Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: OC1CCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnn(C2CCOC2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-nitropyrazole (1 g, 8.8 mmol), 3-hydroxy-tetrahydrofuran (779 mg, 8.8 mmol) and triphenylphosphine (2.81 g, 10.56 mmol) in THF (30 mL) at 0° C. was added diisopropylazodicarboxylate (2.27 g, 1 mmol) dropwise and the reaction was allowed to warm to rt overnight. The reaction was concentrated and purified on SiO2 (30% EtOAc/heptane) to give 4-nitro-1-(tetrahydrofuran-3-yl)-1H-pyrazole as a clear oil. The oil was then dissolved in EtOH (30 mL) and hydrogenated via H-cube with 10% Pd/C at 30 psi H2 for 3 hrs. The solvent was removed and the residue was purified on SiO2 (1%-10% EtOH/EtOAc) to give the title compound (1.0 g, 42% yield) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10-2.21 (m, 1H), 2.22-2.35 (m, 1H), 3.72-3.85 (m, 4H), 3.85-3.96 (m, 2H), 4.76-4.85 (m, 1H), 6.93 (s, 1H), 7.05 (s, 1H). m/z (APCI+) for C7H11N3O 154.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[C:10]12([C:20]3[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=3[O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.C(OCC)(=O)C>[C:10]12([C:20]3[CH:21]=[C:22]([C:2]4[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=4)[CH:23]=[CH:24][C:25]=3[O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH2:11][CH:12]3[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]3)[CH2:19]1)[CH2:17]2
Reactant: O=Cc1ccc(Br)nc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cn2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 56989 %

Procedure:
A mixture of 6-bromopyridine-3-carboxaldehyde (15.00 g, 0.0806 mol), 3-adamantan-1-yl-4-t-butyldimethylsilanyloxyphenyl boronic acid (37.39 g, 0.09677 mmol) and sodium carbonate (1.719 g, 12.44 mmol) in 750 mL of toluene:EtOH (4:1) and 75 mL of water was degassed with argon for 30 minutes. Tetrakis(triphenyl-phosphine)palladium(0) (2.335 g, 0.00202 mmol, 0.025 eq) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ethyl acetate, 9:1) to give 24.689 g of 6-[3-(1-adamantyl)-4-t-butyldimethylsilanyloxyphenyl]-pyridin-3-carboxaldehyde (68%). 1H NMR (300 MHz; CDCl3): δ 0.39 (s, 6H), 1.06 (s, 9H), 1.79 (brs, 6H), [2.11 (brs), 2.19 (s), 9 H], 6.91 (d, J=8.4 Hz, 1H), 7.75–7.85 (m, 2H), 8.04 (d, J=2.1 Hz, 1H), 8.16 (dd, J1=8.4, J2=2.1 Hz, 1H), 9.06(d, J=2.1 Hz, 1H), 10.09 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28](C(OC(C)(C)C)=O)[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.Cl[C:53]1[S:54][C:55]2[CH:61]=[C:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:59]=[CH:58][C:56]=2[N:57]=1>ClCCl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([F:18])([F:16])[F:17])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:53]4[S:54][C:55]5[CH:61]=[C:60]([C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:59]=[CH:58][C:56]=5[N:57]=4)[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c([C@@H]3CCCC[C@H]3C(F)(F)F)noc1C1CC1)C2
Reactant: CCOC(=O)c1ccc2nc(Cl)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c([C@@H]5CCCC[C@H]5C(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (67 mg, 0.13 mmol) in dichloromethane (1 mL) was treated with TFA (500 μL) and stirred for 1 hr at rt. The reaction was concentrated in vacuo and then diluted with NMP (1 mL) and then treated with Hunig's base (110 μL, 0.67 mmol) followed by ethyl 2-chlorobenzo[d]thiazole-6-carboxylate (33 mg, 0.13 mmol). After heating overnight at 120° C., the reaction was poured into water and extracted with EtOAc. The organic phase was collected, dried (MgSO4), filtered, and concentrated. The crude residue was purified by chromatography (SiO2, linear gradient, 0-60%, EtOAc in Hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH2:7].[C:13]([CH2:21][C:22](OCC)=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:22](=[O:23])[CH2:21][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NCCOc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(CC(=O)c1ccccc1)NCCOc1ccc(Cl)cc1Cl
Temperature: 160 °C

