Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:24]([C:20]1[CH:21]=[C:22]([C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2ccc(C#N)c(C#N)c2)cc(C(C)(C)C)c1O
Reaction time: 72 h

Procedure:
To a stirred solution of 4-nitrophthalonitrile (8 g, 0.05 mol) was added 2,6 di-tert-butylphenol (11.44 g, 0.06 mol), potassium carbonate (9 g, 0.07 mol) and DMF (50 ml), producing a deep red colour. The reaction mixture was stirred under a nitrogen atmosphere for 72 h. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×100 ml), the organic layer was further washed with water (3×75 ml) and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded the crude product. Recrystallisation from ethanol yielded the pure product 4-(3,5-di-tert-butyl-4-hydroxyphenyl)phthlonitrile (1) as colourless, prismatic crystals (18.70 g, 81.70%), m.p. 209-210° C.; IR (KBr) 3416 (OH), 2231 (CN) cm- 1; (Found C, 79.55%; H, 7.50%; N, 8.20%. C22H24N2O requires C, 79.47%; H, 7.28%; N, 8.43%.); MS (EI) m/e 332 (M+); δH (200 MHz, solvent CDCl3): 1.51 (18H, s), 5.55 (1H, s), 7.39 (2H, s), 7.75-8.00 (3H, m).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]2[C@@H:15]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C@H:14]([CH3:21])[O:13][C:12](=[O:22])[C@@H:11]([NH:23][C:24](=[O:34])[C:25]3[C:30]([OH:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:41]([O:46][CH2:47]Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>CC(C)=O>[C:41]([O:46][CH2:47][O:31][C:30]1[C:25]([C:24](=[O:34])[NH:23][C@H:11]2[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C@@H:15]([O:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)[C@H:14]([CH3:21])[O:13][C:12]2=[O:22])=[N:26][CH:27]=[CH:28][C:29]=1[O:32][CH3:33])(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CC3CCCC3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1O
Reactant: CC(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2CCC[C@H](CC3CCCC3)[C@@H](OCC3CC3)[C@H](C)OC2=O)c1OCOC(=O)C(C)C
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a mixture of N-((3S,7R,8R,9S)-7-(cyclopentylmethyl)-8-(cyclopropylmethoxy)-9-methyl-2-oxooxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (60 mg, 0.126 mmol) and K2CO3 (34.9 mg, 0.253 mmol) in acetone (1 mL) was added chloromethyl isobutyrate (34.5 mg, 0.253 mmol) and the reaction was heated to 60° C. After TLC analysis indicated full consumption of the picolinamide starting material, the mixture was concentrated under a stream of N2 and the residue purified by column chromatography on SiO2 (gradient, EtOAc/hexanes) to yield the title compound as a colorless semi-solid (60.4 mg, 83%): IR (thin film) 3381, 2942, 1745, 1678, 1506, 974 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 6.93 (d, J=5.4 Hz, 1H), 5.81-5.61 (m, 2H), 4.89 (dd, J=9.2, 6.3 Hz, 1H), 4.57 (dt, J=11.0, 7.5 Hz, 1H), 3.89 (s, 3H), 3.50 (dd, J=9.6, 7.0 Hz, 1H), 3.36 (dd, J=9.6, 6.9 Hz, 1H), 3.01 (t, J=9.0 Hz, 1H), 2.54 (p, J=7.0 Hz, 1H), 2.36 (dd, J=13.1, 6.8 Hz, 1H), 1.92-1.43 (m, 15H), 1.42 (d, J=6.5 Hz, 2H), 1.35-1.19 (m, 2H), 1.14 (d, J=7.0 Hz, 3H), 1.17-0.92 (m, 5H), 0.62-0.48 (m, 2H), 0.29-0.17 (m, 2H); HRMS-ESI (m/z) ([M]+) calcd for C31H46N2O8, 574.3254; found, 574.3262.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)=O>ClCCl.CC(C)=O>[C:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:21]
Reactant: C=C(C)C
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 77 %

Procedure:
Dissolve 2-(3-hydroxypropyl)isoindole-1,3-dione (2 g, 9.74 mmol, 1 eq) in 40 mL of dichloromethane under N2. Add sulfuric acid (780 μL) and cool reaction mixture to −5° C. Condense isobutylene gas to a liquid using a −78° C. cold finger charged with dry ice and acetone. Add approximately 20 mL of the condensed liquid to the reaction mixture and slowly warm the solution to room temperature overnight while stirring. Add saturated, aqueous sodium hydrogencarbonate to the reaction mixture and extract product into the organics. Wash separated organic layer with water and dry over magnesium sulfate to give 1.969 g (77% yield) of 2-(3-tert-butoxypropyl)isoindole-1,3-dione as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:10])[F:11])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: FC(F)(F)c1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 2-trifluoromethylbenzenethiol (0.637 g, 0.00358 mole) in DMF (5 mL) was added cesium carbonate (1.396 g, 0.00429 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 0.00358 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed brine solution, dried over sodium sulfate, filtered and concentrated. The resulting residue was washed with hexane to afford 0.81 g (99%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 362.13 (M+1)+, 99%. A solution of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (0.81 g, 0.00224 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 0.604 g (90%) of 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride which was used in the next step without further purification. LCMS: 262.08 (M+1)+, 95.07%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C@H:10]([O:14][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:27]/[CH:26]=[CH:25]\[CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCC/C=C\C/C=C\CCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound VI-8 (210 mg, 43.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 124 mg, 0.644 mmol) and (11Z,14Z)-icos-11,14-dienyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.61 mmol).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][CH:20]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[S:23][C:19]([CH3:18])=[CH:20][N:21]=2)[CH2:25][CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)s1
Product: Cc1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 75 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white foam (yield 75%). MS (m/e): 424.3 (M+H+, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:34]=[C:35]([C:42]([N:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])=[O:43])[CH:36]=[C:37]([CH:41]=1)[C:38](O)=[O:39].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:2]([NH:1][C:38](=[O:39])[C:37]1[CH:41]=[C:33]([CH3:32])[CH:34]=[C:35]([C:42]([N:44]([CH2:45][CH2:46][CH3:47])[CH2:48][CH2:49][CH3:50])=[O:43])[CH:36]=1)[C@H:3]([OH:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol (VIII, EXAMPLE 6) is dissolved in anhydrous DMF (3 mL) and cooled to 0°. Triethylamine (500 μL, 3.6 mmol) and 5-methyl-N, N-dipropylisophthalamic acid (IX, 156 mg, 0.59 mmol) are added with stirring. The mixture is warmed to 20-25° briefly to allow for complete dissolution of the carboxylic acid, before recooling to 00. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) is added with stirring, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2 mmol). The resulting mixture is stirred at 0° for 5 min, then warmed to 20-25° for 15 hr. The mixture is then quenched with aqueous citric acid (10%), and the mixture extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate, saline, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (2-10% methanol/methylene chloride gradient elution) to give purified title compound, MS (ES) MH+=582.3.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:39]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([O-:41])=[O:40]>CN(C=O)C.O>[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 27 (2.90 g, 6.09 mmol) in anhydrous DMF (11 mL) were added K2CO3 (2.53 g, 18.3 mmol) and 4-nitrophenol (0.847 g, 6.09 mmol), and the reaction mixture was heated to 80° C. for 16 h. After cooling, the reaction mixture was diluted in water, extracted three times with CH2Cl2, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give 28 as an oily residue (2.65 g, 98%): 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=9.2 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 4.69-4.56 (m, 1H), 4.28-4.17 (m, 2H), 3.97-3.42 (m, 18H), 1.95-1.41 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 163.82, 141.40, 125.75, 114.52, 98.83, 70.81, 70.51, 70.43, 69.27, 68.15, 66.54, 62.12, 30.48, 25.34, 19.41.
