Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH:34]([CH3:38])[C:35]([NH2:37])=[O:36])[C:23]([C:39]([F:41])([F:40])[F:42])=[CH:22][N:21]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C(C)C(N)=O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Acetic anhydride (15 μL, 0.15 mmol) was added to a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide 56 (50 mg, 0.10 mmol) in DCM (5 mL) and pyridine (12 μL, 0.15 mmol) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resultant solid was suspended in water (25 mL) and sonicated for 5 minutes. The solid was collected by filtration and washed with sat. aq. Na2CO3 (20 mL), water (50 mL) then petroleum benzine 40-60° C. to give the title compound 58 as a white solid (42 mg, 77%). LCMS-D: rt 3.176 min; m/z 530.4 [M+H]+.
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:24])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:24])[CH2:15][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)C1CCC(F)(F)CC1
Yield: 196.8 %

Procedure:
To 32 mg (0.13 mmol) of 1,3-diethyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2,4-dione and 38.4 mg (0.13 mmol) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide was added 2.2 mL of anhydrous DCE and 34 mg (0.17 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by Bond Elut (ethyl acetate to 5% methanol/DCM) to yield 42 mg (60.9%) of 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[1,3-diethyl-bicyclo[3.2.1]-2,4-dioxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:31])[C:28](O)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@H:27]([CH3:31])[C:28]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:29])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)O
Reactant: C1COCCN1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N1CCOCC1
Yield: 42 %

Procedure:
Using the same procedure as in Example 44, (2R)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (300 mg, 0.66 mmol) was reacted with morpholine to give the title compound as a white solid (144 mg, 42%); NMR Spectrum 1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrum MH+ 527.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.C(N(CC)CC)C>C1COCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CCCCOC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)C12CC3CC(CC(OCOCCOC)(C3)C1)C2
Yield: 94.1 %

Procedure:
A mixture of 200 mmol of n-butyl 3-hydroxy-1-adamantanecarboxylate, 220 mmol of 2-methoxyethoxymethyl chloride, 220 mmol of triethylamine and 200 ml of THF was refluxed for 3 hours. The reaction mixture was concentrated and subjected to column chromatography on a silica gel to give n-butyl 3-(2-methoxyethoxymethoxy)-1-adamantanecarboxylate (yield: 94.1%) at a conversion rate from n-butyl 3-hydroxy-1-adamantanecarboxylate of 99%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[CH3:33][NH2:34]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[NH:14]2)=[C:7]([S:9]([NH:34][CH3:33])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Reaction time: 8 h

Procedure:
5-Cyano-2-{(4S)-5-cyano-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (40 mg, 83 μmol) was dissolved in THF (5 ml), a 2 M solution of methylamine in THF (208 μl, 415 μmol; 5 eq.) was added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Gromsil C-18, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (14.3 mg, 36% of theory).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64](OC2C=CC([N+]([O-])=O)=CC=2)=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:76]([O:80][C:81]([NH:83][CH2:84][CH2:85][OH:86])=[O:82])([CH3:79])([CH3:78])[CH3:77].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:63][C:64]([O:86][CH2:85][CH2:84][NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:82])=[O:65])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)Oc4ccc([N+](=O)[O-])cc4)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)OCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of the compound of Example 5A (83 mg, 0.081 mmol), 2-(tert-butyloxycarbonylamino)ethanol (26 mg, 0.161 mmol), DMAP (10 mg) and Hunig's base (0.1 mL) in acetonitrile (1 mL) was stirred at 90° C. overnight. The reaction mixture was partitioned between H2O and EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (73 mg, 86% yield).
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][N:10]=1.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:34]=[N+:35]=[N-:36])=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Reaction time: 3 h
Yield: 99 %

