Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>O>[CH:35]([C:4]1[CH:3]=[CH:2][C:1]([N:7]([C:14]2[C:24]3[C:25]4[C:17]([CH2:18][CH2:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
32.14 g (0.1 mol) of the above prepared 5-(N,N-diphenylamino)acenaphthene was dissolved in 300 ml of N,N-dimethylformamide, and 22.73 g (0.15 mol) of phosphorus oxychloride was dropwise added thereto at room temperature for 30 minutes. After raising the temperature to 50° C., the reaction mixture was stirred for 14 hours. The reaction was determined to be finished when disappearance of 5-(N,N-diphenylamino)acenaphthene was identified. The reaction product was poured into an aqueous solution having 45 g (1.05 mol) of 93% sodium hydroxide dissolved in 1000 ml of water. The resultant mixture was cooled to precipitate a crystal, and the crystal was filtrated, washed with water and dried to obtain 30.27 g (yield: 86.6%, melting point: 138.0°-141.0° C.) of 5-[N-(4-formylphenyl)-N-phenylamino]acenaphthene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15]OS(C)(=O)=O)[CH2:12][CH2:11][N:10]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[F:8].[F-:31].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][F:31])[CH2:12][CH2:11][N:10]2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [F-]
Reactant: CS(=O)(=O)OC[C@H]1CCN(C(=O)OCc2ccccc2)[C@@H](c2ccc(F)c(F)c2)C1
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@H](CF)C[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A mixture of (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (200 mg, 0.46 mmol), and cesium fluoride (190 mg, 1.3 mmol) in dimethyl sulfoxide (2 mL) was stirred at 100° C. for 18 hours. The reaction mixture was cooled and purified directly by silica gel chromatography (5% to 25% ethyl acetate in hexanes gradient) to give (±)-phenylmethyl (2R,4S)-2-(3,4-difluorophenyl)-4-(fluoromethyl)piperidine-1-carboxylate (85 mg, 51% yield). MS (EI) for C20H20F3NO2: 364 (MH+).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][C:6]1=[O:19])C.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[Na+].[Na+].NC1N=CC2C(=O)CC(C3C=CC(Cl)=CC=3)CC=2N=1>>[NH2:23][C:22]1[N:24]=[CH:4][C:5]2[C:6](=[O:19])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:9][C:10]=2[N:21]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1C(=O)CC(c2ccccc2F)CC1=O
Agent: Cl
Agent: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: O=C([O-])[O-]
Product: Nc1ncc2c(n1)CC(c1ccccc1F)CC2=O

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (919 mg, 3.53 mmol) from stage 1, guanidine hydrochloride (673 mg, 7.04 mmol) and sodium carbonate (1.12 g, 10.59 mmol), following the procedure described for the synthesis of 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2) except that the mixture was heated at reflux for 16 h.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N[C:22](=NO)[C:23]1C=CC(CN(C)CC(OC(C)(C)C)=O)=C(Br)C=1.C(B1OC(C)(C)C(C)(C)O1)=C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.O>[C:19]([C:17]1[CH:16]=[CH:15][C:3]([CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:2]([CH:22]=[CH2:23])[CH:18]=1)#[N:20]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Br
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Br
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of tert-butyl N-(2-bromo-4-cyanobenzyl)-N-methylglycinate (Intermediate 33 Step 1, 658 mg, 1.94 mmol), vinyl boronic acid pinacol ester (597 mg, 3.88 mmol), K2CO3 (536 mg, 3.88 mmol) and tetrakis-triphenylphosphine palladium(0) (224 mg, 0.19 mmol) was prepared in a mixture of dioxane/water (5:1; 6 mL) and heated at 100° C. for 18 hours. The reaction mixture was diluted with DCM/water and separated. The organic phase was passed through a hydrophobic frit and the solvents evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound (508 mg, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.77 (1H, s), 7.58-7.43 (2H, m), 7.13 (1H, dd, J=17.4, 11.0 Hz), 5.69 (1H, d, J=17.4 Hz), 5.42 (1H, d, J=11.0 Hz), 3.80 (2H, s), 3.18 (2H, s), 2.36 (3H, s), 1.50 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.C([O-])=O.[NH4+]>[Pd]>[CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[N:5]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1nc(N2CCOCC2)nc(C)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: Cc1nc(N2CCOCC2)nc(C)c1N
Temperature: 150 °C
Yield: 84.3 %

