Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.[Cl:37]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:37][C:2]1[N:1]=[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6]3[N:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:26][CH2:27][CH2:28]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3cnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of tert-butyl {1-[4-(9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (5.00 g, 10 mmol) and N-chlorosuccinimide (1.39 g, 10 mmol) in chloroform (100 mL) was heated to refluxed temperature for 22 hours. After cooling to room temperature the solvent was evaporated in vacuo. The crude product was purified by silica gel chromatography (hexane/ethyl acetate; 0-100% ethyl acetate over 60 min) to give a yellow solid (75%). 1HNMR (CDCl3) 400 MHz δ: 8.06 (dd, J=5.0, 1.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.32 (td, J=7.7, 1.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.12 (td, J=7.6, 0.92 Hz, 1H), 6.94 (dd, J=8.3, 0.92 Hz, 1H) 6.88 (d, J=8.3 Hz, 1H), 6.66 (dd, J=7.8, 4.6 Hz, 1H), 6.30 (s, 1H), 5.10 (s, 1H), 2.59-2.38 (m, 4H), 2.19-2.07 (m, 1H), 1.95-1.83 (m, 1H), 1.48-1.21 (m, 9H); LC/MS [M+H]: 514.
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:7])[CH3:8])[CH2:14][CH2:13]1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: OC1CCNCC1
Product: CC(C)C(=O)CC(=O)N1CCC(O)CC1
Yield: 94.8 %

Procedure:
0.351 mol (49.6 ml) of 4-methyl-3-oxovaleric acid methyl ester and 0.369 mol (37.3 g) of 4-hydroxypiperidine were stirred for 6 h at 120° C. in a Dean-Stark apparatus. 12 ml of methanol were collected. Subsequently, the excess starting materials were distilled off for 3 h on a rotary evaporator (80° C. water bath, 2 mbar). 71 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>C(COC)OC.O>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[F:12])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(Br)c1F
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccc(N)cc2)c1F
Temperature: 85 °C

Procedure:
To a solution of Example 223A (3.1 g, 13 mmol) in dimethoxyethane (25 mL) was added (4-aminophenyl)boronic acid (2.77 g, 16 mmol) and Na2CO3 (3.38 g, 31.2 mmol) in water (6 mL) followed by 1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride:dichloromethane:complex (652 mg, 0.8 mmol). The mixture was heated to 85° C. for 10 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water followed by brine then dried over magnesium sulfate. After filtration and concentration, the crude product was purified by flash chromatography (1%-100% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][NH:42][C:2]3[N:3]([C:13]4[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=4[N:19]=3)[C@@H:4]3[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]3[OH:6])=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(OCc4ccccc4)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture of a 8-bromoadenosine (0.130 g), 3′-benzyloxy-biphenyl-4-ylmethylamine (0.326 g) and N,N-diisopropyl-ethylamine (0.262 mL) in 1-propanol (3.8 mL) was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=12/1) to give the title compound (0.120 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([O:13][C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=O)=[CH:2]1.O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:13])=[CH:2]1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)maleic anhydride (100 mg, 0.3 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (10 mL) and water (10 mL) was added benzylamine (0.13 mL, 1.2 mmol), and the whole was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF, and the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 2,3-bis(1H-indol-3-yl)-N-benzylmaleimide (110 mg, 86.6%) as red solids.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=5)[C:19]([CH3:30])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:30])=[C:20]([C:22]5[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)ccn1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1-c1cc[nH]c(=O)c1
Temperature: 60 °C
Yield: 36.1 %

