Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[NH2:56][C:57]1[N:62]=[CH:61][C:60]([C:63]([OH:65])=O)=[CH:59][CH:58]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]([N:44]([CH2:43][CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]2[C:25]3([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]4([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:3]([C:2]([F:54])([F:1])[F:55])[CH:4]=5)[CH2:12]4)[CH2:23][CH2:24]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[CH3:46])[CH3:45])=[O:65])=[CH:61][N:62]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc(N)nc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
The compound (200 mg, 0.257 mmol) obtained in Example 1k was dissolved in methylene chloride (3 mL)-N,N-dimethylformamide (2 mL), 6-aminopyridine-3-carboxylic acid (36 mg, 0.257 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74 mg, 0.386 mmol) and 4-dimethylaminopyridine (4 mg, 0.0258 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=40:1, v/v) to give the title compound (196 mg; yield, 85%) as a white solid.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([CH:34]=O)=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1.O>COCCOC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24](/[CH:34]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:26]=2)[CH:23]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Ethyl (diethoxyphosphinyl)acetate (0.44 mL, 0.50 g, 2.2 mmol) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 98 mg, 2.5 mmol) in 1,2-dimethoxyethane (10 mL) and the mixture was stirred at room temperature for 1 h. A suspension of 6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carboxaldehyde (Description 18, 650 mg, 2.2 mmol) in 1,2-dimethoxyethane (10 mL) was added and the mixture was stirred at room temperature for 1 h. Further sodium hydride (60% in mineral oil, 98 mg, 2.5 mmol) was added and the mixture was stirred at room temperature for 2 h. Water (100 mL) was added and the solid was collected. Toluene was added and evaporated under reduced pressure and the residue was dried in vacuo to give the title compound as a pale brown solid (380 mg, 47%). 1H NMR (360 MHz, CDCl3) δ 8.47 (1H, d, J 1.8 Hz), 7.94 (1H, d, J 16.4 Hz), 7.68 (3H, m), 7.48 (2H, d, J 8.4 Hz), 7.34 (1H, dd, J 9.4, 1.8 Hz), 6.37 (1H, d, J 16.4 Hz), 4.30 (2H, q, J 7.1 Hz), and 1.36 (3H, t, J 7.1 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:1][CH2:2][C:3]4[S:4][CH:5]=[CH:6][CH:7]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: NCc1cccs1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3cccs3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
2-Aminomethyl thiophene (0.38 g, 3.363 mmol) and tetrabutylammonium iodide (0.02 g, 0.054 mmol) were added to a suspension of the carboxylic acid of Example 56k (0.4 g, 0.96 mmol) in methanol (5 mL) under nitrogen in a pressure reactor vessel and heated to 110° C. for 4 h. The reaction mixture was concentrated (oily residue), treated with methanolic HCl (15 mL) and refluxed for 3.5 h. It was concentrated, treated with an aqueous sodium bicarbonate solution to pH 8 and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, 0.5% methanol/chloroform) to obtain the title compound. Yield: 0.21 g, (43.5%). 1H NMR (CDCl3): δ 2.68 (s, 3H, CH3), 2.98 (t, 2H, CH2), 3.18 (t, 2H, CH2), 3.9 (s, 3H, CH3), 4.6 (s, 2H, CH2), 4.67 (s, 1H, NH), 5.21 (s, 2H, CH2), 6.50 (s, 1H, Ar), 6.55 (s, 1H, Ar), 6.95 (s, 2H, Ar), 7.2 (m, 1H, Ar), 8.05 (s, 1H, Ar), 8.45 (s, 1H, Ar); MS: m/e (ES+) 505 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[S:12][CH:11]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(#N)C.O>[OH:1][C:2]1([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:16])([CH3:17])[S:12][CH:11]2[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(CCCC2SC(C)(C)C(=O)N2CCC2(O)CCCCC2)cc1
Solvent: CC#N
Solvent: O
Product: CC1(C)SC(CCCc2ccc(C(=O)O)cc2)N(CCC2(O)CCCCC2)C1=O

Procedure:
The product of Step A above is saponified exactly as described in Example 2, Step C, to yield the title product as a crystalline solid, m.p. 132°-137° C. (from acetonitrile-water).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.OOS([O-])=O.[K+].CN(C=O)C>C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (200 mg, 710 μmol), 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (190 mg, 860 μmols) (from Example 6-17) and oxone (286 mg, 470 μmols) in a solution of 5 mL DMF/0.5 mL water was stirred at ambient temperature for 1 h. The mixture was poured into ethyl acetate and extracted once with water and five times with brine. The organic phase was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a gradient of 50-90% heptane/ethyl acetate to afford 3-{4-[6-(4-tert-butylphenylcarbamoyl)-1H-benzimidazol-2-yl]-3,5-dimethylphenyl}-propionic acid methyl ester. 1H-NMR (CDCl3, 400 MHz): δ 8.51 (s, broad, 1H), 8.07 (s, broad, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 6.82 (s, 2H), 3.63 (s, 3H), 2.89 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.92 (s, 6H), 1.30 (s, 9H). MS (ESI) m/z 484.3 (M+H).
