Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[O:4]=[P:5](Cl)(Cl)Cl.[C:9]([CH2:13][CH2:14][CH2:15][O:16][C:17](=[C:25]1[CH:32]2[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:34][CH:26]1[CH2:27]3)[CH2:31]2)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)([O:11][CH3:12])=[O:10].[C:35]([CH:37](O)[CH3:38])#[N:36]>ClCl.N1C=CC=CC=1.N1C=CC=CC=1>[C:9]([CH2:13][CH2:14][CH2:15][O:16][C:17](=[C:25]1[CH:26]2[CH2:34][CH:30]3[CH2:29][CH:28]([CH2:33][CH:32]1[CH2:31]3)[CH2:27]2)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][P:5]([CH2:38][CH2:37][C:35]#[N:36])([CH2:38][CH2:37][C:35]#[N:36])=[O:4])[CH:19]=1)([O:11][CH3:12])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(O)C#N
Reactant: COC(=O)CCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(O)c1
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCOC(=C1C2CC3CC(C2)CC1C3)c1cccc(OP(=O)(CCC#N)CCC#N)c1
Reaction time: 0.25 h

Procedure:
A flask containing 5 mL of CH2Cl2 under a layer of argon was cooled in an ice bath. Pyridine (0.5 mL) was added followed by slow addition of POCl3 (465 mg) and stirring continued for 15 min. A solution of the alkene (360 mg) from step (g) in 0.5 mL of 1:1 CH2 Cl2 /pyridine was added dropwise. The ice bath was removed and the solution stirred for 135 min. To this solution was added 1.0 mL of pyridine and 0.69 mL of 2-cyanoethanol. The reaction mixture was stirred for 4 hours resulting in formation of a white precipitate. TLC showed formation of two materials. Adding an additional 200 μL of cyanoethanol caused the precipitate to dissolve but stirring over night was without effect. The solution was evaporated to dryness and the crude product purified chromatographically. 1H NMR (CDCl3) δ1.79-1.98 (m, 14H), 2.41 (t,2H), 2.61 (br s,1H), 2.80 (m,4H), 3.23 (br s,1H), 3.41 (t,2H), 3.65 (s,3H), 4.32-4.48 (m,4H), 7.15-7.37 (m,4H). ##STR28##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.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>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (Aldrich; 3 g, 16.21 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 2.03 g, 17.83 mmol), HATU (6.77 g, 17.83 mmol), DIPEA (8.5 mL, 48.63 mmol) and DMF (30 mL) were combined and stirred at ambient temperature for 18 hrs. Solvents evaporated and partitioned between DCM (200 ml) and water (100 ml). The aqueous phase was re-extracted with DCM (100 ml). The combined organic phases were dried (MgSO4) and evaporated. The resultant material was taken up in DCM and purified on silica eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM then 5% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give the title compound as a yellow solid (2.67 g, 59%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH2:12][CH3:13]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH3:13])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(Br)ccc1=O
Reaction time: 0.5 h

Procedure:
A solution of 5-bromopyridin-2-ol (1.74 g, 10.00 mmol) in DMF (20 ml) was treated with NaH at room temperature and then stirred for 30 min. Iodoethane (0.823 ml, 12.00 mmol) was added to the mixture and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM, washed with water, dried over Na2SO4, and concentrated to dryness via rotary evaporation to provide the title compound as a crude product which was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[I:16]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O.O>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([I:16])[C:14]=1[OH:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(I)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
Methyl 3-t-butyl-4-hydroxybenzoate (1.83 g) was dissolved in dichloromethane (24 mL) and methanol (3 mL), and N-iodosuccinimide (2.08 g) and trifluoromethanesulfonic acid (3 mL) were added to the solution, and then the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and then the organic layer was separated. The organic layer was washed with 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.77 g) as a brown crystal.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCC(=O)Cl
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Yield: 76.3 %

Procedure:
To a solution of 5.80 gm (0.0211 mole) of the compound of Example 15 in 50 ml of CH2Cl2 was added 3.03 g (0.03 mole) of triethylamine, 384 mg (0.003 mole) of 4-dimethylaminopyridine and 2.78 g (0.03 mole) of propionyl chloride. The mixture was heated at reflux for 15 hours, cooled, and partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give a thick oil which crystallized on trituration with toluene-hexane. The resulting white solid was collected to give 5.32 gm of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1,2,4-triazolo [3,4-a]phthalazin3-yl)propanamide; mp 164-166° C. (ethanol-ether). Calculated: C, 58.16; H, 6.71, N, 25.44. Found: C, 58.17; H, 6.70; N, 25.67.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]=1Br.[Li]CCCC.CN(CCN(C)C)C.[CH:37]1[CH:42]=[C:41]([CH:43]=[O:44])[N:40]=[CH:39][CH:38]=1>CCOCC>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:42][C:41]=1[CH:43]([C:10]1[C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[OH:44]