Procedure:
The suspension of 4-(4,6-dimethyl-5-nitropyrimidin-2-yl)-morpholine (2.2 g, 9.23 mmol), 5% palladium on activated carbon (50% wet, 1.09 g), ammonium formate (8.76 g) was sealed in the Emrys process vial and heated at 150° C. under microwave irradiation for 2 min. The reaction mixture was filtered and evaporated. The residue was treated with ethyl acetate and filtered to give 1.62 g of orange crystalline product after evaporation in vacuo. Yield 84%. LC-MS (m/z) 208.9 (MH+); tR=0.44. 1H NMR (500 MHz, DMSO-d6): 2.2 (s, 6H), 3.44 (m, 4H), 3.62 (m, 4H), 4.19 (br, 2H, NH2).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16](O)=[O:17]>>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccncc1
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccncc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (25 mg, 0.17 mmol) and 3-methyl-4-(4-pyridyl)benzoic acid (D57) (44 mg, 0.21 mmol) as an orange solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.91(dd, 1H), 8.70 (d, 2H), 8.22 (m, 2H), 8.14 (dd, 1H), 8.11 (dd, 1H), 7.84 (m, 3H), 7.36 (m, 2H), 7.28 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: O=C(O)C1Cc2cocc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cocc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan (3.6 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1>CO.C1COCC1.Cl>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[C:19]([O:21][CH2:22][C@H:23]([OH:24])[CH2:27][OH:26])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)c2ccc(OC[C@H](O)CO)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Bromo-9-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ3-1, 18.7 mg, 0.0398 mmol) was dissolved in methanol (1 mL) and THF (0.3 mL), added with 1 N hydrochloric acid (5 drops) and stirred at 50° C. for 1 hr. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residues were added with dichloromethane, and the solid was separated by filtration to obtain the title compound (yellow powder, 16.8 mg, 98%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]Br>O>[Br:12][C:5]1[N:4]=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ncccc1O
Reactant: BrBr
Solvent: O
Product: COC(=O)c1nc(Br)ccc1O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of methyl 3-hydroxypicolinate (5.0 g, 32.65 mmol) in H2O was stirred at RT and then Br2 (5.2 g, 32.65 mmol) was added dropwise. After the mixture was stirred at RT overnight, the mixture was filtered and the precipitate was washed with water and dried to give methyl 6-bromo-3-hydroxypicolinate (6.1 g, yield 80.7%). 1H-NMR (DMSO, 400 MHz) δ 10.71 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 3.87 (s, 3H). MS (M+H)+: 232/234.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CO.C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]2[CH2:9][C:10]3[C:15](=[CH:14][C:13]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2C1=O
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)cccc1N1Cc2ccc(C(C)(C)C)cc2C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 13.9 %

Procedure:
A suspension of 2-(3-bromo-2-methylphenyl)-5-tert-butylisoindoline-1,3-dione (Intermediate 3-2, 1.0 g, 2.69 mmol) in methanol (20 mL) was treated with sodium borohydride (203 mg, 5.37 mmol) and stirred at rt. After a few minutes, additional sodium borohydride (203 mg, 5.37 mmol) was added. After 40 min, the mixture was concentrated, and the residue was dissolved in DCM, washed with water and brine, and dried and concentrated to provide a white solid. This material was dissolved in DCM (10 mL) and treated with TFA (10 mL) and stirred for a few minutes at rt, then was treated with triethylsilane (6.40 mL, 40.1 mmol) and stirred at rt for 2.5 h. The mixture was concentrated and the residue was dissolved in DCM, washed with NaHCO3 (aq) and water. The organic phase was dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)-6-tert-butylisoindolin-1-one (Intermediate 4-3, 134 mg, 28%). 1H NMR (400 MHz, chloroform-d) δ 7.99 (1H, d, J=1.32 Hz), 7.68 (1H, dd, J=7.91, 1.76 Hz), 7.60 (1H, dd, J=7.69, 1.10 Hz), 7.45 (1H, d, J=7.91 Hz), 7.19-7.23 (1H, m), 7.15 (1H, t, J=7.69 Hz), 4.68 (2H, s), 2.31 (3H, s), 1.39 (9H, s). Mass spectrum m/z 358, 360 (M+H)+. Also isolated was 2-(3-bromo-2-methylphenyl)-5-tert-butylisoindolin-1-one (Intermediate 4-4, 250 mg, 52%). 1H NMR (400 MHz, chloroform-d) δ 7.88 (1H, d, J=7.91 Hz), 7.59 (2H, dd, J=8.13, 2.86 Hz), 7.53 (1H, s), 7.20-7.23 (1H, m), 7.12-7.17 (1H, m), 4.69 (2H, s), 2.31 (3H, s), 1.40 (9H, s). Mass spectrum m/z 358, 260 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[N:2]=1.C[N:11]1CCOCC1.ClC(OC(C)C)=O.N>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:11])=[O:9])[N:2]=1
Reactant: O=C(O)c1cccnn1
Reactant: CN1CCOCC1
Agent: CC(C)OC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccnn1
Temperature: -30 °C
Reaction time: 6 h
Yield: 20.4 %

