Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH:16](CCCOC)[C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][NH:22][C:21]=4[CH:26]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][NH2:50]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:21]=4[CH:26]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]([NH:50][CH3:49])=[O:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCC(O[C@H]1CN(S(=O)(=O)c2ccc(C)cc2)[C@H](CC(C)(C)C(=O)O)C[C@@H]1c1ccc(OC)cc1)c1ccc2c(c1)NCCO2
Reactant: CN
Product: CNC(=O)C(C)(C)C[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 150 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid from (from example 65b) and methylamine are used to afford the title compound as a brown oil. Rf=0.18 (EtOAc-heptane 5:1); Rt=4.97.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>O1CCCC1>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:36])[O:18][C:15]2[CH:16]=[C:17]3[C:12]([CH2:11][CH2:10][CH2:9][N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: COc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)N(Cc2ccccc2)CCC3)cc1
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) and triethylamine in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 4-methoxyphenyl isocyanate (407 mg/ml, 3.14 mM) was added at once and then the reaction mixture was further stirred for 72 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chlorophorm-hexane (1:9) to give 8j as solid. Yield: 0.588 g, 72.53%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>C(#N)C>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[CH:6][N:5]=[C:4]([N:17]=[CH:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[N:3]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)N(C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCN(c2nc(N=CN(C(C)C)C(C)C)ncc2C#Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 0.8 g of 4-chloro-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneamino-pyrimidine, 35 mL acetonitrile and 0.71 g 1-acetyl piperazine was refluxed for one and one half hours. A green solution initially forms and the color changes to amber on continued heating. The solution was evaporated in vacuo and partitioned between dichloromethane and water. The organic phase was washed twice with water, dried over sodium sulfate, filtered and evaporated. The orange-brown brittle foam obtained was purified by column chromatography on silica gel, eluting initially with dichloromethane and then with 15% methanol/dichloromethane to give the intermediate derivative, 4-(-4-acetyl piperazino)-5-(4-chlorophenylethynyl)-2-diisopropylaminomethyleneaminopyrimidine. Heating 0.6 g of the intermediate with 40 mL methanolic ammonia in a bomb at 120° C. for 18 hours gave on evaporation in vacuo, a cocoa-colored residue which was purified by column chromatography on silica gel. The desired product 4-(4-acetylpiperazino)-2-amino-5-(4-chlorophenylethynyl)pyrimidine was obtained by elution with 5% methanol/dichloromethane, evaporation and trituration with methanol yielding 0.27 g, m.p. 165° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[N:4][N:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4 and 2×1.5 M KOH and the organics were eluted through a silica plug. The resulting slurry was concentrated to a white solid that was triturated with 1:1 hexanes:EtOAc to give the title compound as a crystalline white solid (75.9 mg). 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.34 (s, 0.7H), 7.57 (s, 0.3H), 7.44 (m, 2H), 7.15 (m, 2H), 5.24 (s, 0.4H), 5.13 (s, 1.6H), 3.92 (m, 0.5H), 3.84 (m, 1.5H), 2.87 (m, 2H), 2.33 (s, 2.3H), 2.32 (s, 0.7H), 2.12 (m, 1.5H), 2.05 (m, 0.5H); MS: (ES) m/z calculated for C19H17ClF4N5O [M+H]+ 442.1, found 442.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:15][C:14]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([F:21])[C:13]=1[F:12]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: COc1ccc(F)c(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(F)c1COc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)([CH3:5])[CH3:4].C1COCC1.Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]2[N:32]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][C:36]=3[F:45])[N:33]=[CH:34][C:27]=12>C(Cl)Cl>[F:45][C:36]1[CH:37]=[C:38]([S:41]([CH3:44])(=[O:42])=[O:43])[CH:39]=[CH:40][C:35]=1[N:32]1[C:28]2=[N:29][CH:30]=[N:31][C:26]([O:19][CH:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH:3]([CH3:5])[CH3:4])=[CH:12][N:11]=4)[CH2:18][CH2:17]3)=[C:27]2[CH:34]=[N:33]1
Reactant: CC(C)Oc1ccc(N2CCC(O)CC2)nc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 364 mg, 0.91 mmol) and 5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (215 mg, 0.91 mmol). THF (anhydrous, 3 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (297 mg, 0.91 mmol) was then added in one portion. The mixture was stirred overnight under N2 at room temperature and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Purification by preparative HPLC gave the desired product as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, 6H), 2.17 (m, 2H), 2.30 (m, 2H), 3.13 (s, 3H), 3.74 (m, 2H), 3.97 (m, 2H), 4.50 (m, 1H), 5.76 (m, 1H), 7.04 (d, 1H), 7.60 (m, 1H), 7.87 (m, 1H), 7.94 (m, 3H), 8.34 (s, 1H), 8.64 (s, 1H). Exact mass calculated for C26H28FN5O4S 525.18, found 526.2 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C

