Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(Cl)Cl>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:31][C:32]1[N:37]=[CH:36][C:35]([C:5]2[CH2:4][N:3]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:2](=[O:1])[CH:6]=2)=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC(c2ccc(F)nc2)=CC1=O
Temperature: 90 °C

Procedure:
To tert-butyl 2-oxo-4-(tosyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.8 g, 2.037 mmol) (See Example 24 for synthesis) in DME (27 mL) and sodium carbonate (7 mL, 14.00 mmol) (2M) was added (6-fluoropyridin-3-yl)boronic acid (0.431 g, 3.06 mmol) and PdCl2(dppf).CH2Cl2 adduct (0.333 g, 0.407 mmol). Purge with N2 for 5 min. The reaction mixture was heated in oil bath at 90° C. for 2 h. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. Purified by flash chromatography column using 0-50% EtOAc/heptane. Fractions contains product were combined and evaporated to provide tert-butyl 4-(6-fluoropyridin-3-yl)-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate as an off white solid (54.7%). LCMS (m/z): 223.2 (MH+-tBu), 0.743 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@H:34]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[CH2:33][CH2:32][C@H:31]2[C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:39][C:38]1[CH:37]=[CH:36][C:35]([C@@H:34]2[CH2:33][CH2:32][C@@H:31]([C:42]3[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=3)[N:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=2)=[CH:41][CH:40]=1)=[O:16])=[O:8])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(N)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of the product from Example 37B (17.7 mg, 0.065 mmol) and the product from Example 37E (50 mg, 0.130 mmol) in anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071 mmol) and Hunig's Base (0.015 mL, 0.084 mmol). The resulting mixture was stirred at rt for 30 min, and was then partitioned between H2O (5 mL) and EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH2Cl2 to give the title compound (20 mg, 24%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.72 Hz, 3 H), 0.93 (d, J=6.72 Hz, 3 H), 1.11 (s, 9 H), 1.52-1.66 (m, 2 H), 1.79-2.06 (m, 4 H), 2.06-2.20 (m, 1 H), 2.34-2.47 (m, 2 H), 3.52 (s, 3 H), 3.56-3.67 (m, 1 H), 3.74-3.87 (m, 1 H), 4.02 (t, J=8.51 Hz, 1 H), 4.42 (dd, J=8.08, 4.83 Hz, 1 H), 4.83-4.94 (m, 2 H), 5.02 (d, J=7.16 Hz, 0.5 H), 5.08 (d, J=7.59 Hz, 0.5 H), 6.18 (d, J=8.78 Hz, 2 H), 6.48 (d, J=8.35 Hz, 2 H), 6.84 (d, J=8.35 Hz, 2 H), 6.93 (d, J=8.89 Hz, 2 H), 7.11 (d, J=8.57 Hz, 2 H), 7.31 (d, J=8.35 Hz, 1 H), 7.48 (d, J=8.57 Hz, 2 H), 9.97 (s, 1 H); MS (ESI) m/z 640.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH3:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[BrH:13]>>[BrH:13].[NH2:11][CH2:10][CH:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: COc1cccc(C(C)CN)c1
Agent: Br
Product: CC(CN)c1cccc(O)c1
Temperature: 100 °C

Procedure:
2-(3-Methoxyphenyl)propan-1-amine (760 mg, 4.61 mmol) was added HBr solution(5.2 mL, 48% solution in H2O 46.1 mmol). The reaction was heated at 100° C. for 4 h. It was cooled down to room temperature. Removal of solvents gave crude 3-(1-aminopropan-2-yl)phenol HBr salt as a greenish foam. HPLC retention time (Method C)=0.95 min. LC/MS (ESI) (M+H)+=152.18. 1H NMR (CDCl3, 400 MHz) δ ppm 1.31 (d, J=6.59 Hz, 3H), 2.90-3.02 (m, 1H), 3.06-3.13 (m, 1H), 3.30 (s, 1H), 6.69-6.79 (m, 3H), 7.14-7.22 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.[Pd]>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[CH2:13][C@@H:12]([OH:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C=C1COCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](O)C[C@H]1COCc1ccccc1
Yield: 94.6 %