Procedure:
To 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (42 mg, 0.1 mmol) in chloroform (2 mL) was added iodotrimethylsilane (63 mg, 0.3 mmol). The reaction mixture was heated to 60° C. for one hour. The reaction was evaporated to dryness and the residue was dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography. The resulting trifluoroacetic acid salt was dissolved in dichloromethane (5 mL) and washed with a saturated sodium bicarbonate solution (5 mL). The organics were dried over sodium sulfate and evaporated to dryness to yield the product (14 mg, 36%) ESI-MS m/z calc. 387.43. found 388.5 (M+1)+. Retention time 1.41 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.19 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.40-7.37 (m, 2H), 7.26-7.24 (m, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.28 (m, 1H), 6.18-6.15 (m, 1H), 4.55 (t, J=8.7 Hz, 2H), 3.19 (t, J=8.6 Hz, 2H), 2.22 (s, 3H), 1.49-1.47 (m, 2H), 1.11-1.09 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([O:37]C(=O)C6C=CC([N+]([O-])=O)=CC=6)[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:23][CH:22]=3)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50]>C(Cl)Cl>[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[OH:55][C:49]([C:51]([F:54])([F:53])[F:52])=[O:50].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[C:28]5[C@H:35]([CH3:36])[CH2:34][C@@H:33]([OH:37])[C:29]=5[N:30]=[CH:31][N:32]=4)=[CH:25][CH:26]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCN(C(=O)OC(C)(C)C)CC4)cc3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C4(c5ccc(Cl)cc5)CCNCC4)cc3)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
tert-Butyl 4-(4-chlorophenyl)-4-(4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperidine-1-carboxylate (36 mg, 0.069 mmol) was dissolved in DCM (3 mL) and cooled to 0° C. Then TFA (1.5 mL) was added dropwise. The resulting solution was stirred at 0° C. for 1 hour, concentrated under reduced pressure, dissolved in DMF (1 mL) and purified by reverse phase HPLC (0-100% AcCN/H2O) to give (5R,7R)-4-(4-(4-(4-chlorophenyl)piperidin-4-yl)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol di-TFA salt (9 mg, 31% yield). 1H NMR (DMSO-d6, 400 MHz) δ 9.09 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.4 Hz, 2 H), 7.42 (q, J=4.8 Hz, 4H), 5.64 (d, J=6.0 Hz, 1H), 5.06 (q, J=6.8 Hz, 1H), 3.85 (br s, 1H), 3.05 (br s, 3H), 2.89 (m, 2H), 2.61 (br s, 3H), 2.11 (m, 2H), 1.16 (t, J=6.4 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H). LCMS: M+1 420.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.248 g (0.00121 mol) of 1-benzyl-4-hydroxymethyl-piperidine was dissolved in 5 ml of toluene and treated with 0.2 ml (0.00145 mol) of triethylamine and 0.155 ml (0.00133 mol) of benzoyl chloride. The mixture was boiled at reflux for 18 hrs., the solvent was distilled off and the residue was taken up in ether. The organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. It was concentrated and the residue was chromato-graphed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.2 g (53%) of 1-benzylpiperidin-4-ylmethyl benzoate was obtained as a yellow oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 18), 308 (17), 232 (14), 204 (41), 159 (18.6), 105 (25.5), 91 (100).
Reaction SMILES: [H-].[Na+].C1(C(Br)CCCl)C=CC=CC=1.FC(F)(F)C1C=CC(O)=CC=1.C1(C(Cl)(OC2C=CC(C(F)(F)F)=CC=2)CC)C=CC=CC=1.[C:46]1([CH:52]=[CH:53][CH2:54][O:55][C:56]2[CH:61]=[CH:60][C:59](C(F)(F)F)=[CH:58][CH:57]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Na].C1(O)C=CC=CC=1.C1(C(Br)CCOC(=O)C)C=CC=CC=1>CS(C)=O>[C:46]1([CH:52]=[CH:53][CH2:54][O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: FC(F)(F)c1ccc(OCC=Cc2ccccc2)cc1
Agent: CC(=O)OCCC(Br)c1ccccc1
Agent: CCC(Cl)(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: ClCCC(Br)c1ccccc1
Solvent: CS(C)=O
Solvent: Oc1ccccc1
Product: C(=Cc1ccccc1)COc1ccccc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Eight grams of sodium hydride were added slowly to a stirred mixture containing 72 g. of 1-phenyl-1-bromo-3-chloropropane and 50 g. of p-trifluoromethylphenol in 600 ml. of dimethylsulfoxide. The reaction temperature was maintained at about 30° C. with external cooling. After all the sodium hydride had been added, the reaction mixture was stirred overnight at room temperature and was then extracted with hexane. The hexane extract was separated, washed with water and dried. The hexane was removed by evaporation in vacuo. The residual oil distilled at about 110° C. at 1 torr. to give a mixture of 1-phenyl-1-(p-trifluoromethylphenoxy)propylchloride and 1-phenyl-3-(p-trifluoromethylphenoxy)-1-propene (see Sliwa et al, Bull. Soc. Chem. France, 1972, 1540 for the production of a similar compound by the reaction of the sodium salt of phenol and 1-phenyl-1-bromo-3-acetoxypropane to yield 1-phenyl-3-phenoxy-1-propene). The distillate was dissolved in a 1:1 hexane/ethyl acetate solvent mixture and the solution cooled. 1-Phenyl-3-(p-trifluoromethylphenoxy)-1-propene solidified and was separated by filtration from the propylchloride product which was an oil. About a 50% yield of the propene compound was obtained. Recrystallization from acetonitrile yielded crystalline 1-phenyl-3-(p-trifluoromethylphenoxy)-1-propene melting at 92°-94° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH:18]=1)[C:14](OC)=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>ClCCl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:19])=[C:13]([CH2:14][OH:15])[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1CO
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of methyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-methylbenzoate (step 2, 810 mg, 2.89 mmol) in dichloromethane (15 mL) was added a 0.95 M solution of diisobutylaluminum hydride in hexane (6.69 mL, 6.35 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h. The reaction was quenched by addition of water (6.7 mL) at −78° C. The mixture was diluted with dichloromethane (50 mL) and hexane (50 mL), and the mixture was stirred at room temperature for 16 h. The mixture was dried over magnesium sulfate, concentrated to afford 724 mg (99%) of the title compound as a colorless oil:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:11][C:12](OCC1C=CC=CC=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:12][NH:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(NC1CCc2ccccc2C1)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CCc2ccccc2C1
Yield: 112.3 %