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10](Cl)[N:9]=[C:8]([Cl:14])[N:7]=1)=[O:5]>O1CCOCC1>[CH3:2][O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([NH2:1])[N:9]=[C:8]([Cl:14])[N:7]=1)=[O:5]
Reactant: N
Reactant: COC(=O)c1nc(Cl)nc(Cl)c1Cl
Solvent: C1COCCO1
Product: COC(=O)c1nc(Cl)nc(N)c1Cl
Yield: 87 %

Procedure:
Ammonia was bubbled through a solution of 2,5,6-trichloro-pyrimidine-4-carboxylic acid methyl ester (15.94 g, 66 mmol, see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for preparation) in p-dioxane (150 mL) for 30 minutes. The solvent was then removed and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated under vacuum. The product was purified by column chromatography to provide 6-amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (12.74 g, 87% yield): mp 164-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:7]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:17][CH2:18][CH2:19][O:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(Cl)ccc1OCCBr
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A mixture of (5-chloro-2-hydroxy-phenyl)-phenyl-methanone (0.93 g, 4.0 mmol), δ 1,2-dibromoethane (3.5 mL, 40 mmol) and potassium carbonate (0.83 g, 6.0 mmol) in acetonitrile (10 mL) is heated at reflux under N2 over weekend (about 60 hours). After cooling to room temperature, solid potassium bromide is filtered off and washed with ca. 70 mL of acetonitrile. The filtrate is evaporated, and the crude mixture purified by column chromatography (SiO2, 5-12% ethyl acetate in hexanes) to afford 1.18 g (87%) of the title compound as colorless product. APCI-MS: m/z 339 [(M+H)+, 35Cl, 79Br], 341 [(M+H)+, 37Cl, 79Br], 343 [(M+H)+, 37Cl, 81Br]. 1H-NMR (300 MHz; CDCl3): δ7.78 (2H d, 8.1 Hz); 7.58 (1H, br t, 7.5 Hz); 7.38-7.50 (4H, m); 6.92 (1H, d, 8.6 Hz); 4.18 (2H, t; 6.5 Hz); 3.26 (2H, t, 6.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1 of ethyl 8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 27A, 3 mmol, 1 equivalent) were initially charged in 60 ml of methanol/THF (5:1), 15 ml of a 1 N aqueous lithium hydroxide solution (15 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 4 h. The mixture was then cooled and, with ice cooling, adjusted to pH 4 using 6 N aqueous hydrochloric acid. The organic solvents were removed on a rotary evaporator, water was added to the precipitated product and the product was filtered, washed with water and dried under high vacuum. This gave 797 mg (87% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C(O)C>[C:8]([C:7]1[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:3][C:4]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[N:5][C:6]=1[O:10][CH3:11])#[N:9]
Reactant: COc1nc(N2CCSCC2)nc(Cl)c1C#N
Reactant: C1CNCCN1
Solvent: O
Solvent: CCO
Product: COc1nc(N2CCSCC2)nc(N2CCNCC2)c1C#N
Temperature: 130 °C

Procedure:
18 gm (0.067 mol) of 4-chloro-5-cyano-6-methoxy-2-thiomorpholino-pyrimidine (m.p. 218°-219°C) were admixed with 60.3 gm (0.7 mol) of piperazine, and the mixture was heated at 130°C for 3 hours. After cooling, water was added, and the aqueous mixture was extracted with chloroform. The chloroform phase was dried, and the chloroform was removed in vacuo. The residue, the free base reaction product, was dissolved in hot ethanol, and the hydrochloride was precipitated by addition of ethanolic hydrochloric acid, suction-filtered off and washed with ethanol. Yield: 13 gm (54.8% of theory); m.p. 261°C.