Reactant: Brc1c(COC2CCCCO2)cccc1COC1CCCCO1
Reactant: O=Cc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccccn1)c1c(COC2CCCCO2)cccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a solution of 2,6-di(tetrahydro-2H-2-pyranyloxymethyl)-phenyl bromide (15.5 g, 39 mmol) in ether at -30° C. was added n-BuLi (2.5M, 16.4 ml, 41 mmol) and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was cooled to 0° C., and TMEDA (4.56 g, 37 mmol) was added, and the resulting mixture was cooled to -50° C. After stirring for 20 minutes, 2-pyridylcarboxaldehyde (6.31 g, 58 mmol) was added. The above mixture was warmed to room temperature over a period of 2 hours, quenched with saturated sodium bicarbonate, and diluted with ethyl acetate with stirring. The organic layer was washed with brine and concentrated in vacuo to afford 11.7 g (73%) of 1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanol as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:10]=2)[CH2:3]1.Br[C:39]1[S:43][CH:42]=[N:41][CH:40]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@H:2]1[C@H:6]([CH2:7][OH:8])[CH2:5][N:4]([C:9]2[C:28]([C:39]3[S:43][CH:42]=[N:41][CH:40]=3)=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)=[O:14])=[CH:11][N:10]=2)[CH2:3]1
Reactant: Brc1cncs1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2C[C@H](CO)[C@@H](O)C2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@@H](CO)[C@H](O)C2)c(-c2cncs2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
6-((3R,4R)-3-Hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 17.1, 50 mg, 0.096 mmol), 5-bromothiazole (78 mg, 0.478 mmol), Pd(Ph3P)4 (11.04 mg, 9.55 μmol), K3PO4 (81 mg, 0.382 mmol) toluene (478 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred for 16 h at 110° C. The RM was diluted with DME (2 mL)/EtOAc (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 39.8 mg, 0.057 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, isocratic at 30% in 8 min) to afford the title compound as an amber wax. UPLC-MS (Condition 3) tR=0.90 min, m/z=481.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.05-2.15 (m, 1H) 2.99 (dd, J=10.79, 3.14 Hz, 1H) 3.18-3.23 (m, 1H) 3.22-3.28 (m, 1H) 3.39 (m, J=5.40 Hz, 2H) 3.52 (dd, J=11.30 Hz, 1H) 3.94-4.03 (m, 1H) 4.66 (t, J=5.27 Hz, 1H) 5.00 (d, J=4.27 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.83-7.89 (m, 2H) 7.94 (d, J=0.50 Hz, 1H) 8.09 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.38 Hz, 1H) 9.20 (d, J=0.50 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:25])=[O:24])=[CH:21][CH:20]=1)#[N:18]>>[ClH:25].[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: Cl
Product: N#Cc1ccc(C(=O)Nc2ccc(N3CCN4CCC3CC4)cc2)cc1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and 4-cyanobenzoyl chloride. Mp. 250° C. (decomp.).
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC(=O)OCC>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (1226 mg, 3.43 mmol) in THF (15 mL) was added n-BuLi (2.145 mL, 3.43 mmol), stirred for 10 min then 3-fluoro-4-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (0.691 mL, 3.12 mmol) was added. The mixture was stirred at 0° C. for 1 h, then at room temperature for another 2 h. The reaction mixture was diluted with EA, washed with water, brine (50 mL), and concentrated. The residue was purified via flash chromatography to afford the title compound (449 mg, 49.8% yield) as colorless oil. LCMS: rt=3.13 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1O>>[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC1CCCC1O
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: CC1CCCC1OC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 2-methylcyclopentanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:21][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:12]3[NH:13][C:14](=[O:18])[C:15]([CH3:17])=[N:16][C:11]=3[N:10]=[CH:9][CH:8]=2)[CH:19]=[CH:20][C:2]=1[NH:1][C:34]([NH:33][C:24]1[CH:25]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:27]=[CH:28][C:23]=1[F:22])=[O:35]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cc1nc2nccc(Oc3ccc(N)c(F)c3)c2[nH]c1=O
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c2[nH]c1=O
Yield: 85 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)-3-methylpyrido[3,2-b]pyrazin-2(1H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate to afford the title compound. yield=85%.