Procedure:
Into ethyl acetate was suspended 1.91 g of 6-(trifluoromethyl)nicotinic acid, and then 1.52 g of triethylamine and 3.03 g of DPPA were added thereto, followed by 3 hours of stirring. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and saturated saline and the solvent was removed by evaporation to obtain 2.0 g of 6-(trifluoromethyl)nicotinyl azide as a solid. The resulting acid azide was dissolved into 20 ml of toluene and the solution was heated and refluxed to convert the acid azide into 5-isocyanato-2-(trifluoromethyl)pyridine. Thereafter, 1 ml of methanol was added thereto at room temperature, followed by 1 hour of stirring. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation to obtain 1.2 g of the title compound.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1.CCCCCC>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of veratrole (16.6 g, 0.120 mol) in tetrahydrofuran (130 mL) at −78° C. was added n-butyllithium (50.5 mL, of a 2.5 M solution in hexane, 0.126 mmol). The resulting mixture was allowed to warm to ambient temperature over 1 hour and then stirred at this temperature for 4 hours before recooling to −78° C. and treating the resulting slurry with a solution of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (30.71 g, 0.1128 mol) in tetrahydrofuran (180 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight and then recooled to 0° C. and quenched by the addition of saturated aqueous ammonium chloride solution (110 mL). The aqueous layer was extracted with ether (110 mL) and the combined organic extracts were washed with brine (220 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (7).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(-n2ccnc2)n(-c2ccccc2)c2ccccc12
Yield: 12 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with imidazole as described in Example 1 to afford 2-imidazol-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (12% yield) as a white solid. LC/MS: 288 (M+H); RT 2.55 min; NMR (CDCl3): 9.94 (1H, s), 8.45 (1H, d), 7.63 (1H, s), 7.35-7.54 (6H, m), 7.17-7.29 (2H, m), 7.12 (1H, s), 7.03 (1H, s).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][C:13]2[C:18]([C:19]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH2:36][C:37]4[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=4)[N:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cccc(OC(F)F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 3-(difluoromethoxy)aniline (0.038 mL, 0.303 mmol) (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.090 g, 0.202 mmol) in THF (3.0 mL) at 0° C. was treated with LiHMDS 1.0 M in THF (0.606 mL, 0.606 mmol) (Aldrich) dropwise. The solution was stirred at 0° C. for 1.5 h and was then quenched with a saturated solution of NH4Cl at 0° C. The mixture was extracted with EtOAc (15 mL), dried over MgSO4, filtered and concentrated to give 4-(2-(3-(difluoromethoxy)phenylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.121 g, 0.207 mmol, 99% yield) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 12.12 (br. s., 1H); 8.84 (d, J=8.2 Hz, 1H); 8.35 (br. s., 1H); 7.72 (br. s., 1H); 7.31 (d, J=8.4 Hz, 1H); 7.20 (d, J=7.8 Hz, 5H); 7.11 (t, J=8.0 Hz, 4H); 6.84-6.90 (m, 4H); 6.80 (d, J=7.8 Hz, 1H); 6.71 (d, J=8.4 Hz, 1H); 6.65 (br. s., 1H); 6.45-6.54 (m, 10H); 6.42 (br. s., 4H); 6.28 (br. s., 1H); 4.84 (br. s., 4H); 3.80 (d, J=3.5 Hz, 7H); 2.60 (br. s., 3H). m/z (ESI, +ve ion) 585.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Reactant: O=C(O)C1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)C3CCCC3)ccc2n1
Yield: 48 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using cyclopentanecarboxylic acid instead of cyclopropylacetic acid, to the title compound (56 mg, 48%) which was obtained as an off-white solid. MS: m/e=387.3 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])([CH3:12])([CH3:11])[CH3:10].CCOCC>C(#N)C>[Br:1][C:17]1[CH:16]=[CH:15][C:14]([OH:19])=[C:13]([C:9]([CH3:12])([CH3:10])[CH3:11])[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1O
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)c1cc(Br)ccc1O
Reaction time: 4 h
Yield: 100 %

Procedure:
N-bromosuccinimide (580 g) was gradually added to a solution of 2-(tert-butyl)phenol (489 g) in acetonitrile (4000 ml) while cooling on ice. After stirring for 4 hours at below 20° C., ether (3000 ml) was added and the reaction mixture was washed twice with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (746 g) as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(F)=NC(F)=NC=1[F:21].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:21])=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)F)c1ccccc1
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with 24k (125.8 mg, 0.50 mmol) was added 1.25 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (225 μL, 2.5 mmol). The reaction was stirred at −15 C for 15 minutes then anhydrous pyridine (40 μL, 0.5 mmol) was added. Stirring was maintained at −15 C for 60 minutes. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 115.3 mg of a mixture of 24k and 25k as an off-white solid. FTIR (film) 1849.3 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].CO.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[C:17]1([C:3]2[C:4]3[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(C3=CCCC3)c[nH]c2c1
Temperature: 75 °C