Procedure:
To a cooled solution of pyridazine-3-carboxylic acid (1.0 g, 8.06 mmol) in tetrahydrofuran (40 mL) in a dry-ice bath was added 4-methyl-morpholine (0.9 g, 8.87 mmol) and isopropyl chloroformate (1.1 g, 8.87 mmol) slowly. The reaction was stirred at −30° C. for 6 hours, then an aqueous solution of ammonia (8 mL, 10% W/W) was added. The resulting mixture was stirred at room temperature overnight, washed with a saturated aqueous solution of potassium bisulfate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 202.5 mg of the desired product (yield was 20.4%). MS obsd. (ESI+) [(M+H)+] 124, 1H NMR (400 MHz, CD3OD) δ ppm 9.45-9.35 (t, J=1.6 Hz, 1 H), 8.58 (s, 1 H), 8.23-8.15 (d, J=7.6 Hz, 1 H), 7.98-7.88 (m, 2 H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH3:22])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH3:22])[CH:15]=1)[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2C)c1
Temperature: 60 °C

Procedure:
To a solution of 4-methyl-2-[5-(2-methyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester (18 mg, 0.04 mmol) in MeOH (1 mL) was added 3N NaOH (0.200 mL) and heated to 60° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH 2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 4-methyl-2-[5-(2-methyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid. 1H-NMR (MeOD-d4): δ 0.96 (m, 6H), 1.10 (dd, 3H), 1.51 (m, 1H), 1.76 (m, 1H), 1.82 (m, 2H), 1.96-2.10 (m, 4H), 2.19 (d, 1H), 3.73 (m, 2H), 3.89 (t, 1H), 3.95 (m, 1H), 7.68 (s, 1H), 7.80-7.89 (m, 6H); Calcd for C25H30F3NO2 (M+H) 434.51, Found 434.2
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:13]([C:28]2[CH:33]=[C:32]([Cl:34])[C:31]([O:35]CC3C=CC=CC=3)=[CH:30][C:29]=2[O:43]CC2C=CC=CC=2)[O:12][N:11]=1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)=[C:13]([C:28]2[CH:33]=[C:32]([Cl:34])[C:31]([OH:35])=[CH:30][C:29]=2[OH:43])[O:12][N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Yield: 64.3 %

Procedure:
BCl3 (1M sol. in CH2Cl2, 3.87 ml, 3.87 mmol) was added dropwise to a solution of the crude 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (810 mg, ˜1.29 mmol) in CH2Cl2 (30 ml) at 0° C. The reaction was then allowed to reach RT. Saturated aqueous NaHCO3 (40 ml) was then added slowly and the resultant mixture concentrated in vacuo. This was then partitioned between EtOAc (3×50 ml) and water (50 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo. Flash chromatography eluting with CH2Cl2—10% MeOH/1% NH3/CH2Cl2 afforded 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (380 mg, 64% over 2 steps) as a yellow foam, LC/MS: RT=1.751 min. 458.2 (MH+).
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.CN(C)[CH:8]=[CH:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH:1]1([N:4]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5]2)[CH2:3][CH2:2]1
Reactant: NNC1CC1
Reactant: CCOC(=O)C(=O)C=CN(C)C
Product: CCOC(=O)c1ccn(C2CC2)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using cyclopropylhydrazine (Step 17.2) and ethyl 4-(dimethylamino)-2-oxobut-3-enoate at 125° C. for 8 hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-45%). tR: 3.45 min (HPLC 1); tR: 0.74 min (LC-MS 2); ESI-MS: 181 [M+H]+ (LC-MS 2); Rf=0.59 (hexane/EtOAc 1:1).
Reaction SMILES: Cl.[F:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][NH2:6].CN1CCCC1.[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:23]2[CH:34]=[N:33][C:26]3[N:27]=[C:28]([NH:31][CH3:32])[N:29]=[CH:30][C:25]=3[CH:24]=2)=[CH:18][C:17]=1[NH:35][C:36](=O)[O:37]C(C)=C>O1CCOCC1>[F:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][NH:6][C:36]([NH:35][C:17]1[CH:18]=[C:19]([C:23]2[CH:34]=[N:33][C:26]3[N:27]=[C:28]([NH:31][CH3:32])[N:29]=[CH:30][C:25]=3[CH:24]=2)[C:20]([CH3:22])=[CH:21][C:16]=1[F:15])=[O:37]
Reactant: CC(C)(F)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cnc3nc(NC)ncc3c2)c(C)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)F)c(F)cc3C)cnc2n1
Temperature: 80 °C
Yield: 105.7 %