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:29][C:10]=1[O:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:9]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:29][C:10]=1[O:11][CH:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CCC(=O)OC(C)(C)C)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of tert-butyl 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate, thought to be the (R)-enantiomer, (1 g) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL) is treated with 5 M aqueous sodium hydroxide solution (7.5 mL) and the reaction stirred at ambient temperature for 24 hours. The reaction is concentrated to low volume, acidified to pH 5 with dilute hydrochloric acid, and extracted into dichloromethane (2×30 mL). The combined organic layers are washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow gum. Trituration with diethyl ether and recrystallization of the resultant solid from acetonitrile containing a little decolourizing charcoal gives 4-[2-benzoyl-5-(pyridin-3-ylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (0.2 g) as a pale yellow solid, m.p. 185-186° C. [Elemental analysis:- C, 74.83; H, 5.65; N, 2.91%; Calculated:- C, 75.01; H, 5.72; N,2.87%].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][CH:21]=1)[CH:14]=[CH:13]2.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH2:26])=[O:25])=[CH:27][CH:28]=1)[CH2:14][CH2:13]2
Reactant: NC(=O)c1ccc(Cn2ccc3cc(CNCCc4cccs4)ccc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)c1ccc(CN2CCc3cc(CNCCc4cccs4)ccc32)cc1
Yield: 70.1 %

Procedure:
Mix 4-{5-[(2-Thiophen-2-yl-ethylamino)-methyl]-indol-1-ylmethyl}-benzamide (0.20 g, 0.51 mmol) and acetic acid (5 mL) in a flask. Add sodium cyanoborohydride (0.09 g, 1.52 mmol) and stir for 3 hrs. Neutralize reaction with 5M aqueous NaOH (10 mL) and dilute with water (50 mL). Extract with CH2Cl2 (3×50 mL). Purification on silica using 40:1 CH2Cl2/2M NH3 in CH3OH to 20:1 CH2Cl2/2M NH3 in CH3OH gradient eluent yields the product as an oily substance. Trituration with ether gives the product as a white solid (0.14 g, 72%). Mass spectrum (ion spray): m/z=392.2 (M+1); 1H NMR (DMSO-d6) 7.91 (bs, 1H), 7.82 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.30 (bs, 1H), 7.27 (d, J=4.8 Hz, 1H), 6.99 (s, 1H), 6.92-6.87 (m, 2H), 6.82 (d, J=2.2 Hz, 1H), 6.46 (d, J=7.9 Hz, 1H), 4.25 (s, 2H), 3.54 (s, 2H), 3.21 (t, J=8.1 Hz, 2H), 2.92-2.81 (m, 4H), 2.69 (t, J=7.1 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[CH:17]1([OH:21])[CH2:20][CH2:19][CH2:18]1.[K].[O-]CCCC>O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:21][CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH:7]=2)[CH:13]=1
Reactant: OC1CCC1
Reactant: COc1ccc(Cl)cc1-c1ccnc(Cl)c1
Agent: CCCC[O-]
Agent: [K]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1-c1ccnc(OC2CCC2)c1
Temperature: 101 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 864, 150 mg, 0.00059 mol) and cyclobutanol (76.6 mg, 0.00106 mol) were dissolved in 1,4-dioxane (2 mL). Potassium Pert-butoxide (132 mg, 0.00118 mol) was added and the solution stirred at 101° C. for 15 hours. The reaction was partitioned between ethyl acetate (15 mL) and a 10% aqueous solution of citric acid (10 mL). The organic layer was washed with water (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give a yellow oil (195 mg). The material was purified using an ISCO™ companion (12 g column, eluting with 100% heptane to 7:3 heptane/ethyl acetate). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (84 mg).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([CH3:26])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:4].[Br:34]Br>O>[F:33][C:2]([F:1])([F:32])[C@H:3]([NH:5][S:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[N:16]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][C:20]([Br:34])=[C:19]([CH3:26])[CH:18]=3)=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH3:4]
Reactant: BrBr