Reaction SMILES: [CH2:1]([O:9][N:10]=[C:11]([C:17](=[O:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[CH2:1]([O:9][N:10]=[C:11]([C:17](=[O:19])[CH2:18][Cl:23])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 90.9 %

Procedure:
Ethyl 2-n-octyloxyimino-3-oxobutyrate (syn isomer, 165.5 g.), sulfuryl chloride (84.7 g.) and acetic acid (165 ml.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-octyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 169.6 g.), oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:32]=[C:31]([C:39]([N:41](C)[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16].[CH3:58][O:59][CH2:60]CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:19][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[N:32]=[C:31]([C:39]([NH:41][CH2:42][CH2:58][O:59][CH3:60])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:21]1)#[N:16]
Reactant: CN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reactant: COCCN
Solvent: O=C(O)C(F)(F)F
Product: COCCNC(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared by a procedure similar to that of Example 46 using 6-[(cis-4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (20.00 mg, 0.02866 mmol) (Example 46, Step 4) and 2-methoxyethylamine (4.98 μL, 0.0573 mmol). 1H NMR (300 MHz, CD3OD) δ 9.09 (s, 1H), 8.88 (s, 1H), 8.79 (brs, 1H), 8.59 (s, 1H), 7.79 (d, 1H), 7.58 (s, 1H), 7.25 (d, 1H), 5.53 (m, 1H), 5.10 (d, 2H), 4.82 (d, 2H), 3.73 (s, 2H), 3.65-3.45 (m, 5H), 3.37 (d, 3H), 2.31 (m 2H), 2.04 (m, 2H), 1.90-1.55 (m, 4H). MS (ES): 625(M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=O)[O:11][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([C:10]1([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]2[S:13][CH2:14][CH2:15][C:8]=2[C:7]2[C:2]([OH:1])=[CH:3][C:4]([CH3:16])=[CH:5][C:6]=2[O:11]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC[Mg]Br
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3
Product: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno [2,3-c] [1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][N:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[CH:19][N:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (730 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (650 mg, yield: 95%). This was recrystallized from acetone-hexane. Melting point: 133–134° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([Si](C)(C)C)([F:20])[C:16]([F:19])([F:18])[F:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[F:14][C:15]([F:20])([C:16]([F:19])([F:18])[F:17])[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)([OH:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of methyl 4-acetylbenzoate (700 mg, 3.85 mmol) in tetrahydrofuran (7.7 mL) were added (pentafluoroethyl)trimethylsilane (1370 mg, 6.93 mmol) and tetrabutylammonium fluoride (tetrahydrofuran solution, 1 mol/L, 5.7 μL, 5.78 mmol) at 0° C., and the mixture was stirred at room temperature overnight. To the solution was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, filtered through Phase-separator (Varian Inc.), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→70:30) to give methyl 4-(2,2,3,3,3-pentafluoro-1-hydroxy-1-methylpropyl)benzoate (765 mg, 67%) as a pale yellow viscous material.