Procedure:
7.43 g (26.4 mmol) of phenylmethyl 1,2,3,4-tetrahydronaphthalene-2-carbamate were added in portions to a suspension of 4.5 g (26.4 mmol) of lithium aluminium hydride in 200 ml of tetrahydrofuran and the mixture was heated to reflux for 3 h 30, allowed to cool, and hydrolysed with an excess of aqueous 1N sodium hydroxide solution, the mixture was filtered and concentrated, and the residue was distilled at about 80 Pa between 140 and 240° C. 4.78 g of impure oil were obtained, which was utilised in its impure state in the following step.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH3:28])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)O
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2cc(-c3ccccc3)nn2C)cn1

Procedure:
With a procedure similar to example 16 above, 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid (made by hydrolysis of the corresponding commercially available ethyl ester) and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C20H23N5O2 (m/e) 365, obsd 366 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([NH:14]C(OCC1C=CC=CC=1)=O)(=[O:13])=[O:12])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)C1CCCCN1S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCCN1S(N)(=O)=O
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-2-piperidinecarboxylic acid methyl ester (29.8 g) in methanol (300 ml) under nitrogen was cooled to 0° C. and 1.8 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 2 hours at 55 psi. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (35-40% ethyl acetate/hexane) to afford 17 g (46%) of N-(aminosulfonyl)-2-piperidinecarboxylic acid methyl ester (Formula VII: R=CH3 ; R1 =H; R2 and R3 together=--(CH2)4 --) as a solid, m.p. 72°-74° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][C@@:11]1([NH:30]C(=O)OC(C)(C)C)[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1)([O:6]CC)=[O:5])C.Br[Si](C)(C)C.O.CCCCC>ClCCl>[NH2:30][C@:11]1([CH2:10][CH2:9][P:4](=[O:3])([OH:6])[OH:5])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](CCP(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Solvent: CCCCC
Product: CCCCCCCCc1ccc([C@H]2CC[C@](N)(CCP(=O)(O)O)C2)cc1
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Tert-butyl (1R,3S)-1-(2-(diethoxyphosphoryl)ethyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.236 g, 0.439 mmol) was dissolved in dichloromethane (4.39 ml) under nitrogen to give a colorless solution. Bromotrimethylsilane (0.569 ml, 4.39 mmol) (Aldrich) was added and the reaction stirred for about 4 h. Solvents were removed under reduced pressure. Methanol (4 mL) and water (0.2 mL) were added and the solution was stirred for about 16 h. Solvents were removed under reduced pressure to give a brown oil/solid. Water was added and the solution sonicated while scraping the sides of the vial. The solution was stirred with a stir bar for about 1 h. The resulting solid was collected by vacuum filtration and washed with water and then pentane to provide 2-((1R,3S)-1-amino-3-(4-octylphenyl)cyclopentyl)ethylphosphonic acid (0.150 g, 0.393 mmol, 90% yield) as a off-white solid on drying under vacuum at 60° C.: LC/MS (method a) Rt=3.15 min.; MS m/z: 382.27 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[Na].Cl[C:17]1[C:18]([N+:34]([O-:36])=[O:35])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=[CH:20]2>C1COCC1>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[CH:10]=[CH:9][C:8]=1[O:11][C:17]1[C:18]([N+:34]([O-:36])=[O:35])=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[N:21]=[CH:20]2
Reactant: C[Si](C)(C)CCOCn1ncc2c([N+](=O)[O-])c(Cl)ccc21
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Oc2ccc3c(cnn3COCC[Si](C)(C)C)c2[N+](=O)[O-])c(OC)c1