Procedure:
To an anhydrous suspension of 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 25 ml of methylene chloride was added with stirring at ambient temperature and pressure 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was thereafter stirred for 16 hours and filtered. The filtrate was evaporated to dryness, the residue was triturated with butyl chloride and the product removed by filtration. The product thus obtained melted at 165°, and had absorption peaks in the infrared at 1550, 1600, 1680 and 1700 cm-1 and in the NMR spectrum at 2.5, 3.65, 4.0 with an aromatic multiplet at 7.2-8 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[CH:5][N:4]([CH3:10])[C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].C[O:19][CH:20](O)[C:21]([F:24])([F:23])[F:22]>CO>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([OH:9])=[C:5]([CH:20]([OH:19])[C:21]([F:24])([F:23])[F:22])[N:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1c(Cl)c(=O)c(O)cn1C
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(Cl)c(=O)c(O)c(C(O)C(F)(F)F)n1C
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
3-Chloro-5-hydroxy-1,2-dimethylpyridin-4(1H)-one (500 mg, 2.80 mmol) was suspended in trifluoroacetaldehyde methyl hemiacetal (3 mL). Potassium carbonate (119 mg, 0.86 mmol) was added and the mixture was heated to 120° C. After 2.5 hours, the reaction mixture was allowed to cool to room temperature, then diluted with methanol and filtered. The filtrate was concentrated to dryness and diluted with acetone. The solution was filtered and the filtrate was concentrated to give 3-chloro-5-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (650 mg) as a pink solid. Yield=85%; 1H-NMR (MeOD-D4, 90 MHz) δ (ppm): 5.9 (q, J=9.1 Hz, 1H), 4.01 (s, 3H) and 2.65 (s, 3H); MS-ESI m/z 272 [M+1]+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13]I>CN(C=O)C>[CH3:13][O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: CI
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Potassium hydroxide (2.12 g) was added to 4-hydroxyindole (4.99 g) in DMF (100 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (2.80 ml) was added to the mixture and the resultant was stirred at room temperature for 150 minutes. Since the reaction had not been completed, potassium hydroxide (0.64 g) was added and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and water (20 ml) was added to the residue, followed by extraction with ether (3×30 ml). The organic layers were washed with saturated brine, and dried over sodium sulfate. After removing solids by filtration, the solvent was removed under reduced pressure and the obtained crude product was purified by silica gel column chromatography to obtain the desired product (3.38 g, yield: 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]2[NH:11][CH:12]=[CH:13][C:5]=12)([O-:3])=[O:2].C[Si](C)(C)N[Si](C)(C)C.[Cl:23]C(OC)=O>C1COCC1>[Cl:23][C:8]1[N:7]=[C:6]2[NH:11][CH:12]=[CH:13][C:5]2=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c2[nH]ccc12
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon, 5.00 g (27.9 mmol) of 4-nitro-1H-pyrrolo[2,3-b]pyridine 7-oxide and 11.8 ml (55.8 mmol) of hexamethyldisilazane are initially charged in 290 ml of THF. At RT, 10.8 ml (140 mmol) of methyl chloroformate are added. The solution is stirred at RT overnight. The reaction solution is filtered through a silica gel cartridge, and the cartridge is washed with dichloromethane/methanol 10:1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:21])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12].[CH3:22]I>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([NH:21][CH3:22])[C:5]2[N:6]=[CH:7][N:8]([C:19]=2[N:20]=1)[C@@H:9]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:10]1[O:11][CH3:12]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(C)nc21
Reactant: CI
Solvent: CN(C)C=O
Product: CNc1nc(C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC
Temperature: 100 °C
Reaction time: 0.58 h

Procedure:
1 g of 2,2'-O-dimethyladenosine (Compound 5) was dissolved in 5 ml of dimethylformamide, and 2 ml of methyl iodide was added thereto and the solution was stirred for 30 to 40 minutes. After the solvent was distilled off, 5 ml of 0.5N sodium hydroxide was added and the solution was heated for 75 minutes at 100° C. The solution was neutralized and desalted by hydrophobic column chromatography, and then recrystallized from methanol to give 2,N6,2'-O-trimethyladenosine (Compound 21).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67]O)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52].C(N(CC)CC)C>ClCCl>[C:51]([O:55][C:56]([N:58]1[C:66]2[C:61](=[CH:62][CH:63]=[C:64]([CH2:67][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:16][CH3:17])=[CH:14][CH:13]=3)[CH:65]=2)[CH:60]=[CH:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(CO)cc21
