Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:15][N:16]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[N:17]2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[C:33]([Cl:38])[C:32]=1[CH:39]([O:41][C:42]1[C:43]([NH2:49])=[N:44][CH:45]=[C:46](I)[CH:47]=1)[CH3:40].C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:49][C:43]1[N:44]=[CH:45][C:46]([C:19]2[CH:18]=[N:17][N:16]([CH2:15][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:4][CH2:3]3)[CH:20]=2)=[CH:47][C:42]=1[O:41][CH:39]([C:32]1[C:33]([Cl:38])=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[Cl:30])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(Oc1cc(I)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1cc(-c2cnn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
A reaction mixture of compound (3-4) (361 mg; 0.89 mmol) and 3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-iodopyridin-2-amine (3-5) (378 mg; 0.89 mmol) in 9.0 mL of ethylene glycol dimethylether, anhydrous (DME) was purged with N2 for 15 minutes, then Pd(II)(PPh3)2Cl2 (32 mg, 0.05 mmol) was added and continued to purge with N2 for another 15 minutes. Another 1.0 N Na2CO3 solution (3.9 mL; 3.9 mmol) was added after purging with N2 for 15 minutes. The resulting mixture was stirred at 85° C. under N2 for overnight. The reaction mixture was filtered through Celite pad and washed well with MeOH. The filtrate was concentrated by vacuum. The residue was partitioned between EtOAc (200 mL) and saturated NaHCO3 solution (2×50 mL); brine (50 mL). The organic layer was dried (Na2SO4), then concentrated by vacuum. The residue was purified by Dionex system (25% to 95% MeCN:H2O w 0.1% HOAc buffer) to collect the desired fraction to afford 147 mg of (3-6) as a white solid (28% yield). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.34-1.39 (m, 9H) 1.70-1.77 (m, 2H) 1.79 (d, J=6.57 Hz, 3H) 3.06 (d, J=12.63 Hz, 2H) 3.62 (s, 2H) 4.03 (s, 2H) 4.79 (s, 1H) 5.66 (s, 2H) 6.08 (d, J=6.82 Hz, 1H) 6.86 (d, J=1.52 Hz, 1H) 7.44 (t, J=8.72 Hz, 1H) 7.51-7.58 (m, 2H) 7.58-7.65 (m, 2H) 7.73 (d, J=1.52 Hz, 1H) 7.78 (s, 1H). LCMS calcd for C27H32Cl2FN5O4 (M+H) 581, found 581. HPLC purity 87%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[N:11]=[C:10]2[O:24][CH3:25])=[C:4]([F:26])[CH:3]=1.[C:27](Cl)(=[O:31])/[CH:28]=[CH:29]/[CH3:30].[H-].[Na+]>CN(C)C=O>[C:27]([O:8][C:7]1[CH:6]=[C:5]([N:9]2[C:14](=[O:15])[C:13]([F:16])=[C:12]([C:17]([F:22])([F:23])[C:18]([F:19])([F:21])[F:20])[N:11]=[C:10]2[O:24][CH3:25])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:31])/[CH:28]=[CH:29]/[CH3:30]
Reactant: C/C=C/C(=O)Cl
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/C(=O)Oc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and crotonoyl chloride with sodium hydride in dimethylformamide there is obtained {2-chloro-4-fluoro-5-[5-fluoro-2 -methoxy-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-phenyl} crotonate, 1H-NMR (CDCl3, 400 MHz): 7.42 ppm (d,1H), 7.28 ppm (m,1H), 7.20 ppm (d,1H), 6.08 ppm (m,1H), 3.98 (s,3H), 2.01 ppm (q,3H);
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[CH:10]([C:19]([OH:21])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[S:14][CH:15]=[C:16]([Br:18])[CH:17]=2)[CH:10]([C:19]([Cl:25])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Yield: 100 %

