Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.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>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 70 °C
Yield: 61.6 %

Procedure:
A 100 ml RB flask was charged with (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (3.3 g, 7.22 mmol), pyridin-3-ylboronic acid (1.163 g, 9.39 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.834 g, 0.722 mmol). To this were added DME (51.6 mL) followed by sodium carbonate (10.83 mL, 21.66 mmol) (2M solution) and the mixture was heated at 70° C. for 24 hrs. The mixture was diluted with water and ethyl acetate, filtered and organic layer was separated and concentrated. The crude material was purified by FC on 80 g RediSep column using 5-70% gradient of DCM/MeOH/NH4OH in DCM to give (S)-2′-bromo-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (1.82 g, 4.45 mmol, 61.6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][NH:6][CH2:7][CH2:8][OH:9].O1C[C@@H]1[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:30]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:5][N:6]1[CH2:30][CH2:29][O:9][CH:8]([CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH2:7]1
Reactant: OCCNCc1ccc(Cl)c(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 3 °C
Reaction time: 2.25 h

Procedure:
A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (2.038 g) and (S)-2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (2.032 g) in tetrahydrofuran (3.3 ml) was stirred and heated at reflux under nitrogen. After 21.5 h more tetrahydrofuran (12.5 ml) was added and the mixture was cooled to 3° C. Triphenyl phosphine (2.793 g) was added and the mixture was stirred until all the solid had dissolved. Diisopropylazodicarboxylate (2.1 ml) was then added over 12 min maintaining the temperature at <7° C. After 2.25 h the mixture was allowed to warm to 22° C. After 5.3 h more triphenylphosphine (121 mg) and diisopropylazodicarboxylate (0.09 ml) were added. After 22.5 h the reaction mixture was concentrated to near dryness. Propan-2-ol (12 ml) was added and the concentration repeated, this was repeated once more. More propan-2-ol (12 ml) was added and the mixture was heated to 70° C. After 0.5 h the slurry was cooled to 22° C. and then after a further 2 h the product was collected by filtration. The bed was washed with propan-2-ol (2×4 ml) and then dried in vacuo at 40° C. to give the product, (2.622 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1.[O-:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>>[CH3:20][C:4]1[C:5]([CH3:19])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCCO)c1C
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCO)c1C

Procedure:
Using the general method of Example 90 Part B, 6-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]hexan-1-ol (14.00 g, 46.39 mmol) was reacted with sodium phenoxide to provide 12.40 g of 6-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]hexan-1-ol as a yellow powder.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH3:31])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:40][C:41]([F:50])([F:49])[C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:48][C:45]2[CH:46]=[CH:47][C:42]([C:41]([F:40])([F:49])[F:50])=[CH:43][CH:44]=2)[CH3:31])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
The bromide 48.1 (80 mg, 0.16 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (200 mg, 0.62 mmol) and 4-trifluoromethylphenol (100 mg, 0.62 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL) and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc: hexanes) to obtain 48.2 (39 mg). MS ESI (pos.): m/e 595.2 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](OC)([O:20]C)[C:16]([F:19])([F:18])[F:17])=[CH:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O.C(N(CCCC(OCC)=O)CCOC1C=CC(CCC(=O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:24]([N:3]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])=[CH:11][CH:12]=1)[CH2:1][CH3:2])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCN(CC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCN(CC)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Yield: 53.7 %

Procedure:
N-Ethyl-N-[2-[4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenoxy]ethyl]dodecylamine (123 mg, 0.244 mmol) was treated with trifluoroacetic acid as described in the preparation of 4-[N-dodecyl-N-[2-[4-(4,4,4-trifluoro-3-oxobut-1-yl)phenoxy]ethyl]amino]butanoic acid, ethyl ester and afforded the title compound (60 mg, 54%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][N:16]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:17]3[CH:18]=[C:19]([CH2:21][N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[CH:20]=[CH:15][N:16]=3)[N:10]=2)[CH:7]=1
Reactant: Nc1cn2cc(Br)ccc2n1
Reactant: Clc1cc(CN2CCCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc2nc(Nc3cc(CN4CCCC4)ccn3)cn2c1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (200 mg; 0.94 mmol) in dry THF (4 mL) was added NaH (90 mg; 3.76 mmol) in portions at 0° C. The reaction mixture was stirred at r.t. for half an hour. Then 2-chloro-4-(pyrrolidin-1-ylmethyl)pyridine (222 mg, 1.1 mmol) was added. The mixture was heated to 120° C. for 24 hrs. The mixture was quenched by addition of H2O (20 mL) slowly at 0° C., extracted with DCM (30 mL×3). The combined organic phases were concentrated under reduced pressure and purified by column chromatography on silica (DCM:MeOH=15:1) to obtain 6-bromo-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine (110 mg, yield 80%) as a brown solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Si]([O:13][C@@H:14]([CH3:39])[C@@H:15]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[C:31]([Cl:37])[C:30]=1[CH3:38])[C:16]([NH:18][CH2:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)(C(C)(C)C)(C)C>C1C=CC=CC=1>[Cl:37][C:31]1[C:30]([CH3:38])=[C:29]([NH:28][C@@H:15]([C:16]2[O:27][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:19][N:18]=2)[C@@H:14]([OH:13])[CH3:39])[CH:34]=[CH:33][C:32]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](C(=O)NCC(=O)c2ccccc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(N[C@@H](c2ncc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 3.6 %