Procedure:
A suspension of (1R,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)silyl]-oxy}cyclopent-2-en-1-ol (7.54 g, 0.0225 mol) (Ruediger, E; Martel, A; Meanwell, N; Solomon, C; Turmel, B. Tetrahedron Lett. 2004, 45, 739-742), sodium carbonate (5.7 g, 0.054 mol) and 10% Pd/C (2 g, 0.002 mol) in EtOAc (90 mL) was stirred under an atmosphere of hydrogen for three hours. The reaction flask was purged with nitrogen and the mixture was filtered through celite with EtOAc. The filtrate was concentrated to obtain 7.16 g (76%) of the title compound as a 4:1 mixture of diastereomers (desired:undesired).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1C[O:24]CC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[CH2:10][C:9]1([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C=CC1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reaction time: 1 h
Yield: 68 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1═H, R2-3═methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL) was treated with 1.0 M BH3-THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3 M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1H), 7.42 (t, J=7.8, 1H), 7.31 (d, J=7.8, 1H), 7.02 (t, J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9H), 1.49 (s, 6H).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][C:8](=[O:13])[CH2:9]2.OC(CC)CCC1C(=O)CC2C1CCC2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]([CH2:14][CH3:15])[CH2:3][CH2:4][CH:5]1[CH2:12][CH2:11][CH:10]2[CH:6]1[CH2:7][C:8](=[O:13])[CH2:9]2
Reactant: CCC(O)CCC1CCC2CC(=O)CC12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CCC(O)CCC1C(=O)CC2CCCC21
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(=O)CCC1CCC2CC(=O)CC12

Procedure:
The procedure followed is the same as that described in Example 13, making the following substitutions made: the starting material prepared in Example 31, 2-(3-hydroxypent-1-yl)bicyclo[3.3.0]octan-3-one {hexahydro-4-(3-hydroxypentyl)-2(1H)-pentalenone} (0.8 g, 3.8 mmoles), and pyridinium dichromate (0.82 g, 2.1 mmoles) dissolved in methylene chloride (10 ml). The crude product is chromatographed on silica gel and subsequently kugelrohred under reduced pressure leaving a clear, colorless oil (0.55 g, 2.6 mmoles).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][NH:9][C:10](=O)[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([C:10]([CH3:11])=[N:9][N:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NNc1ncccc1Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1nnc2c(Br)cccn12
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a solution of 0.17 g (0.74 mmol) of N′-(3-bromopyridin-2-yl)acetohydrazicle from step A in 40 mL of anhydrous toluene was added 3 mL of glacial acetic acid and the resulting mixture was heated to reflux for 20 h employing a Dean-Stark trap. The reaction mixture was cooled to ambient temperature then evaporated to dryness in vacuo to afford the title compound (0.13 g, 84%) LC-MS: m/z (ES) 212, 214 (MH)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=2)=[C:11]([CH3:24])[C:10]=1[Cl:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.[BH4-].[Na+].O>O1CCCC1>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[C:10]=1[Cl:25])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)c(Cl)c(C)c1-c1cccc(CO)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 4′-{[tert-butyl(dimethyl)silyl]oxy}-3′-chloro-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.78 g, 4.75 mmol) in a mixed solvent of in tetrahydrofuran (10 mL) and methanol (5 mL) was added sodium borohydride (90%, 90 mg, 2.38 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 2 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (1.74 g, yield 97%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:26]I.O>C1COCC1>[CH3:26][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10][CH2:9]2)[C:13]1=[O:23]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (1.5 g, 4.7 mmol) was dissolved in dry THF (20 ml) under nitrogen atmosphere. NaH (0.125 g, 5.2 mmol 60% in mineral oil) was added at 0° C. The reaction mixture was allowed to reach ambient temperature and then CH3I (324 μL, 5.2 mmol) was added. The reaction mixture was left stirring at room temperature for 24 hours, few drops of water were added and the solvent was removed under reduced pressure. The residue was suspended in water and 112 mg of NaOH were added. The mixture was heated at 100° C. for 30 minutes. The solution was allowed to reach room temperature and acidified to pH 3 with HCl 6N with the formation of a white precipitate which was isolated by filtration. (1.0 g, yield 66%)
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Yield: 76.9 %