Procedure:
A 3 L three-necked flask equipped with a mechanical stirrer was charged with indole 6-carboxylic acid (220 g, 1.365 mole) and KOH pellets (764.45 g, 13.65 mole, 10 equivalents). Water (660 mL) and MeOH (660 mL) were added and the mixture heated to 75° C. Cyclopentanone (603.7 mL, 6.825 mole, 5 equivalents) was added dropwise over 18 h using a pump. The reaction mixture was heated for an additional 3 h (after which the reaction was judged complete by HPLC) and cooled to 0° C. for 1 h. The precipitated potassium salt is collected by filtration, and washed with TBME (2×500 mL) to remove cyclopentanone self-condensation products. The brown solid was re-dissolved in water (2.5 L) and the solution washed with TBME (2×1 L). Following acidification to pH 3 with conc. HCl (425 mL), the beige precipitate was collected by filtration, washed with water (2×1 L) and dried under vacuum at 70° C. The crude product weighed 275.9 g (88.9% mass recovery) and had an homogeneity of 85% (HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].ClC1C=CC=CC=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(OCC)(=O)C>[CH3:21][CH:20]([CH3:22])[C:19]([C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][C:3]([O:2][CH3:1])=[O:18])=[CH:7][CH:8]=1)=[O:23]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)C)cc1
Temperature: 4 °C
Reaction time: 7 h
Yield: 66.8 %

Procedure:
A mixture of 80 g (0.333 mol) of methyl3,3-diphenylpropanoate, 42.6 g (0.399 mol) of isobutyryl chloride, and 600 mol of 1,2-dichlorobenzene is cooled to 4° C. Aluminum chloride (112 g, 0.832 mol) is added portion wise over 2 hours while the reaction temperature is kept between −5 and 5° C. The reaction is kept within this temperature range for 7 hours, and then stirred at room temperature for 13 hours. The reaction mixture is poured into a mixture of ice and concentrated hydrochloric acid, and then stirred for 1 hour. The organic layer is washed twice with dilute hydrochloric acid, and then concentrated under vacuum to give 115 grams of crude product. Purification by column chromatography on silica gel with 9:1 heptane:ethyl acetate as the eluent gives 69 g (60% yield) of methyl 3-[4-(2-methylpropionyl)phenyl]-3-phenylpropanoate.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]4[CH2:28][CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:31]=[C:22]34)[CH:18]=[CH:17][N:16]=2)[CH3:13])=[CH:7][CH:6]=1)=[N+]=[N-].C1CC=CCC=1>[Pd].C(OC(=O)C)C>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]4[CH2:28][CH:29]=[C:30]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:31]=[C:22]34)[CH:18]=[CH:17][N:16]=2)[CH3:13])=[CH:7][CH:6]=1
Reactant: CC(Cc1ccc(CN=[N+]=[N-])cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCC=CC1
Product: CC(Cc1ccc(CN)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1

Procedure:
The mixture of 1-{2-[2-(4-azidomethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one, 1,4-cyclohexadiene (80 μL, 0.80 mmol) and palladium on carbon (100 mg) in ethylacetate (10 mL) was heated to reflux for 3 h and brought to room temperature. The mixture was filtered through celite and concentrated to afford a white solid. M+1=468. 1NMR (CDCl3) d (3H, 1.22 ppm), m (2H, 2.23 ppm), m (1H, 2.76 ppm), m (1H, 2.98 ppm), s (2H, 3.84 ppm), m (4H, 4.11 ppm), m (1H, 4.31 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.23 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.18 ppm).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[C:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>>[C:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Product: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C2CCCCC2)(C2CCCCC2)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11]COCC.[N+](=C)=[N-]>O1CCCC1>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(I)cc1
Yield: 99.3 %

Procedure:
Fifty (50) mmol (12.4 g) of commercially available 4-iodobenzoic acid was dissolved in 200 ml of tetrahydrofuran and then added to an ether solution containing freshly prepared diazomethane. The excess diazomethane was subsequently consumed by addition of glacial acetic acid and the resultant solution was concentrated in vacuo. The residue thus obtained was partitioned between ethyl acetate and saturated NaHCO3. The layers were separated and the aqueous phase was extracted with 100 ml of ethyl acetate. the organic extracts were combined, dried over Na2SO4, and concentrated in vacuo, yielding 13.01 grams (99.3% yield) of a yellow solid which melted at 111° C.