Procedure:
A 100 mL round bottomed flask was charged with phosphorous oxychloride (0.5 mL, 5.24 mmol) and benzene (20 mL). (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-N-(2-oxo-2-phenylethyl)butanamide (1.14 g, 2.28 mmol) was then added to the mixture which was then placed under reflux for 4 h. The mixture was then concentrated en vacuo, then partitioned between EtOAc (40 mL) and a saturated solution of sodium bicarbonate (30 mL). The organic layer was washed with water (20 mL), dried (Na2SO4). Purification by flash column chromatography [hexanes/Et2O (3:2) as eluent] afforded the title compound as a white solid (30 mg, 4% yield). 1H NMR (500 MHz, CDCl3, δ in ppm) 7.59 (d, J=8 Hz, 2H), 7.32-7.42 (m, 4H), 7.28 (s, 1H), 6.58 (d, J=8 Hz, 1H), 5.17 (d, J=7 Hz, 1H), 4.93-4.95 (m, 1H), 4.66-4.75 (m, 1H), 2.40 (s, 3H) and 1.63 (d, J=6 Hz, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:35])=[O:34])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3].Cl[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48]>O1CCCC1.O>[CH2:2]([O:4][C:5]([CH2:7][NH:8][C:9]([CH2:11][N:12]([S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)(=[O:34])=[O:35])[C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:27])=[N:26][C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])=[CH:28][CH:29]=3)=[N:19][C:15]=2[CH:14]=1)=[O:10])=[O:6])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OCc3ccccc3)cc1)n2C)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 97 from 4-[(5-(N-ethoxycarbonylmethylaminocarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and benzyl chloroformate in tetrahydrofuran/water.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#CC1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC(C#N)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[O-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>CO.O>[OH:9][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:12][C:26]=1[C:25]([NH:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)=[O:28]
Reactant: O=C(CCl)NCc1cccc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc(Cl)c1)c1sc2ccc(Cl)cc2c1O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of methyl 5-chloro-2-mercaptobenzoate (1.02 g; 0.005M) in 20 ml of methanol is added solid sodium methoxide (0.81 g; 0.015M; 3 eqv.) followed by N-[(3-chlorophenyl)methyl]chloroacetamide (1.10 g; 0.005M) and the mixture is refluxed under a nitrogen atmosphere for 30 minutes. The mixture is cooled to room temperature and added to a solution of 1.25 ml of glacial acetic acid in 20 ml of water and cooled to 0° C. The white solid is collected, washed with 50% methanol-water and air dried to give 1.60 g (91% yield) of the title compound; m.p. 184°-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12]Br)[CH:10]=[CH:11][C:4]=2[S:3]1(=[O:15])=[O:14].[F:16][C:17]1[CH:18]=[C:19]([OH:30])[CH:20]=[C:21]([C:23]2([O:28][CH3:29])[CH2:27][O:26][CH2:25][CH2:24]2)[CH:22]=1.[C:31](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:21]([C:23]2([O:28][CH3:29])[CH2:24][CH2:25][O:26][CH2:31][CH2:27]2)[CH:22]=1)[O:30][CH2:12][C:9]1[CH:10]=[CH:11][C:4]2[S:3](=[O:15])(=[O:14])[N:2]([CH3:1])[C:6](=[O:7])[C:5]=2[CH:8]=1
Reactant: CN1C(=O)c2cc(CBr)ccc2S1(=O)=O
Reactant: O=C([O-])[O-]
Reactant: COC1(c2cc(O)cc(F)c2)CCOC1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1(c2cc(F)cc(OCc3ccc4c(c3)C(=O)N(C)S4(=O)=O)c2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
A mixture of 2-methyl-5-bromomethyl-1,1-dioxo-benzo[d]isothiazole-3-one (3.2 g), 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydrofuran (2.4 g) and potassium carbonate (4.4 g) in 25 ml of dimethylformamide was stirred at room temperature for about 18 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was triturated with ether and filtered. The resulting solid was recrystallized from dichloromethane/ether to give 3 g of the title compound. m.p. 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=4[C:16]([CH3:19])([CH3:17])[CH3:18])=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 77.6 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-t-butyl-4-hydroxyphenoxy)phenyl]-N-methyl-carbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.76 g), diethyl cyanophosphonate (0.44 g), triethylamine (0.27 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.24 g).
Reaction SMILES: Cl.C([NH:4][CH2:5][C:6]([OH:8])=[O:7])C.[CH:9](N(C(C)C)CC)(C)[CH3:10].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[N+:26]([O-:28])=[O:27].O>CC(N(C)C)=O>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][NH:4][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[C:20]=1[N+:26]([O-:28])=[O:27])[CH3:10]
Reactant: CCNCC(=O)O
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)CNc1cccc(Br)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
9.90 g (69.6 mmol) ethylglycinate hydrochloride are suspended under argon in 100 mL of dry DMA. 24.3 mL (139 mmol) diisopropylethylamine and 10.21 g (46.4 mmol) of 2-bromo-6-fluoronitrobenzene are then added at RT. The orange solution is then heated to 80° C. for 16 h. After cooling, the reaction mixture is poured onto iced-cold water and the suspension is collected by filtration to afford, after drying in HV at 50° C., the title compound as a dark orange solid, which is used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)=[O:17].CCOC(C)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1[N:19]=[CH:20][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1c[nH]cn1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccc3ccccc3c2)cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 24.3 %