Procedure:
A mixture of 4-hydroxy-7-(pyridin-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (24 mg), 3-amino-propionic acid (29 mg) and NaOMe (0.48 mL, 0.5 M solution in MeOH) was microwaved at 130° C. for 1 h; then cooled, concentrated, residue was dissolved in water, acidified with 2 M HCl; solids were collected via filtration, washed with water and air dried to give the desired product (22 mg). LC MS ESI: 354 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][C:28]=1OC)C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:37]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:36])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:37]
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (87%). MS (ESI): m/z=252.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]\[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]1[O:37][C@H:36]1[CH2:38][OH:39]>C(O)C.CO>[OH:37][C@@H:36]([CH2:38][OH:39])[CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]/[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CO1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCc3ccc(O)cc3)N2)nc1Cl
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@H](CCCc3ccc(OC[C@@H](O)CO)cc3)N2)nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-[3-(4-hydroxy-phenyl)-propyl]-imidazolidin-(2E)-ylidene]-amide (Example 18) (37.5 mg, 0.09 mmol) in Ethanol (2 ml) is added triethylamine (63 l, 0.45 mmol) and (S)-glycidol (6.07 l, 0.09 mmol). The resulting mixture is heated at reflux for 18 hours and then allowed to cool to room temperature. The reaction mixture is diluted with MeOH (1 ml) and purified on a Waters 3000 prep HPLC system, (Microsorb C18, Water (0.1% TFA): MeCN) to afford the title compound; [M+H]+ 464.
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[C:8]1[CH2:16][CH2:15][CH2:14][C:9]21[O:13][CH2:12][CH2:11][CH2:10]2)=[O:6])([CH3:4])[CH3:3].[BH4-].[Na+]>C1COCC1.CO>[CH3:4][C:2]([S:5]([NH:7][CH:8]1[CH2:16][CH2:15][CH2:14][C:9]21[O:13][CH2:12][CH2:11][CH2:10]2)=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)N=C1CCCC12CCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1CCCC12CCCO2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the compound prepared in Example 1 above (1.73 g, 7.10 mmol) in THF (50 mL) was treated with a solution of sodium borohydride (462 mg, 12.2 mmol) in methanol (10 mL). After stirring for 45 min at room temperature, the reaction was quenched by the addition of saturated ammonium chloride (10 mL) and the resulting mixture was extracted with ethyl acetate. The reaction mixture was then concentration, and the residue was purified by flash chromatography to yield the title compound as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:2]=1.[H][H]>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:2]=1
Reactant: [H][H]
Reactant: OCCCCC#Cc1cnc2ccccc2c1
Agent: [Pd]
Product: OCCCCCCc1cnc2ccccc2c1

Procedure:
3-Quinolinehexanol was prepared by reduction of 13.5 g of 6-(3-quinolinyl)-5-hexyn-1-ol over 1.0 g of 10% palladium on carbon at 1 atmosphere of hydrogen. The crude product obtained after filtration and evaporation was chromatographed over silica gel by high pressure liquid chromatography eluting with 2% methanol-dichloromethane. The first product to elute amounted to 0.95 g which was evaporatively distilled to yield 0.76 g (6%) of 6-[3-(1,2,3,4-tetrahydro)quinolinyl]hexanol, bp 180°-185° C./0.1 mm. The second product to elute amounted to 9.1 g which was evaporatively distilled to give 8.3 g (61%) of 3-quinolinehexanol, bp 195°-205° C. 0.25 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[CH:31]=[C:32]([I:34])[S:33][C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[CH:31]=[C:32]([I:34])[S:33][C:26]=12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: Clc1ccnc2cc(I)sc12
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O
Temperature: 150 °C
Reaction time: 168 h

Procedure:
A suspension of 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.113 g, 0.266 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.075 g, 0.254 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.003 g, 0.025 mmol) in bromobenzene (3 mL) was stirred under nitrogen. The reaction mixture was allowed to stir for 7 days at 150° C. and then for 2 days at room temperature. The reaction was concentrated in vacuo to remove as much bromobenzene as possible. The resulting gummy brown residue was dissolved in CH2Cl2 and then EtOAc was added to yield a dark brown solid precipitate that was filtered and washed with EtOAc. The filtrate, which contained the desired product, was concentrated and purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. Product containing fractions were pooled and concentrated to yield (0.020 mg) of the desired product. Impure fractions were pooled, concentrated and repurified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product isolated from the two purifications were combined to yield the desired product (39 mg; 27%) as a yellow solid. LRMS (APCI pos) m/e 571 (M+1).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCCCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 65 %

Procedure:
In substantially the same manner as in Working Example 1, 6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexanol was allowed to react with 1,2,4-triazole to give 1-[6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]hexyl]-1,2,4-triazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 90-91° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]=[C:8](Cl)Cl)=[CH:3][CH:2]=1.C(N(CC)CC)C.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C(Cl)Cl>[C:4]1([N:7]=[C:8]2[N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH2:19][O:18]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: OCC1CCCCN1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(N=C2OCC3CCCCN23)cc1
Reaction time: 12 h

Procedure:
3 g Phenyl isocyanide dichloride in 10 ml methylene chloride was treated at room temperature with a solution of 5.4 ml triethylamine and 1.7 g 2-hydroxymethylpiperidine in 20 ml methylene chloride. After 12 hours at room temperature, the mixture was washed with water, the organic phase was dried over magnesium sulphate, the solvent was distilled and the residue recrystallised from diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:14]=[C:15]1[C:16]2[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=2[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2
Reactant: COc1cc(F)cc(B(O)O)c1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: COc1cc(F)cc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 52 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-fluoro-5-methoxyphenylboronic acid (300 mg, 1.76 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (450 mg, 1.6 mmol)provides 275 mg of title compound in 52% yield as a pale yellow oil. HPLC shows 97% purity.