Procedure:
A solution of the product from step c) (4.6 g, 12.6 mmol) in CH2Cl2 (63 ml) was treated with DMF (3-5 drops) and oxalyl chloride (2.4 g, 18.9 mmol) for 2 hours. Next, the solvent was evaporated in vacuo to give 4.04 g (100%) of the subtitle compound that was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([C:19]3[CH:20]=[CH:21][C:22]([O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:23][C:18]=3[O:17][CH2:16]2)[C:8]1=[O:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:24][C:22]1[CH:21]=[CH:20][C:19]2[C:9]3([CH2:16][O:17][C:18]=2[CH:23]=1)[C:10]1[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:7]([CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[C:8]3=[O:35]
Reactant: CC(C)[Si](Oc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6-{[tris(1-methylethyl)silyl]oxy}spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.69 g, 3.43 mmol) in anhydrous tetrahydrofuran (15 mL) under nitrogen was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 10 mL, 10 mmol), and the mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated, and the residue was re-dissolved in ethyl acetate (25 mL), washed with water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography with 40% ethyl acetate in hexanes to afford 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.00 g, 86%) as a colorless solid: mp 72-74° C.; 1H NMR (300 MHz, CDCl3) δ7.29 (ddd, J=7.5, 7.5, 1.2 Hz, 1H), 7.18-7.01 (m, 3H), 6.80-6.67 (br., 1H), 6.44 (d, J=8.4 Hz, 1H), 6.24 (d, J=2.1 Hz, 1H), 6.17-6.09 (m, 1H), 4.96-4.90 (m, 1H), 4.69-4.63 (m, 1H), 4.36-4.24 (m, 1H), 4.00-3.71 (m, 4H), 2.12-1.61 (m, 4H); MS (ES+) m/z 338.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:21]([O:28][C:29]([N:31]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](Br)[N:38]=1)[CH2:32][C:33]([OH:35])=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:39]1[N:38]=[C:37]([CH2:36][N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH:42]=[CH:41][CH:40]=1)=[O:8]
Reactant: O=C(O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN(CC(=O)O)C(=O)OCc4ccccc4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 with 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (500 mg, 1.70 mmol) and N-[(benzyloxy)carbonyl]-N-[(6-bromopyridin-2-yl)methyl]glycine (Example 179, Step 3) (644 mg, 1.70 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (0.85 g) and 4-nitrophenol (0.5 g) in 5 mL of carbon tetrachloride and 5 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (0.62 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 1.0 g of (2E,4Z)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH2:23][CH:24]3[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]3)C(=O)OC(C)(C)C)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:23][CH:24]3[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]3)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(-c2cc(F)ncc2Cl)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (950 mg, 2.111 mmol) in methanol (5 mL) was added 4M HCl/dioxane (15 mL, 494 mmol). The resulting mixture was stirred for ˜45 min at ambient temperature. The mixture then was concentrated in vacuo and the resulting residue was dissolved in EtOAc (˜50 mL) and saturated aqueous NaHCO3 solution (˜50 mL). The separated organic layer was washed with saturated aqueous NaHCO3 solution (1×), brine (1×), dried over Na2SO4, filtered off and concentrated in vacuo providing crude (R/S)-5′-chloro-N-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-2′-fluoro-2,4′-bipyridin-6-amine as a colorless oil, which was directly used in the next reaction without further purification. Yield: 740 mg. LCMS (m/z): 350.1 [M+H]+; Retention time=0.69 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[OH2:12]>>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O
Product: O=C(O)Cc1ccccc1O

Procedure:
The process of the invention is conveniently carried out by suspending an alkali metal hydroxide in an organic solvent and adding (2-chlorophenyl)acetic acid and a catalyst to this suspension. The reaction mixture is heated to a temperature above 130° C. The reaction can be followed by a chromatographic technique for (example gas/liquid chromatography or high pressure liquid chromatography (using reverse phase medium)) to follow its progress. When the reaction is complete the mixture is cooled and water is added to it. After washing the aqueous phase with a suitable solvent (for example, hexane) it is acidified and extracted with a suitable solvent (for example, ethyl acetate). The extracts are combined, dried and evaporated to leave crude (2-hydroxyphenyl)acetic acid which may be purified.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:24]1[C:28]([CH3:29])=[CH:27][S:26][C:25]=1[CH3:30])CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:30][C:25]1[S:26][CH:27]=[C:28]([CH3:29])[C:24]=1[C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[F:18])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8]
Reactant: COc1ccc(-c2nn(C)c(C#N)c2Br)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)csc1C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn(C)c(C#N)c2-c2c(C)csc2C)c(F)c1
Temperature: 85 °C
Yield: 31.1 %