Procedure:
To a solution of 2-(2,4-Dichloro-phenoxy)-ethylamine 29 (412 mg, 2.0 mmol) in toluene (1.5 mL) is added ethyl benzoylacetate 34 (384 mg, 2.0 mmol). The mixture is heated to 160° C. for 10 minutes in a microwave. The resulting mixture is concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford N-[2-(2,4-dichloro-phenoxy)-ethyl]-3-oxo-3-phenyl-propionamide 35 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.98 (d, J=7.2 Hz, 2H), 7.60-7.35 (m, 5H), 7.15 (dd, J=2.5 Hz, J=8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 4.10 (t, J=5.2 Hz, 2H), 3.98 (s, 2H), 3.76 (q, J=5.3 Hz, 2H). MS calculated for C17H16Cl2NO3 (M+H+) 352.0, found 352.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]=[C:17](N)[CH3:18])=[S:15])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24](=[O:27])[CH2:25]Br.CCN(CC)CC>C(O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[S:15][C:25]([C:24](=[O:27])[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[CH3:21])=[C:17]([CH3:18])[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CC(N)=NC(=S)NCCCCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1C(=O)c1sc(NCCCCCNC(=O)OC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.9 %

Procedure:
To a solution of 290 mg (0.96 mmol) {5-[3-(1-Amino-ethylidene)-thioureido]-pentyl}-carbamic acid tert-butyl ester in 5 ml ethanol was added 213 mg (1 mmol) o-Methylphenacyl bromide and 139 μl NEt3 and allowed to stir for 5 h at room temperature. Afterwards the mixture was directly applied to preparative HPLC on reversed phase eluting with an acetonitrile/water gradient. The evaporation of the product fractions yielded 180 mg (45%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH3:7])[O:5][CH:4]([CH3:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CO>C(O)C1C=CC=CC=1>[O:1]=[C:2]1[CH:6]([CH3:7])[O:5][CH:4]([CH3:8])[CH:3]1[C:9]([O:11][CH2:12][C:13]1[CH:7]=[CH:6][CH:2]=[CH:3][CH:4]=1)=[O:10]
Reactant: CCOC(=O)C1C(=O)C(C)OC1C
Solvent: OCc1ccccc1
Solvent: CO
Product: CC1OC(C)C(C(=O)OCc2ccccc2)C1=O
Yield: 168.7 %

Procedure:
40 g of 4-oxo-2,5-dimethyl-3-carboethoxytetrahydrofuran in 200 ml of benzyl alcohol are heated at 180°-200° C. The methanol formed is distilled off. The excess benzyl alcohol is distilled off under reduced pressure and the residue is fractionated. 45 g (corresponding to 78% of theory) of 4-oxo-2,5-dimethyl-3-carbobenzyloxytetrahydrofuran of boiling point 102° C/0.02 mm Hg and refractive index nD25 = 1.5070 are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)[nH]c(=O)c21
Solvent: O=C(O)C(F)(F)F
Product: CC#CCn1c(N2CCNCC2)nc2nc(Cl)[nH]c(=O)c21

Procedure:
8 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.45 mg of the title compound.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][C:6]2[C:11]3[N:12]([CH3:18])[N:13]=[C:14]([NH2:17])[C:15]=3[S:16][C:5]=2[CH:4]=1.Br.[OH-].[NH4+]>O>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][C:6]2[C:11]3[N:12]([CH3:18])[N:13]=[C:14]([NH2:17])[C:15]=3[S:16][C:5]=2[CH:4]=1
Reactant: COc1cc2sc3c(N)nn(C)c3c2cc1OC
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cn1nc(N)c2sc3cc(O)c(O)cc3c21

Procedure:
A solution of 0.1 mole of 6,7-dimethoxy-1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-amine in 300 ml. of 48% aqueous hydrobromic acid was refluxed for 3 hours. The warm reaction mixture was poured into 1 liter of water and the aqueous mixture was adjusted to pH 7 using concentrated ammonium hydroxide solution. The precipitate which formed was removed by filtration and recrystallized from N,N-dimethyl formamide/water to give 6,7-dihydroxy-1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-amine, m.p. 305°-307° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[CH2:27]([O:6][C:5](=[O:7])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=1)[CH2:3][CH:2]([CH3:21])[CH3:1])[CH3:28]
Reactant: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 83 %