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:24])([F:23])[C:9]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[F:7][C:8]([F:23])([F:24])[C:9]([C:10]([F:12])([F:11])[F:13])([C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=1)[O:14][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(OCC(=O)OC(C)(C)C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A 1M solution of t-BuOK in THF (25.00 mL, 25.00 mmol) was slowly added to a solution of 1,1,1,3,3,3-Hexafluoro-2-(4-vinylphenyl)-2-propanol (5.48 g, 20.30 mmol) in THF (25 mL). The reaction mixture was allowed to stir at room temperature for 30 min, then cooled to −78° C. using a dry ice /acetone bath followed by the addition of t-butyl bromoacetate (3.75 mL, 25.40 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight, concentrated, diluted with hexane, filtered through celite, and concentrated to provide 7.96 g of a reddish-yellow oil. This material was purified by column chromatography on silica gel using 50:1 hexane/ethyl acetate to provide 6.44 g (82%) of a colorless oil; 1H NMR (CDCl3) δ 7.60 (d, 2ArH), 7.50 (d, 2ArH), 6.75 (dd, CH═), 5.85 (dd, ═CHH), 5.40 (dd, ═CHH), 4.05 (s, CH2), 1.50 (s, t-Bu).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23]C)[CH:19]=3)[CH:14]=2)[CH:12]=1)[C:6]([NH:8][CH3:9])=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[CH:12]=1)[C:6]([NH:8][CH3:9])=[O:7]
Reactant: CNC(=O)c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: CNC(=O)c1cc(O)cc(-c2ccc3cc(O)ccc3c2)c1

Procedure:
The compound is prepared by reaction of 3-methoxy-5-(6-methoxynaphthalene-2-yl)-N-methylbenzamide (110 mg, 0.34 mmol, 1 eq) with boron tribromide solution (5 eq) according to method G. Purification by column chromatography was not necessary. The desired product was already obtained after the processing in quantitative yield (99.6 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CS(O[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:32][N:31]=[C:30]([CH:33]([CH3:35])[CH3:34])[N:29]=2)[CH2:24][CH2:23]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:35][CH:33]([C:30]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=4)=[N:14][CH:13]=3)[CH2:27][CH2:26]2)[O:32][N:31]=1)[CH3:34]
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CSc1ccc(-c2ccc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A mixture of 6-[4-(methylthio)phenyl]-3-pyridinol (53.2 g, 245 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 74.3 g, 735 mmol), K2CO3 (101.5 g, 735 mmol) and DMF (500 mL) was stirred at 80° C. for 2 h. The mixture was charged with water, allowed to stand for 30 min, and the resulting precipitate was filtered, washed with water, heptane, and air dried to give 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylthio)phenyl]pyridine (93.7 g, 90%) as a tan solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (d, 1H, J=2.8 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.61 (d, 1H, J=8.7 Hz), 7.30 (d, 2H, J=8.5 Hz), 7.22 (d, 1H, J=3.0 Hz), 4.30-4.10 (m, 2H), 3.90 (d, 2H, J=6.2 Hz), 3.15-3.05 (m, 2H), 2.92-2.82 (m, 1H), 2.50 (s, 3H), 2.14-1.99 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.3 Hz); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([F:18])[C:12]([F:19])=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Zn].O>[CH2:1]([O:8][C:9]1[C:10]([F:20])=[CH:11][C:12]([F:19])=[C:13]([F:18])[C:14]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)c(F)cc(F)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1c(F)c(F)cc(F)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