Procedure:
4-bromo-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (49 mg, 0.16 mmol), tributyl(2,4-dimethylthiophen-3-yl)stannane (82.24 mg, 0.20 mmol), Pd2(dba)3 (14.44 mg, 0.02 mmol) and trio-tolylphosphine (9.6 mg, 0.03 mmol) were mixed with 1.5 mL DMF and the mixture was degassed under nitrogen in a vial. The vial was sealed and the reaction was heated at 85° C. over night. Water was added, the mixture was extracted with CH2Cl2 and the organic layer was concentrated. The crude product was purified on silica to give 4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (17 mg, 32%).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([C:14]([CH2:32][CH3:33])([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([CH2:29][CH3:30])([OH:28])[CH2:26][CH3:27])=[C:19]([CH3:31])[CH:18]=2)[CH2:15][CH3:16])=[CH:11][C:12]=1[CH3:13])=[O:7].[OH-].[Na+].Cl>CO.O>[CH2:15]([C:14]([C:10]1[S:9][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:34])=[O:2])=[O:7])=[C:12]([CH3:13])[CH:11]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([CH2:26][CH3:27])([OH:28])[CH2:29][CH3:30])=[C:19]([CH3:31])[CH:18]=1)[CH2:32][CH3:33])[CH3:16]
Reactant: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)OC)s2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)c(C(=O)NCC(=O)O)s2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
2-[(5-{1-Ethyl-1-[4-(2-ethyl-2-hydroxy-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carbonyl)-amino]-acetic acid methyl ester (Example 52) (0.34 g, 0.69 mmol) is dissolved in MeOH (2 mL), treated with H2O (0.5 mL) and NaOH (0.14 g, 3.47 mmol) and the resulting mixture is heated at a reflux for two hours cooled to at ambient temperature and stirred overnight. The solution is diluted with H2O (10 mL), the pH value is adjusted to about 3-4 using 1 M HCl, it is extracted with EtOAc (40 mL). The EtOAc layer is washed with brine (20 mL), dried with MgSO4, filtered and concentrated to yield the titled compound (0.244 g, 0.51 mmol, 74%). 1H NMR (CD3OD), δ 0.72 (t, J=7.4 Hz, 6H), 0.94 (t, J=7.4 Hz, 6H), 1.64-1.74 (m, 4H), 2.03-2.20 (m, 4H), 2.18 (s, 3H), 2.44 (s, 3H), 3.79 (s, 2H), 3.97-3.99 (m, 2H), 6.71 (s, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.99-7.02 (m, 1H), 7.06-7.10 (m, 1H), 7.88-7.94 (t, J=5.7 Hz, 1H). LC/MS (m/z): calcd. for C26H36NO5S (M−H)−: 475.6; found: 474.3
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[F-].C([N+:10]([CH2:19][CH2:20][CH2:21][CH3:22])(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:1]([CH2:4][C:21]1([CH2:20][C:19]#[N:10])[CH2:22][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-:3])=[O:2]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C[N+](=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 91.1 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>Cl>[ClH:17].[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1F
Reactant: O=C(O)CCS
Agent: Cl
Product: Nc1ccc(Cl)cc1C(SCCC(=O)O)c1ccccc1F

Procedure:
100 g of 2-amino-5-chloro-2'-fluorobenzhydrol, 45.6 g of 3-mercaptopropionic acid and 200 ml of 6N hydrochloric acid are stirred together at 100° for 1.5 hours. After cooling the mixture, the precipitated crystals are filtered off and washed with 6N hydrochloric acid. There is obtained 3-[(2-amino-5-chlorophenyl)(2-fluorophenyl)methylthio]propionic acid hydrochloride of melting point 139°-141°.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:13][CH2:14][CH3:15])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH2:14]([O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)[C:3]=1[CH3:16])[CH3:15]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: CCOc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 43 %

Procedure:
By using 5-bromo-7-ethoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (570 mg, 2.0 mmol) synthesized in Reference example 84 and 1-(4-methylphenyl)piperazine (704 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 327 mg (yield 43%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:42][CH2:43][CH2:44][CH3:45])[C:12]2[N:17]=[C:16]([C:18]3[CH:39]=[C:38]([CH3:40])[C:21]([O:22][CH2:23][C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[C:20]([CH3:41])[CH:19]=3)[O:15][C:13]=2[N:14]=1>ClCCl.FC(F)(F)C(O)=O>[F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[O:8][C:9]1[N:10]=[C:11]([O:42][CH2:43][CH2:44][CH3:45])[C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[C:20]([CH3:41])[C:21]([O:22][CH2:23][C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([OH:33])=[O:32])=[O:25])=[C:38]([CH3:40])[CH:39]=3)[O:15][C:13]=2[N:14]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)N4CCC[C@H]4C(=O)O)c(C)c3)nc12
Reaction time: 16 h

