Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[C:33]2[CH:40]=[N:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[C:34]=2[N:35]=[CH:36][N:37]=1)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1c(Cl)cccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Sodium hydride (60% in mineral oil) (0.191 g, 4.77 mmol) was added in one portion to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.6 g, 3.97 mmol) in THF (15 mL) cooled to 0° C. under nitrogen. Slow gas evolution. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AE5) (1.109 g, 3.97 mmol) in THF (10 mL) was added dropwise over 2 minutes. The resulting suspension was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and stirred for 72 hours to give an orange solution. Cooled to ˜5° C., 1M citric acid (30 mL) added, the mixture stirred for 10 minutes, diluted with EtOAc (50 mL), the organic phase separated and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (2.1 g, 82%). 1H NMR (400 MHz, DMSO) δ 0.95 (9H, s), 2.03 (3H, s), 3.68 (3H, s), 3.67-3.74 (2H, m), 3.78-3.82 (2H, m), 4.04-4.07 (1H, m), 5.87-5.91 (1H, m), 7.37-7.45 (8H, m), 7.61-7.65 (4H, m), 7.67-7.69 (1H, m), 8.48 (1H, s), 8.57 (1H, s); m/z (ESI+) (M+H)+=645; HPLC tR=3.65 min.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:19](Cl)=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:19]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc2oc(C3CCCCC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.2 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.13 mmol) and cyclohexane carbonyl chloride (0.29 mL, 2.13 mmol) in dichloromethane (20 mL) was added triethylamine (0.90 mL, 6.41 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (485 mg, 2.55 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (7×100 mL), brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by re-crystallization from ethyl acetate and hexanes to afford 2-cyclohexylbenzoxazole-4-carboxylic acid (346 mg, 66%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 13.01 (br s, 1H), 7.92 (dd, J=8.0, 0.9 Hz, 1H), 7.84 (dd, J=7.8, 0.9 Hz 1H), 7.44 (t, J=7.8 Hz, 1H), 3.08-3.02 (m, 1H), 2.14-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.38 (m, 2H), 1.35-1.25 (m, 1H); MS (ESI+) m/z 246 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:24]([C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[O:25])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[NH2:1][C:2]1[C:3]([C:20]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:39][CH:40]=3)=[N:23][N:22]=2)=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC(=O)OC(C)(C)C)cc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.4 %

Procedure:
A mixture of tert-butyl 4-(2-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbonyl)hydrazinecarbonyl)benzylcarbamate (136 mg, 0.24 mmol) and DIPEA (109.8 mg, 148.0 μL, 0.8499 mmol) in acetonitrile (3.000 mL) at 0° C. was treated portionwise with dibromo(triphenyl)phosphorane (143.5 mg, 0.3400 mmol) and the resulting mixture stirred at room temperature for 48 h. The mixture was concentrated in vacuo and pre-absorbed onto silica gel and purified by column chromatography on silica gel eluting with 50% EtOAc/CH2Cl2 to give the product (46.8 mg, 30% yield); MS (ES+) 551.31
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(C3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 416 was used, staring from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclohexylmagnesium bromide to give (1-Cyclohexyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 337 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCc1ccc(-c2ccccc2)c(OCCCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 26.5 h

Procedure:
To a solution of 3-hydroxy-4-phenylbenzonitrile (0.600 g) in N,N-dimethylformamide (4.1 mL) was added potassium carbonate (0.850 g). Then 4-benzyloxy-1-bromobutane (0.703 mL) was added, and the resulting mixture was stirred at 50° C. for 26.5 hours. The reaction mixture was cooled to room temperature and then partitioned between diethyl ether (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue (1.25 g) was dissolved in tetrahydrofuran (13 mL) and added to an ice-cold suspension of lithium alminiumhydride (0.175 g) in tetrahydrofuran (18 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and then quenched by sequential addition of water (0.175 mL), 15% aqueous sodium hydroxide (0.175 mL) and water (0.175 mL). After addition of anhydrous sodium sulfate (10.4 g), the mixture was stirred at room temperature for 13 hours and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure to give the title compound (1.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.[CH2:23](I)[CH2:24][CH2:25][CH3:26]>>[CH2:23]([N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2)[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reactant: CCCCI
Product: CCCCn1cc(C(=O)OCC)c(=O)c2oc3ccc(Cl)cc3c(=O)c21
Yield: 95.1 %

Procedure:
Prepared from ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (3.195 g, 0.01 mole) and butyl iodide (7.36 g, 0.04 mole) by the method described for Example 9. Recrystallization from methanol gave white crystals (3.575 g, 95%), m.p. 226°-228°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[H-].[Na+].I[CH3:29]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:17][N:18]([CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(ncn2C2CCCCO2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(ncn2C2CCCCO2)c1Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 56.2 %