Procedure:
A suspension of 2-naphtylboronic acid (1.4 g, 8 mmol), 1H-imidazole-4-carboxylic acid methyl ester (1.0 g, 8 mmol) and cupric acetate (1.4 g, 8 mmol) in CH2Cl2 (20 ml) was stirred at 20° C. for 24 h. AcOEt (100 ml) and saturated aqueous Seignette salt solution (50 ml) was added and the resulting mixture was stirred for another 2 h. After separation the organic phase was dried (Na2SO4), concentrated and chromatographed (silica, elution with CH2Cl2/MeOH 99:1) to yield the title compound (0.49 g, 24%) of the title compound as a white crystalline material. Mp. 143-144° C. (AcOEt), MS: m/e=252 (M+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>C(Cl)Cl>[CH3:31][C@H:11]1[C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C[C@@H](O)c2ncnc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (77 μL, 1.0 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate (13 mg, 0.04 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to give (5R,7R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol as an oil, which was used further without purification.
Reaction SMILES: [K].[CH3:2][CH:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH:8]([C:12]2[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=2)[C:7](=[O:21])[CH2:6]1)[CH3:4].[C:22](Cl)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C.CCCCCC>[C:22]([O:21][C:7]1[CH2:6][CH:5]([CH:3]([CH3:2])[CH3:4])[CH2:10][C:9](=[O:11])[C:8]=1[C:12]1[C:17]([CH3:18])=[N:16][C:15]([CH3:19])=[C:14]([CH3:20])[N:13]=1)(=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)Cl
Reactant: Cc1nc(C)c(C2C(=O)CC(C(C)C)CC2=O)nc1C
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCC(=O)OC1=C(c2nc(C)c(C)nc2C)C(=O)CC(C(C)C)C1
Temperature: 25 °C

Procedure:
The subject compound was prepared by reaction of 5-(1-methylethyl)-2-(3,5,6-trimethyl-2-pyrazinyl)-1,3-cyclohexanedione potassium salt (Example 8) with hexanoyl chloride employing the general procedure described in Example 3, but allowing the reaction mixture to stir at room temperature over the weekend. Following the reaction, the ether solution of crude product was extracted quickly with ice-cold 0.25N NaOH, dried (MgSO4), filtered and evaporated to give a residue product showing some acid chloride contamination by IR examination. Dry-column chromatography using 1:1 ethyl acetate/hexane gave analytically pure material as shown by the elemental analysis of Table II.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(2-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=166° C.). The reaction was monitored by tlc (Rf=0.55 in 5% MeOH/methylene chloride) and the product was purified by preparative tlc using 5% MeOH/methylene chloride as the eluent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:19]1([CH2:25][CH2:26][C:27](Cl)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([CH2:25][CH2:26][C:27]([N:16]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15]2)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCN2
Reactant: O=C(Cl)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)N1CCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 0.2 g (0.93 mmol) of 7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one in 5 ml of N,N-dimethylformamide was treated with 48 mg (1.20 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was stirred at room temperature for 15 min and then cooled to 0° C. 0.251 g (1.49 mmol) of 3-phenylpropionyl chloride was added and the reaction mixture was stirred at room temperature during 18 h.