Procedure:
76 mg of tert-butyl(S)-1-(2-{4-[5-(trans-2-fluorocyclohexyloxy)-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethylphenoxy}acetyl)pyrrolidine-2-carboxylate were dissolved in 1.6 ml of dichloromethane and 0.8 ml of trifluoroacetic acid. After 16 h at room temperature, the mixture was concentrated under reduced pressure and freeze-dried. This gave 83 mg of the title compound.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:16]=[N-:17]
Reactant: CCOC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The trans-ethyl 2-methanesulfonyloxymethyl-1-cyclopropanecarboxylate from the previous step (1.655 g, 7.45 mmol) was dissolved in dry dimethyl sulfoxide (20 ml), treated with sodium azide (0.969 g, 14.89 mmol), and stirred at room temperature for 16 h. (tlc indicated no substrate left). After dilution with water, (50 ml), the reaction mixture was extracted with ether (3×50 ml) and the combined organic extracts washed several times (×6) with water and then brine (×3). After drying on anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure gave an oil. Bulb to bulb distillation gave a clear liquid; 1.178 g (93%); bp 86°-90° C./4.0 mm Hg (air bath temperature); ir (film) νmax : 2090 (N3), 1725 cm-1 (C=O); 1Hmr (CDCl3) δ:4.13 (2H, q, J=7, CH2 --CH3), 3.21 (2H, d, J=6, CH2 --OMs), 2.0-0.6 (4H, m, cyclopropyl), 1.23 (3H, t, 5.7, CH2 --CH3). Anal. calcd for C7H11N3O2 : C 49.69, H 6.55, N 24.83; found: C 49.81, H 6.71, N 24.29.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[N:21](CCCCBr)[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8])[N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: BrCCCCCCBr
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCCCCCBr)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 1,6-dibromohexane as described for compound 58. M.p. 55°-56° C.
Reaction SMILES: [CH2:1]1[O:9][C:4]([CH2:7][CH3:8])([CH2:5]Br)[O:3][CH2:2]1.[I-:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]1[O:9][C:4]([CH2:7][CH2:8][I:10])([CH3:5])[O:3][CH2:2]1
Reactant: [I-]
Reactant: CCC1(CBr)OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(CCI)OCCO1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of 4 bromo-2-butanone ethylene ketal (16.4 mmol, 3.2 g) in acetone (30 mL) was treated with sodium iodide (24 mmol, 3.7 g) and sodium carbonate (50 mmol, 5.1 g) and was reluxed overnight. The resulting mixture was filtered, washed with acetone (10 mL) and evaporated to dryness to a white solid. The residue was triturated with a mixture of 1:1 ether:pet ether (20 mL), stirred 30 min., filtered and evaporated to give 3.74 g (94%) of a pale yellow oil. LR-ES (C13H22O4): 243 (M+H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([Cl:20])[C:10]=2[N:9]=[C:8]1[CH3:21])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][OH:4])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CC(=O)OCCn1c(C)nc2c(Cl)nc3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc2c(Cl)nc3ccccc3c2n1CCO
Temperature: 26 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A round bottom flask was charge with a stir bar, 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl acetate (9.2 g, 30.5 mmol), methanol (200 mL) and potassium carbonate (0.4 g, 3.0 mmol). The reaction was judged complete after stirring for 5 hours at 26° C. The solution was partitioned between chloroform and brine. The organic layer was removed and the aqueous fraction extracted with chloroform (6×). The organic fractions were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure to approximately 200 mL when crystallization was observed. The solution was stoppered and maintained at ambient temperature for 24 hours. The resulting fine white crystals were collected by filtration to provide 4.49 g of 2-(4-chloro-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethanol. MS (CI) for C13H12ClN3O m/z 262 (MH+), 218.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([NH2:8])=[NH:7].[Cl:13][C:14]1[CH:15]=[C:16]([S:21](Cl)(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1[F:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH:7][C:6](=[NH:8])[C:5]2[CH:9]=[CH:10][C:11]([F:12])=[C:3]([Cl:2])[CH:4]=2)(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: N=C(N)c1ccc(F)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: Cl
Product: N=C(NS(=O)(=O)c1ccc(F)c(Cl)c1)c1ccc(F)c(Cl)c1

Procedure:
A mixture of 3-chloro-4-fluorobenzamidine hydrochloride (0.025 g, 0.133 mmol) and 3-chloro-4-fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol); the title compound is prepared essentially as described in Example 115. ES Positive Ion MS [M+H]+ ions observed: m/z 365 (35Cl, 35Cl), m/z 367 (35Cl, 37Cl) and m/z 369 (37Cl, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1

Procedure:
Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (2.8 g, 11.52 mmol), 3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.42 g, 12.1 mmol), and K2CO3 (3.2 g, 23.0 mmol) in DMA at 60° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.