO
Product: CC1(C)Cc2cccc(CC3CCc4nc(N)nc(N)c4C3)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.4 grams (0.013 mole) of 4-(2,3-dihydro-2,2-dimethylbenzofuran- 7-ylmethyl)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1.[C:23]1(=O)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]1.[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[O:28]=[C:25]1[CH2:26][CH2:27][C:23]([NH:1][C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:16])=[O:13])=[CH:10][C:5]=3[NH:4][N:3]=2)=[CH:24]1
Reactant: O=C1CCC(=O)C1
Reactant: C[C@@H](NC(=O)Nc1cc2[nH]nc(N)c2cn1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(NC3=CC(=O)CC3)c2cn1)c1ccccc1
Temperature: 150 °C
Yield: 4.6 %

Procedure:
A mixture of (R)-1-(3-amino-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (52.9 mg, 0.179 mmol), cyclopentane-1,3-dione (34.1 mg, 0.348 mmol) and MgSO4 (167.7 mg, 1.393 mmol) in toluene (2 ml) was heated in a sealed 5 ml microwave vial to 150° C. for 1 hr. LCMS shows formation of product. The mixture was poured directly onto silica gel and purified via flash chromatography (Biotage SNAP 10 g, 0-20% MeOH/DCM) to provide (R)-1-(3-((3-oxocyclopent-1-en-1-yl)amino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (3.11 mg, 8.26 μmol, 4.63% yield) as a yellow solid. MS ESI calc'd. For C20H21N6O2 [M+H]+ 377. found 377. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.39 (s, 1H), 8.99 (s, 1H), 8.87 (s, 1H), 7.77 (br s, 1H), 1.53 (s, 1H), 7.34 (m, 5H), 7.23 (s, 1H), 6.11 (br s, 1H), 4.86 (t, J=6.5 Hz, 1H), 3.32 (s, 3H, overlaps with H2O peak), 2.81 (s, 2H), 2.26 (s, 2H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][C:9]([C:11]([CH3:26])([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:16]([C:17](N)=[O:18])[C:15]=2[C:23]([NH2:25])=[O:24])[CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][C:9]([C:11]([CH3:12])([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:16]3[C:17]([NH:25][C:23](=[O:24])[C:15]=23)=[O:18])[CH3:26])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(Oc1cccc(C(N)=O)c1C(N)=O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: O
Product: CC(C)(Oc1cccc2c1C(=O)NC2=O)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
The reaction mixture is then poured into water slowly with stirring and a white solid forms which is filtered after 30 minutes. The precipitate is collected, dissolved in dichloromethane, washed with water, dried, filtered, and concentrated in vacuo to a small volume. The crystals that form are collected and dried over P2O5 in vacuo to yield 53.82 g. of (1-diphenylmethoxycarbonyl-1-methylethoxy)phthalamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>CN(C)C=O>[CH3:17][C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])[CH:7]=[CH:6][CH:5]=3)=[CH:9][N:10]=[C:11]2[CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Cc1ccn2c(-c3cccc(N)c3)cnc2c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2c(-c3cccc(Nc4ccccc4[N+](=O)[O-])c3)cnc2c1
Temperature: 120 °C
Yield: 10.3 %