Procedure:
Add 3-fluoro-3-methyl-butan-1-amine hydrochloride (88 mg, 0.62 mmol) followed by N-methylpyrrolidine (0.065 mL, 0.62 mmol) to a stirred solution of isopropenyl N-[2-fluoro-4-methyl-5-(2-methylaminopyrido[2,3-d]pyrimidin-6-yl)phenyl]carbamate (184 mg, 0.50 mmol) in 1,4-dioxane (5 mL) and heat at 80° C. under N2 overnight. Concentrate and purify on silica eluting with 0-5% MeOH (2N NH3)/DCM. Purify on SCX column eluting with NH3/MeOH to obtain the title compound (219 mg, 70%). MS (m/z): 414.8 (M+1).
Reaction SMILES: [CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>N1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:19]([F:24])[CH:18]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(=O)Cl
Reactant: CCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCCCC)c(F)c2)cn1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
0.80 g (2.42 mM) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidine was dissolved in 10 ml of pyridine. Under stirring on an ice water bath, 0.62 ml (4.00 mM) of heptanoyl chloride was added dropwise to the above solution, followed by stirring for 15 minutes on the ice water bath and further stirring for 20 minutes at 45°-56° C. on a water bath. After the reaction, the reaction mixture was poured into 150 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water. The washed crystal was dissolved in toluene and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized two times from a mixture solvent of acetone-methanol to obtain 0.66 g of 2-decyl-5-(3-fluoro-4-heptanoyloxyphenyl)pyrimidine (Yield: 61.6%). ##STR26##
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl.[NH2:29][OH:30]>>[OH:30][NH:29][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[NH:27]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(C#N)CC2)C3)CC1
Reactant: NO
Agent: Cl
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(C(=N)NO)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2,3-dihydro-furo[2,3-c]pyridine-2-yl]-piperidine-1-carbonitrile (Intermediate 44, the configuration of the stereocenter is arbitrarily assigned) and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 6): tR=0.75 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C.Cl.[OH-].[Na+]>O>[N:12]1([CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(CCN2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(CCN2CCCCC2)cc1
Temperature: 65 °C
Yield: 58.4 %

Procedure:
1-[2-(4-Nitro-phenyl)-ethyl]-piperidine (0.1178 gms.) is suspended in 4.5 mL of a 1:1 (v:v) solution of acetic acid and water. The suspension is then immersed in a 65° C. oil bath and treated in dropwise fashion with 9 mL of an ˜10 wt. % solution of TiCl3 in 20–30 wt. % HCl. Over the course of the addition a color change from colorless to purple to black ensues. The reaction mixture is maintained in the 65° C. oil bath overnight following the addition of TiCl3. The reaction mixture is then cooled to 0° C., and made basic with the addition of a 10% aqueous solution of NaOH. The basic reaction mixture is then extracted with chloroform. The emmulsion that forms is filtered through glass wool, re-extracted with chloroform, and then dried over anhydrous sodium sulfate. Following evaporation of the solvent the residue is chromatographed by flash silica gel chromatography (10% methanol in chloroform) to yield 60 mg of 4-(2-piperidin-1-yl-ethyl)-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH:25]1(C2NN=C(N)N=2)C[CH2:26]1>>[CH:1]1([C:2]2[N:24]=[C:5]3[N:6]=[C:7]([C:16]4[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:22][CH:23]=4)[C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:9][N:4]3[N:3]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Nc1n[nH]c(C2CC2)n1
Product: O=Cc1ccc(-c2nc3nc(C4CC4)nn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 5-cyclopropyl-1,2,4-triazol-3-amine in the first step.