Procedure:
To a solution of 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid (42.3 g, 139 mmol) in absolute ethanol (300 mL) was added concentrated sulfuric acid (95-98%, 9.0 mL) and the solution was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure; the residue was treated with a solution of sodium carbonate (5%, 300 mL) and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica-gel flash chromatography eluting with heptane/EtOAc (10:1) gave 4-methyl-2-(4-nitro-3-trifluoromethyl-phenyl)-pentanoic acid ethyl ester (38.4 g, 83%) as a yellowish oil: 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H, J=8.4 Hz), 7.82 (s, 1H), 7.74 (dd, 1H, J=8.4, 1.5 Hz), 4.18 (m, 2H), 3.83 (t, 1H, J=7.5 Hz), 2.06 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 0.97 (d, 3H, J=6.6 Hz), 0.96 (d, 3H, J=6.3 Hz); 13C NMR (75 MHz, CDCl3): δ 172.24, 146.83, 145.04, 132.40, 127.51 (q, J=5 Hz), 125.28, 123.80 (q, J=32 Hz), 121.78 (q, J=272 Hz), 61.45, 49.45, 42.65, 26.03, 22.41, 22.17, 14.10.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([NH2:21])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 50 °C
Yield: 61.5 %

Procedure:
7-Nitro-3,4-dihydro-2(1H)-naphthalenone (200 mg, 1.1 mmol) was combined with ammonium acetate (807 mg, 10.5 mmol), sodium cyanoborohydride (86 mg, 1.4 mmol) and MeOH (5 mL) and heated to 50° C. for 15 h. The reaction was cooled and concentrated under vacuum and the residue was partitioned between EtOAc and water. The organic layer was washed with 5% aqueous potassium carbonate, brine and dried over Na2SO4. The crude was concentrated under vacuum and purified by silica gel flash column chromatography (0-100% (90% DCM/9% MeOH/1% NH4OH)/DCM). Purification provided 130 mg (65%) of the desired amine as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 7.90-7.89 (m, 2H), 7.31 (d, J=8.5 Hz, 1H), 3.06-2.88 (m, 3H), 2.84-2.72 (m, 1H), 2.54-2.44 (m, 2H), 1.81 (d, J=35.2 Hz, 2H), 1.51-1.42 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N#N>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][C:6]=12
Reactant: C1CNCCN1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: N#N
Solvent: CCOC(C)=O
Product: Brc1cnn2ccc(N3CCNCC3)nc12
Temperature: 120 °C
Yield: 86.2 %

Procedure:
3-Bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (15.4 g, 66.2 mmol) and piperazine [110-85-0] (56.8 g, 659.5 mmol) were ground together in a mortar to an intimate mixture and transferred to a 250 mL round bottomed flask containing a magnetic stir bar. The flask was fitted to a reflux condenser, N2 blanketed, and the reaction pot immersed in an ambient temperature oil bath. While the neat solid mixture stirred, the bath was heated to 120° C. over 0.5 h and held at nominal temperature for a total of 2 h. The bath was removed and the molten reaction allowed to cool to approximately 75° C. Ethyl acetate was cautiously added down the condenser to dissolve the reaction product to prevent its setting up into a solid mass. The reaction solution was transferred to a separatory funnel, further diluted with ethyl acetate, and washed with water. The ethyl acetate extract was dried (MgSO4) and evaporated to obtain 16.1 g of clear yellow oil. The oil was crystallized from methanol to provide 15.8 g of light yellow crystalline powder in two crops, mp. 108-109° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51 (s, 1 H) 3.16-3.24 (m, 3 H) 3.38 (s, 1 H) 3.93-4.00 (m, 3 H) 6.85 (d, J=7.83 Hz, 1 H) 8.03 (s, 1 H) 8.78 (d, J=8.08 Hz, 1 H) 9.61 (br. s., 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 41.25, 42.16, 77.73, 97.78, 136.77, 144.01, 144.18, 155.53. LRMS (ESI) m/z 282.0/284.0 [(M+H)]+, calc'd for C10H12BrN5: 282.14.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Br:18])=[C:12]([O:19][CH3:20])[CH:11]=2)=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([Br:18])=[C:12]([O:19][CH3:20])[CH:11]=2)=[CH:4][N+:3]=1[O-:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1Br
Solvent: C1COCCO1
Product: COc1cc(Cc2c[n+]([O-])c(N)nc2N)cc(OC)c1Br
Reaction time: 0.08 h