A round bottom flask containing 2-benzyloxy-1,4,5-trifluoro-3-nitrobenzene (0.44 g, 1.54 mmol), zinc dust (0.50 g, 7.71 mmol) and solid ammonium chloride (0.17 g, 3.08 mmol) is added a mixture of ethanol and water (2:1 ratio, 15 mL total). The resulting slurry is heated at 60° C. for 90 min. The mixture is filtered, washed with methanol and the filtrate is concentrated. The residue is extracted twice with EtOAc and water, dried over MgSO4 and concentrated. The crude product is used directly in the next step without purification.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>ClCCl>[CH3:17][O:18][CH2:19][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC(=O)C(c1ccccc1)c1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Diphenylacetic acid methoxymethyl ester was prepared in the following manner: to a mixture of 10.0 g (47.1 mmol) diphenylacetic acid and 4.0 ml (4.16 g, 51.8 mmol) of chloromethyl methyl ether in 50 ml of dichloromethane cooled to -5° C. was added 7.2 ml (5.24 g, 51.8 mmol) of triethylamine in 50 ml dichloromethane. The mixture was allowed to warm to room temperature and stir overnight at which point the reaction mixture was washed with aqueous sodium bicarbonate, dried with MgO-MgSO4, and concentrated in vacuo. The residue was distilled to give 7.25 g (28.3 mmol, 60% yield) of the corresponding methoxymethyl ester, bp 135°-140° C./0.1 mm Hg.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]1[OH:12].[Cl:13][C:14]1[C:19]([NH2:20])=[C:18](Cl)[N:17]=[C:16]([S:22][CH2:23][CH2:24][CH3:25])[N:15]=1.C(N(CC)CC)C>C(OCC)(=O)C.CCCCCC>[NH2:20][C:19]1[C:18]([NH:1][C@@H:2]2[CH2:6][C@H:5]([O:7][CH2:8][CH2:9][OH:10])[C@@H:4]([OH:11])[C@H:3]2[OH:12])=[N:17][C:16]([S:22][CH2:23][CH2:24][CH3:25])=[N:15][C:14]=1[Cl:13]
Reactant: N[C@@H]1C[C@H](OCCO)[C@@H](O)[C@H]1O
Reactant: CCCSc1nc(Cl)c(N)c(Cl)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Temperature: 75 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
A mixture of (1S,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLA; 1.06 g, 6 mmol), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (CLINA; 1.43 g, 6 mmol), triethylamine (1.09 g, 7.8 mmol) and polyethyleneglycol PEG400 (2 mL) was stirred for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) and evaporated under reduced pressure to give a resinous material which solidified upon trituration in n-hexane (25 mL). After filtration there was obtained OLACINA as a grey powder (2.0 g, 88% yield): 13C NMR (DMSO-d6, 125 MHz) δ13.3, 22.8, 32.2, 34.7, 54.8, 60.4, 69.8, 72.4, 75.2, 82.4, 119.9, 137.5, 152.5, 155.1.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][O:2][CH:3]=1)=[O:8])=[O:21]
Reactant: NCC(=O)c1ccoc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccoc1
Yield: 82.4 %

Procedure:
5.0 g of (3-furylcarbonyl)methylamine hydrochloride, 6.5 g of sodium bicarbonate and 6.8 g of 3,4-dichlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 7.6 g of N-(3,4-dichlorobenzoyl)-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 82.0%
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[CH:11]([NH:14][NH2:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>CCO>[NH2:9][C:8]1[N:14]([CH:11]([CH3:13])[CH3:12])[N:15]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CC(C)NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(Ethoxymethylene)malononitrile (12.83 g, 105 mmol) and isopropylhydrazine hydrochloride (11.06 g, 100 mmol) were combined in EtOH (250 mL). Diisopropylethylamine (36.6 mL, 210 mmol) was added drop-wise, resulting in some warming of the reaction mixture. The reaction was allowed to stir for about 18 h at room temp. Volatiles were then removed in vacuo, and the resulting viscous yellow oil was dissolved in dichloromethane and loaded onto a short column of silica gel. The column was eluted with dichloromethane (about 300 mL), followed by a 1:1 mixture of EtOAc and hexanes (about 750 mL), and the EtOAc:hexanes eluant was concentrated under reduced pressure to provide C20 as a pale yellow solid. Yield: 12.1 g, 80.6 mmol, 81%. LCMS m/z 151.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=6.6 Hz, 6H), 4.41 (septet, J=6.5 Hz, 1H), 6.52 (br s, 2H), 7.53 (s, 1H).