Procedure:
To methyl-3-methoxy-4-hydroxyphenylacetate (0.062 g, 0.32 mmol) in dry THF (5 mL) under nitrogen was added sodium hexamethyldisylazide (1M solution in THF) (312 μl, 0.31 mmol). After 10 min. stirring at room temperature 5-chloro-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (93 mg, 0.28 mmol) in 5 mL of THF was added. The resulting mixture was stirred at reflux for 5 days. After that time the mixture was quenched with water and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The desired product was isolated by chromatography (10% ethyl acetate/hexane). 1H NMR (400 MHz) (CDCl3) δ 8.40 (s, 1H); 7.70 (d, J=9.1 Hz, 1H); 7.05 (d, J=9.1 Hz, 1H); 6.95 (m, 2H), 6.84 (dd, J=1.5, 8.0 Hz, 1H); 5.75 (s, 2H); 3.82 (s, 3H), 3.62, s, 3H); 3.62 (s, 2H); 3.57 (t, J=8.0 Hz, 2H); 0.89 (t, J=8.0 Hz, 2H); 0.0 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1>CN1C(=O)CCC1>[CH3:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][N:24]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(N)ccc1O
Reactant: Clc1ncccc1-c1ccncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Temperature: 100 °C

Procedure:
To 4-amino-2-methyl-phenol (193 mg, 1.57 mmol) was added Cs2CO3 (1.02 g, 3.14 mmol) and NMP (2.0 mL). The mixture was heated for 5 minutes at 100° C., cooled to RT and 4-(2-chloro-pyridin-3-yl)-pyrimidine (300 mg, 1.57 mmol) was added. The mixture was heated in the microwave to 210° C. for 20 minutes, cooled, filtered through a plug of cotton and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield 3-methyl-4-(3-pyrimidin-4-yl-pyridin-2-yloxy)-phenylamine. MS m/z=279 [M+1]+. Calc'd for C16H14N4O: 278.32.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[CH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].N.[ClH:13]>[Ni].C(O)C>[ClH:13].[NH2:9][CH2:8][C:7]1[C:6](=[O:10])[CH:5]=[C:4]([CH3:11])[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(=O)c(C#N)c(C)[nH]1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Product: Cc1cc(=O)c(CN)c(C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A 250 mL Erlenmeyer flask was charged with 2,6-dimethyl-4-oxo-1,4-dihydropyridine-3-carbonitrile (360 mg, 2.430 mmol) and cold 2 M ammonia in EtOH (39.5 mL, 79 mmol). Ethanol (40 mL) was added to solubilize the remaining reactant. The solution was passed through a Raney Ni cartridge on a continuous flow hydrogenation reactor (40 psi, 40° C., 1 mL/min) for 16 h. The reaction solvent was removed in vacuo and the residue was dissolved in EtOH (1 mL) and CHCl3 (15 mL), then concentrated in vacuo. The residue was dissolved and concentrated in CHCl3 (2×15 mL) and DCM (15 mL). The sticky residue was suspended in diethyl ether (30 mL) and treated with 4 M HCl in 1,4-dioxanes (10.63 mL, 42.5 mmol). The suspension was stirred at room temperature overnight, at which time the white solid was collected via vacuum filtration, washed with diethyl ether (10 mL), and dried under high vacuum to give 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one hydrochloride (200 mg, 0.975 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.26 (br. s., 1H), 3.90 (br. s., 2H), 2.64 (s, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 1.22-1.30 (m, 2H). MS(ES) [M+H]+ 152.9.