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(=O)([O-])[O-:15].[Cs+].[Cs+]>C(#N)C>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:15])[CH2:12][CH3:13]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCCC(CC)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 399.2 %

Procedure:
A mixture of TMIT (1.0 g, 6.33 mmol), 2-ethylhexyl acrylate (1.16 g, 6.33 mmol) and cesium carbonate (1.0 g, 3.3 mmol) in acetonitrile (15 mL) was stirred at room temperature for 24 h. The reaction mixture was filtered to separate solid cesium carbonate and solvent was evaporated from the filtrate to obtain the product as a colorless oil (1.9 g, 88 %). IR: 3325, 2961, 1732, 1595, 1480 cm31 1; 1H NMR (CDCl3, 500 MHz): δ3.96 (overlapping d, 2 H), 3.83 (t, 1.72 H), 3.22 (t, 0.28 H), 2.82 (t, 1.72 H), 2.71 (t, 0.28 H), 1.91 (bs, 1H), 1.42 (s, 6 H), 1.40 (s, 6H), 1.35-1.20 (m, 8 H), 0.85 (overlapping t, 6 H) ppm; 13C NMR (CDCl3, 125 MHz): δ205.8, 173.6, 171.9, 171.3, 130.2, 128.5, 88.7, 82.9, 70.35, 69.6, 67.2, 66.9, 66.8, 40.6, 38.6, 33.9, 31.4, 30.26, 30.21, 28.79, 28.71, 28.23, 25.8, 23.64, 22.83, 13.9, 10.9 ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:18]=1[CH3:24]>ClCC(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl>[OH:16][C:17]1[C:18]([CH3:24])=[C:19]([OH:23])[CH:20]=[CH:21][C:22]=1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: Cc1c(O)cccc1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(O)ccc(C(=O)c2ccccc2C(=O)O)c1O
Reaction time: 1 h

Procedure:
Aluminum chloride (21.4 g, 161 mmol) was added to a stirring suspension of phthalic anhydride (6 g, 40 mmol) in tetrachloroethane (200 mL) under nitrogen. 1,3-Dihydroxy-2-methylbenzene (5 g, 40 mmol) was added and the mixture quickly thickened. After the precipitates were broken up with a spatula the reaction continued for 1 hour. The solution was diluted with ethyl acetate (˜600 mL) and washed with 1 M hydrochloric acid (2×200 mL). The product was extracted from the organic layer into a saturated solution of sodium bicarbonate in water (600 mL). The basic aqueous phase was acidified with 3M hydrochloric acid to a pH of 5. The product was extracted from the aqueous phase into ethyl acetate (400 mL), washed with brine (2×100 mL), dried over magnesium sulfate and concentrated to give a brownish solid. The solid was slurried in dichloromethane (20 mL) and filtered to give 2-(2,4-dihydroxy-3-methylbenzoyl)benzoic acid as an off white powder (4.6 g, 16.9 mmol, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]([OH:28])[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][C:21]3=[O:26])=[C:16]([F:27])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[C:29](=C1N=CC=N1)=[O:30].CN(C1C=CC=CN=1)C.C(#N)C>O1CCOCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:28][C:29](=[O:30])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][C:21]4=[O:26])=[C:16]([F:27])[CH:15]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C=C1N=CC=N1
Reactant: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCC1CN(c2ccc(N3CCOCC3=O)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
260 mg (0.608 mmol) of 5-chloro-N-(3-{[3-fluoro4-(3-oxo4-morpholinyl)phenyl]-amino}-2-hydroxypropyl)-2-thiophenecarboxamide (from Example 61), 197 mg (1.22 mmol) of carbonylimidazole and 7 mg of dimethylaminopyridine in 20 ml of dioxane are boiled under reflux for 5 hours. 20 ml of acetonitrile are then added, and the mixture is stirred in a closed vessel in a microwave oven at 180° C. for 30 minutes. The solution is concentrated using a rotary evaporator and chromatographed on an RP-HPLC column. This gives 53 mg (19% of theory) of the target compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Br[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1>O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[N:21][CH:22]=1
Reactant: Oc1ccccc1F
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2F)cn1
Temperature: 60 °C
Yield: 55.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was mixed with 3-5 ml of dry dimethylformamide and 2-fluorophenol (0.24 ml, 2.7 mmol) was added to the stirred suspension. When the gas evolution was ceased the reaction mixture was heated at stirring at 60° C. and 5-bromo-2-nitropyridine (0.5 g, 2.5 mmol) was added to the reaction mixture in one portion. The reaction mixture was stirred at 60° C. for about 12 hours. The reaction mixture was then mixed with 50 ml of water and extracted into methylene chloride (3×20 ml). Organic extract was washed with water and brine, dried over magnesium sulfate and concentrated by rotary evaporation. The resulting mixture was purified by column chromatography on silica (30 g, EtOAc/hexane 1:3) to give 326 mg (57% yield) of desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]([OH:17])[C:14]([O:16][CH3:22])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To solution of [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510 mg, 1.77 mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by (trimethylsilyl)diazomethane (1.06 mL of a 2M solution in hexanes, 2.12 mmol). After 10 minutes, the reaction was quenched with several drops of HOAc (add until yellow color disappears). The reaction was concentrated and purified by flash chromatography with 10 to 80% EtOAc/hexanes to afford methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 2H), 7.85 (s, 1H), 5.32 (s, 1H), 3.83 (s, 3H), 3.68 (bs, 1H).