Procedure:
3.4 G. of 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine were suspended in 40 ml. of dioxane and treated with 2.4 g. of 3-chloroperbenzoic acid with stirring. The temperature rose to 38° C. and, after 5 minutes (no more oxidizing agent was detectable), an additional 1.2 g. of 3-chloroperbenzoic acid were added. A clear solution resulted which, after stirring for 15 minutes, became cloudy. After 2 hours, the white precipitate was removed by filtration under vacuum, washed with a small amount of dioxane and recrystallized from ethanol, whereby there was obtained 2,4-diamino-5-(4-bromo-3,5-dimethoxybenzyl)-pyrimidine N1 -oxide of melting point 277°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.O.Cl.Cl.[NH2:40][CH2:41][C:42]1[NH:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=1>>[NH:43]1[C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=[C:42]1[CH2:41][NH:40][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NCc1nc2ccccc2[nH]1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nc3ccccc3[nH]2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-aminomethyl-benzimidazole dihydrochloride hydrate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:15][CH2:14]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) cooled the contents to about −10° C. then N-butyl lithium (1.6 M, 23 ml) was added drop wise under nitrogen atmosphere and maintain the same temperature for about 45 minutes and cooled to about −75° C. for about 15 minutes then 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (step 1, 5 g) in THF (30 ml) was added and stirred for about 30 minutes then increase the reaction temperature to −35° C. and stirred for about 45 minutes and again cooled to −75° C. then benzyl bromide (3.5 g in 20 ml THF) was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow colour liquid. 1H NMR (300 MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); 7.03-7.06 (m, 2H); 7.23-7.24 (m, 3H); ES Mass: 370 (100%) [M+Na].
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:15]=1)=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN2CCCCC2)nc1
Agent: Cl
Solvent: CO
Product: NCc1ccc(CN2CCCCC2)nc1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
Dissolve 3-(tert-butoxycarbonylamino-methyl)-6-(piperidin-1-ylmethyl)-pyridine (540 mg, 1.76 mmol) in methanol (10 mL) and cool to 0° C. Bubble hydrogen chloride through the vigorously stirred solution for 30 min. Concentrate in vacuo. Partition the residue between 3N aqueous NaOH (10 mL) and DCM (20 mL). Separate the two layers and extract the aqueous layer with DCM (2×20 mL). Wash the combined organic extracts with brine (20 mL). Dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a colorless oil (351 mg, 95%). MS (APCI+) m/z: 206 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[ClH:25].FC1C=C(N[C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:52])C=CC=1OC1C=CN=C2C=C(C(N3CCCC3)=O)SC=12>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:51]([NH:53][C:54](=[O:62])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:52])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Agent: Cl
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 15 %

Procedure:
Starting from the compound 219 (scheme 47) and following the procedure described above for the synthesis of compound 305a, title compound 305b was obtained in 15% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.07(s, 1H), 10.66(s, 1H), 8.67(d, 1H, J=5.5 Hz), 8.27(s, 1H), 7.85-7.80(m, 2H), 7.65(s, 1H), 7.51(t, 1H, J=8.6 Hz), 7.46(d, 1H), 7.34-7.28(m, 5H), 6.85(d, 1H, J=5.3 Hz), 4.03(s, 3H), 3.74(s, 2H). MS (m/z): 502.2(M+H) (found).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2.[OH:29][CH2:30][CH2:31][NH2:32]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH:32][CH2:31][CH2:30][OH:29])=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1
Reactant: NCCO
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(CNCCO)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-[7-(2-methyl-1H-Indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde (60 mg, 0.156 mmol) and 2-hydroxyethylamine (57 mg, 0.939 mmol) by a procedure analogous to example 82. RP18-HPLC RT: 4.078 minutes; API MS: 465.0 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH3:20])[CH2:3][NH:4][C:5]([C@@H:7]1[C@H:14]2[C@@H:10]([O:11][C:12]([CH3:16])([CH3:15])[O:13]2)[C@H:9]([O:17][CH3:18])[O:8]1)=[O:6].C(O)(=O)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>ClCCl>[CH3:18][O:17][C@H:9]1[C@@H:10]2[O:11][C:12]([CH3:16])([CH3:15])[O:13][C@H:14]2[C@@H:7]([C:5]([NH:4][CH2:3][C:2](=[O:1])[CH2:19][CH3:20])=[O:6])[O:8]1
Reactant: CCC(O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(=O)CNC(=O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 20 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of (3aR,4S,6R,6aR)-N-(2-hydroxybutyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carboxamide (3.81 g) in anhydrous dichloromethane (115 ml), containing powdered 4 Å molecular sieves (5.7 g) at 0° C., under nitrogen, were added acetic acid (2.59 ml) and potassium dichromate (7.93 g), portionwise. The reaction mixture was stirred at 0° C. for 15 min and at 20° C. for a further 2 h. The mixture was quenched with isopropanol (40 ml) and stirred for 30 min, silica gel (Merck 9385) (40 g) and ethyl acetate (100 ml) were added, and the mixture was stirred for a further 30 min. This mixture was filtered through ‘harborlite®’ filter aid and the filtrate concentrated in vacuo to give a crude product which was purified by flash column chromatography on silica gel, eluting with 2:1 ethyl acetate:cyclohexane to give the title compound (1.91 g)