Procedure:
3-(3-Aminophenyl)-7-methylimidazo[1,2-α]pyridine (1.0 g, 4.5 mmol) and 1-fluoro-2-nitrobenzene (0.55 ml, 5.2 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 ml) and heated at 120° C. for 2 days. The cooled reaction mixture was poured into water (25 ml), extracted with ethyl acetate (2×20 ml) and the combined organic phases dried over anhydrous magnesium sulphate and concentrated in vacuo. Purification by flash chromatography eluting with 5% methanol in dichloromethane gave the title compound as an orange oil (160 mg, 10%). 1H NMR (400 MHz, d4-methanol) δH 2.61 (3H, s), 6.89-6.93 (1H, m), 7.33-7.35 (1H, m), 7.40-7.42 (1H, m), 7.47-7.52 (2H, m), 7.55-7.57 (1H, m), 7.62-7.69 (2H, m), 7.74 (1H, s), 8.06 (1H, s), 8.24 (1H, d, J 7), 8.67 (1H, d, J 8); m/z (ES+) 345 (M++H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](OC(C)=O)[C@H:9]([O:16][C:17]([CH3:19])=[O:18])[C@@H:8]([O:20][C:21]([CH3:23])=[O:22])[C@@H:7]1[O:24][C@@H:25]1[O:30][C@H:29]([CH2:31][O:32][C:33]([CH3:35])=[O:34])[C@@H:28]([O:36][C:37]([CH3:39])=[O:38])[C@H:27]([O:40][C:41]([CH3:43])=[O:42])[C@H:26]1[O:44][C:45]([CH3:47])=[O:46])=[O:3].[BrH:48]>C(O)(=O)C>[CH3:35][C:33]([O:32][CH2:31][C@H:29]1[O:30][C@@H:25]([O:24][C@H:7]2[C@H:8]([O:20][C:21]([CH3:23])=[O:22])[C@@H:9]([O:16][C:17]([CH3:19])=[O:18])[C@@H:10]([Br:48])[O:11][C@@H:6]2[CH2:5][O:4][C:2]([CH3:1])=[O:3])[C@H:26]([O:44][C:45]([CH3:47])=[O:46])[C@@H:27]([O:40][C:41]([CH3:43])=[O:42])[C@@H:28]1[O:36][C:37]([CH3:39])=[O:38])=[O:34]
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
α-D-Cellobiosyl bromide heptaacetate was prepared form α-D-cellobiose octaacetate and hydrogen bromide in glacial acetic acid using a modified procedure of Freudenberg and Nagari1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:31]=[C:30]([O:38]C)[CH:29]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[N:31]=[C:30]([OH:38])[CH:29]=1
Reactant: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(C(F)(F)F)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)nc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
(S)-2-(1-((6-Amino-5-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.07 mmol) was dissolved in dichloromethane (1 ml). A solution of boron tribromide (1M in dichloromethane, 223 μl, 0.22 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. Further boron tribromide (1M in dichloromethane, 223 μl, 0.22 mmol) was added and the reaction mixture stirred at room temperature an extra night. The reaction mixture was then diluted with dichloromethane and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 8 mg (20% yield) of the title compound as a white solid. Purity 99%.
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:56])([F:55])[C:49]1([CH2:53][OH:54])[CH2:52][CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:54][CH2:53][C:49]2([C:48]([F:56])([F:55])[F:47])[CH2:52][CH2:51][CH2:50]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC1(C(F)(F)F)CCC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with (1-(trifluoromethyl)cyclobutyl)methanol, the title compound was obtained as a colorless solid (0.05 g, 12%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.38 (d, J=12.2 Hz, 1H), 4.41 (s, 2H), 2.88 (s, 6H), 2.38-2.26 (m, 2H), 2.19-2.08 (m, 3H), 2.02-1.91 (m, 1H); MS (ES−) m/z 431.1, 433.1 (M−1).
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)[C:3](=[O:7])C(O)=O.[OH-:18].[Na+].OO>>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:2]([CH3:1])[C:3]([OH:7])=[O:18])=[CH:9][CH:10]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: [OH-]
Reactant: CC(C)Cc1ccc(C(C)C(=O)C(=O)O)cc1
Agent: OO
Agent: [Na+]
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 78 %

Procedure:
The procedure of Example 5(ii) was repeated using 7.1 g. of 3-methyl-3-(4-isobutylphenyl)-pyruvic acid obtained in Example 7(i), 50 ml of aqueous 8% sodium hydroxide and 4.5 ml of 30% aqueous hydrogen peroxide. 4.9 g. of 2-(4-isobutylphenyl)-propionic acid was afforded. mp. 75.0°-76.5°C. Yield 78% (based on the theoretical).