Procedure:
To a solution of 216 (620 mg, 1.7 mmol) in DMF (8 mL) at 0° C. was added NaH (102 mg, 2.54 mmol, 60% in oil). The reaction was warmed to RT and stirred for 25 min then re-cooled to 0° C. and iodomethane (0.19 mL, 3.05 mmol) was added. The reaction was warmed to RT and stirred for 3 h. The conversion was low so the reaction mixture was cooled back to 0° C. and additional NaH (67 mg, 1.69 mmol, 60% in oil) was added. The reaction was warmed to RT and stirred for 20 min, re-cooled to 0° C. and iodomethane (0.11 mL, 1.69 mmol) was added. The reaction was warmed to RT and stirred for 3 h then partitioned between EtOAc and H2O. The combined organic extracts were thrice washed with H2O, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography to afford 363 mg (56%) of tert-butyl (4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl(methyl)carbamate (218): MS (ESI) m/z=380.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25]([F:27])[CH:26]=4)=[N:16][C:17]=3[F:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:30][N:31](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.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]>[F:18][C:17]1[C:12]([CH2:11][C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:30]#[N:31])[CH:3]=3)[NH:8][CH:9]=2)=[CH:13][CH:14]=[C:15]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:28][CH3:29])=[C:25]([F:27])[CH:26]=2)[N:16]=1
Reactant: CC(=O)N(C)C
Reactant: COc1ncc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)c(F)n2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: COc1ncc(CNc2ccc(Cc3c[nH]c4ncc(C#N)cc34)c(F)n2)cc1F
Temperature: 120 °C
Yield: 88.8 %

Procedure:
To 5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-6-fluoro-N-[(5-fluoro-6-methoxy-3-pyridyl)methyl]pyridin-2-amine (125 mg, 0.27 mmol) was added 2 mL of N,N-dimethylacetamide. The mixture suspension was degassed by bubbling with argon. To this suspension was added Zinc (5 mg, 0.08 mmol), 11,1′-Bis(diphenylphosphino)ferrocene (6 mg, 0.01 mmol), Zinc Cyanide (0.01 ml, 0.19 mmol), and Tris(dibenzylideneacetone)dipalladium (0) (7 mg, 0.01 mmol) at room temperature under argon. The mixture was heated to 120° C. for 2 hrs and cooled to room temperature. The reaction mixture was extracted with ethyl acetate and water (+saturated sodium chloride). The organic layer was washed with water and brine, dried by MgSO4. The volatiles were removed under vacuum. The residue was suspended in acetonitrile and sonicated for 45 mins. The precipitate was collected by filtration and washed with acetonitrile. A tan solid was obtained (98 mg, 88.8% yield). LC-MS showed one major peak with 98.6% purity. The structure of the product is confirmed by H1-NMR (DMSO-d6). MS (ESI) [M+H]+=406.9.
Reaction SMILES: [Na].[NH:2]([C:4]1[S:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:3].[C:13](#[N:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:22][C:13]1[CH2:14][CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:2]([C:4]2[S:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[N:3]=1
Reactant: N#CC=Cc1ccccc1
Reactant: NNc1nc2ccccc2s1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2nc3ccccc3s2)C(c2ccccc2)C1

Procedure:
A 0.46 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 16.5 g. of 2-hydrazinobenzothiazole is added, followed by 12.9 g. of cinnamonitrile. The reaction mixture is refluxed for 16 hours, then is cooled. Some of the solvent is removed in vacuo and the mixture is filtered. The precipitate is washed with hexane to give 25.67 g. of crude product. A 3.0 g. amount of this material is recrystallized from acetone-hexane to give 2.35 g. of the product of the Example as buff colored prisms, m.p. 270°-271.5° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH3:34])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:17]=2)=[C:10]([CH3:33])[CH:9]=1)=[O:6].[OH-].[Na+]>O.CO.CCOC(C)=O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH:4]([CH3:34])[C:3]([OH:35])=[O:2])=[CH:9][C:10]=2[CH3:33])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: COC(=O)C(C)C(=O)Nc1cc(C)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(NC(=O)C(C)C(=O)O)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[3-(4-Fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-methyl-malonamic acid methyl ester (155 mg, 0.31 mmol) in H2O/MeOH (1/1, 4 mL) was added 1N NaOH (0.6 mL, 0.6 mmol). After stirring at room temperature for 1 h, the solution was diluted with EtOAc (15 mL) and extracted with 0.1 N NaOH (3×10 mL). The combined basic extracts were acidified with 1M HCl and extracted with EtOAc (3×15 mL). The organic extracts were combined, washed with brine, dried and concentrated to give the title compound of Step B and Example 4-4 (131 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ 7.98-7.95 (m, 2H), 7.35 (s, 2H), 7.27-7.22 (m, 3H), 6.93-6.90 (dd, 1H), 6.80 (d, 1H), 3.57-3.52 (q, 1H), 2.05 (s, 6H), 1.41 (d, 3H). MS (ES31) Calc: 487.1, Found: 485.9 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][CH:6]=2.C1C(=O)N([Br:37])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.22 g, 2.88 mmol), NBS (0.667 g, 3.75 mmol) and diphenylperoxyanhydride (0.070 g, 0.288 mmol) in carbon tetrachloride (50 mL) were heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed in vacuo to afford methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 502.0 (M+H+).
Reaction SMILES: [P:1](=[O:10])(Cl)([S:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3][CH3:4].[C:11]1([S:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.P([S-])(=S)([O-])[O-]>C(#N)C>[P:1]([S:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:26][CH:25]=1)(=[O:10])([S:5][CH2:6][CH2:7][CH3:8])[O:2][CH2:3][CH3:4]
Reactant: CCCSP(=O)(Cl)OCC
Reactant: O=S(=O)(Oc1ccc(S)cc1)c1ccccc1
Agent: [O-]P([O-])(=S)[S-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Sc1ccc(OS(=O)(=O)c2ccccc2)cc1
Temperature: 4 °C