Reactant: Cc1ccc2c(C#N)c(-c3ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn3)n(C3CCCC3)c2c1
Solvent: O
Product: Cc1cc2c(cc1Br)c(C#N)c(-c1ccc(S(=O)(=O)N[C@H](C)C(F)(F)F)cn1)n2C1CCCC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of (R)-6-(3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide (0.48 g, 1.05 mmol) in acidic acid (3 mL) was added bromine (0.35 g, 2.1 mmol) dropwise. The solution was stirred at 90° C. for 30 min, cooled to room temperature and then diluted with water (20 mL). The precipitate was collected and washed thoroughly with water, then dried to give (R)-6-(5-bromo-3-cyano-1-cyclopentyl-6-methyl-1H-indol-2-yl)-pyridine-3-sulfonic acid (2,2,2-trifluoro-1-methyl-ethyl)-amide as a light yellow solid (0.54 g, 93%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:14]=1)C1C=CC=CC=1.C(S)C.B(F)(F)F.CCOCC>CO>[OH:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)[CH:14]=1
Reactant: Cn1cc(-c2nccc(-c3ccccc3)n2)cc(OCc2ccccc2)c1=O
Agent: FB(F)F
Solvent: CCS
Solvent: CO
Solvent: CCOCC
Product: Cn1cc(-c2nccc(-c3ccccc3)n2)cc(O)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
To a solution of 3-(benzyloxy)-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one (21 mg, 0.057 mmol) was added ethanethiol (31.8 mg, 0.512 mmol) followed by BF3.OEt2 (73 mg, 0.512 mmol). The resulting solution was stirred at room temperature for 18 h, diluted with MeOH and concentrated. Purification by preparative HPLC (5-50% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 7.3 mg 3-hydroxy-1-methyl-5-(4-phenylpyrimidin-2-yl)pyridin-2(1H)-one (46%) as a light purple solid. 1H NMR (500 MHz, DMSO-d6): δ 9.41 (br s, 1H), 8.84 (d, J=5.3 Hz, 1H); 8.44 (s, 1H); 8.33 (s, 2 H); 7.90 (d, J=5.3 Hz, 1H); 7.72 (s, 1H); 7.59 (s, 3H); 3.65 (s, 3H). High resolution mass spec (FT/ICR) calc (M+H)+=280.1081 found 280.1080.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:18].O>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([CH3:11])([CH3:12])[C:8](=[O:10])[N:9]([CH3:18])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC1(C)Oc2ccc(Br)cc2NC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)Oc2ccc(Br)cc21
Reaction time: 0.08 h
Yield: 67.7 %

Procedure:
To a solution of 6-bromo-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (185 mg, 0.722 mmol) in DMF (3 mL) at 0° C. was added NaH (43.3 mg, 1.08 mmol, 60%), and the reaction was stirred for 5 minutes. Iodomethane (205 mg, 1.45 mmol) was added the reaction was stirred at room temperature for 60 minutes. Water, EtOAc, and brine were added, the layers were separated and the organic layer was washed with brine. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (10-35% EtOAc in hexanes) to afford 6-bromo-2,2,4-trimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one 7.31 (132 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C11H13BrNO2: 270.0; found: 270.0.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCl)cc1
Temperature: 26 °C
Reaction time: 22 h
Yield: 92.4 %

Procedure:
A mixture of 4-Amino benzonitrile (1.0 g, 0.0084 mol) and triethyl amine (1 ml, 0.010 mol) was taken in DCM (15 ml). Chloro acetyl chloride (0.67 ml, 0.0084 mol) was added slowly and stirred for 22 hours at 25-27° C. Solvent was removed and the residue was dissolved in ethyl acetate (20 ml), washed with water (1×15 ml) followed by brine (2×15 ml). The organic layer was dried over Na2SO4 and the solvent was removed to get pure 2-chloro-N-(4-cyano-phenyl)-acetamide (1.51 g, 92%).
Reaction SMILES: [CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:8](=O)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:18]([NH:26][NH2:27])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)/[C:8](=[N:27]/[NH:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-butyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.98 (t, 3H), 1.38 to 1.45 (m, 4H), 1.67-1.73 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.97 (br s, 1H).