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
To 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (472 mg, 2 mmol, 2 eq) was added polymer-bound triphenyl-phosphine (667 mg, 2 mmol, 2 eq) and dichloromethane (10 mL). The mixture was placed under nitrogen, cooled in an ice bath, diisopropyl azodicarboxylate (0.394 mL, 2 mmol, 2 eq) was added drop-wise, stirred for 1.5 hr. A solution of 6-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (247 mg, 1 mmol, 1 eq) and triethylamine (0.279 mL, 2 mmol, 2 eq) in dichloromethane (2 mL) was added drop to portion wise and the reaction allowed to warm to room temperature overnight (20 hr). The reaction was filtered over Celite, adsorbed onto silica gel, and purified by flash chromatography with a gradient from 1-15% ethyl acetate in hexanes to yield 6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indole-1-carboxylic acid tert-butyl ester white/clear solid (288 mg, 62%). LC-MS (ES) calculated for C27H25F2NO2, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:13][CH2:12][CH:11]([C:9](=[O:10])[C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:16][CH2:15]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1cc(Cl)ccc1Cl)C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3cc(Cl)ccc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from (2,5-Dichloro-phenyl)-piperidin-4-yl-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (m/e): 483.5 (M+H+)
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC(F)F)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of C7 (17 g, 84 mmol) in tetrahydrofuran (100 mL) and water (50 mL) was cooled to 0° C. and treated with lithium hydroxide (6.0 g, 250 mmol). After the reaction mixture had stirred at room temperature for 2 hours, it was acidified to a pH of 3 with 1 M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated under reduced pressure to provide the product as a white solid. Yield: 13 g, 69 mmol, 82%. LCMS m/z 189.8 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=2.4 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.6, 2.4 Hz, 1H), 6.68 (t, JHF=71.5 Hz, 1H).
Reaction SMILES: O=[C:2](C1C=CN=CC=1)CC(OCC)=O.[OH:15][C:16]1[C:21]([CH2:22][O:23]C)=[CH:20][C:19]([CH3:25])=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C.Cl[Pd]Cl>[C:26]([C:17]1[C:16]([OH:15])=[C:21]([C:22](=[O:23])[CH3:2])[CH:20]=[C:19]([CH3:25])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: COCc1cc(C)cc(C(C)=O)c1O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)cc(C(C)=O)c1O

Procedure:
A mixture of a bromo derivative 1 (324 mg, 1 mmol), (R)-(+)-α-methylbenzylamine 2 (122 mg, 1 mmol), potassium t-butoxide (225 mg, 2 mmol) and PdCl2 (dppf) (35 mg, 0.05 mmol) in THF was stirred at refluxing temperature for 20 hours over a nitrogen atmosphere. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The ethyl acetate layers was concentrated in vacuo and the residue was subjected to column chromatography (silica gel, ethylacetate) to give the required product 3. 1H NMR (300 MHz, CDCl3), δ 8.78 (br s, 2H), 8.21 (s, 1H), 7.92 (d, J=5.9 Hz, 2H), 7.4-7.26 (m, 5H), 6.90 (s, 1H), 6.50 (d, J=5.5 Hz, 1H, —NH), 6.27 (s, 1H), 4.60 (m, 1H), 2.23 (s, 3H), 1.71 (d, J=6.9 Hz, 3H). MS (m/z)=357.13 (m+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:26][CH2:25]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[CH2:33][O:32][C:31]4=[O:40])[CH2:28][CH2:29]3)=[O:23])=[C:17]([O:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:47])[F:46])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)OCc5ccccc54)CC3)c(OCC(F)(F)C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(OC2CCNCC2)cc1OCC(F)(F)C(F)(F)F)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a stirred solution of 1-(1-(4-(1-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,3,3,3-pentafluoropropyloxy)phenylacetyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one (0.35 g, 0.53 mmol) from Step 4 above in EtOAc (25 mL) at 0° C. was bubbled HCl gas for 15 min. The resulting suspension was stirred at 0° C. for 45 min. Excess HCl was removed by bubbling argon though the mixture for 15 min. Ether (50 mL) was added and the cold suspension was filtered. The solids were washed with additional ether and then dried under reduced pressure for 18 h to give the hydrochloride salt of the title compound as an amorphous white powder.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19](=O)[CH2:20][CH2:21][C:22](O)=[O:23])([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>O>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[NH:29][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1C(=O)CCC(=O)O
Reactant: NN
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1C1=NNC(=O)CC1

Procedure:
A solution of equimolar amounts of 4-(3-t-butylamino-2-hydroxypropoxy)-3-(3-carboxypropionyl)benzoic acid and hydrazine hydrate in water was heated under reflux for 16 hours. The volume of the solution was reduced in vacuo to give 4-(3-t-butylamino-2-hydroxypropoxy)-3-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoic acid.