Procedure:
A solution of 5.47 g. (0.026 mole) of O-ethyl S-n-propyl phosphorochloridothioate in 20 ml. of acetonitrile is charged in one portion to a solution of 6.65 g. (0.025 mole) of 4-(benzenesulfonyloxy)thiophenol in 200 ml. of acetonitrile. The solution is stirred and cooled to 4° C. while 2.53 g. (0.025 mole) of triethylamine in 20 ml. of acetonitrile is added dropwise over a 30 minute period. The mixture is held at 5° C. for an additional hour and then concentrated in vacuo. The residue, a mixture of oil and solid, is taken up in 200 ml. of benzene and filtered to remove amine hydrochloride. The filtrate is washed once with 50 ml. of 5% sodium bicarbonate, once with 30 ml. of water, once with 30 ml. of saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo to give 9.1 g. (84%) of the phosphorodithioate as a pale yellow oil. Anal. calc. (found): C 47.2 (47.3); H 4.8 (5.15).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCCC1=O.C(OCC)(=O)C>[Cl-].[Na+].O>[NH:9]([C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1cc(Nc2ccccc2)ncn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
4,6-Dichloropyrimidine (1 g) and aniline (746 mg) were added to N-methylpyrolidin-2-one (20 mL) and stirred at 120° C. for 24 hours. The resultant mixture was cooled to room temperature, to which ethyl acetate (30 mL) and brine (30 mL) were added, and stirred for 30 minutes. An organic layer was separated, dried (MgSO4), filtered and then concentrated under reduced pressure. The title compound (950 mg) was obtained by silica gel column chromatography (ethyl acetate/n-hexane=1/5).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([F:38])([F:37])[F:36])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH2:39])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>C(#N)C.CN(C=O)C>[Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:25]=4[C:35]([F:37])([F:36])[F:38])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH:39][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2OC[C@@H]1N
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,4R)-4-(tert-Butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-amine (50 mg, 0.09 mmol) was dissolved in acetonitrile (716 μl). To this solution was added K2CO3 (12.4 mg, 0.09 mmol) and tert-butyl 2-bromoacetate (15.9 μl, 0.11 mmol). The resulting solution was stirred at room temperature overnight. This was diluted with DMF and filtered to remove solid material and was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give tert-butyl 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetate (LCMS [M+H]+=673.3), which was dissolved in CH2Cl2 (4 mL) and TFA (1.5 mL). This solution was stirred for 2 h before it was concentrated. The resulting residue was dissolved in 4 N HCl in dioxane (1.0 mL) and 6 N HCl aqueous solution (0.5 mL) and stirred overnight. Next, the reaction was stirred at 50° C. for 4 h. After cooling, the solution was mixed with MeCN and purified by preparative HPLC (Column: PHENOMENEX® Luna C18, 5-μm particles (30×100 mm; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15%-100% B over 10 minutes; Flow: 30 mL/min, uv detection 254 nM) to give 2-((3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetic acid, TFA salt Ex 67 (44.5 mg): LCMS [M+H]+=503.0; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (1H, dd, J=8.03, 1.65 Hz), 7.60-7.76 (8H, m), 5.17 (1H, d, J=4.18 Hz), 4.44-4.58 (2H, m), 4.06 (2H, d, J=2.64 Hz), 3.90-3.97 (1H, m); HPLC Peak RT=7 5 min (Analytical Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:9][CH:8]=[C:7](C(O)=O)[C:6]=2[CH:13]=1>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1coc2c([N+](=O)[O-])cc(Br)cc12
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cc(Br)cc2ccoc12
Temperature: 190 °C

Procedure:
5-Bromo-7-nitro-1-benzofuran-3-carboxylic acid (4.65 g, 16 mmol; obtained in Step 2) was suspended in quinoline (25 mL), 0.1 g CuO was added and the mixture heated to 190° C. for 30 minutes. The warm reaction mixture was diluted with hot toluene (100 mL), filtered and the filter cake washed with hot toluene (total 400 mL). The combined toluene extracts were washed with 1 M HCl (2×100 mL) and brine, evaporated and the solid product washed with hexane, collected by filtration and dried. Yield: 1.9 g (48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.13 (d, J=2.3 Hz, 1H) 8.20 (d, J=2.0 Hz, 1H) 8.28 (d, J=2.3 Hz, 1H) 8.32 (d, J=2.0 Hz, 1H).