Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]([O:26][C:27]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:30])=[O:28])([CH3:25])([CH3:24])[CH3:23]>Cl[Pd]Cl.CN(C=O)C>[C:22]([O:26][C:27](=[O:28])[N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:30]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:14]=[C:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1ccccc1C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N(N)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccccc1)n1c(-c2ccccc2)cc2ccccc21
Temperature: 110 °C
Yield: 85.8 %

Procedure:
Following the general procedure outlined above, a reaction tube was charged with 4.4 mg PdCl2 (5 mol %), 14.5 mg tBu3PHBF4 (10 mol %), 228.1 mg Cs2CO3 (1.4 equiv.) and 2.5 mL DMF. After stirring for 30 min at RT under a flow of argon, 1-chloro-2-phenylethynyl-benzene (106.3 mg, 1.0 equiv.) and N-phenylhydrazine carboxylic acid tert-butyl ester (145.8 mg, 1.4 equiv.) were added and the reaction was heated to 110° C. for 3 hours. After cooling to RT, the reaction mixture was quenched with 30 mL NaHCO3 (saturated aqueous) and extracted with EtOAc (2×30 mL) and the organic phase was dried by eluting through a Varian Chem Elut 12198007 cartridge. Removal of the solvents afforded the crude N-aminoindole as a dark-brown oil that was purified by flash chromatography on silica using CH2Cl2/heptane to afford 164.8 mg (86%) of Phenyl-(2-phenyl-indol-1-yl)-carbamic acid tert-butyl ester as a yellowish oil. 1H-NMR (DMSO-d6) δ 1.25 (s, 9H), 6.85 (s, 1H), 7.10-7.14 (m, 3H), 7.15-7.18 (m, 1H), 7.23 (d, 2H, J=4.0 Hz), 7.26-7.30 (m, 2H), 7.39-7.41 (m, 1H), 7.44 (t, J=7.2 Hz, 2H), 7.52 (d, 2H, J=7.9 Hz), 7.65 (d, 1H, J=7.8 Hz); 13C-NMR (DMSO-d6) δ 27.3, 82.5, 101.4, 109.2, 120.8, 121.0, 123.1, 125.3, 125.7, 127.4, 128.4, 128.7, 128.8, 130.5, 136.7, 139.7, 140.9, 152.0; HRMS (FAB): Calculated for C25H25N2O2 (M+H+) 385.1916. found 385.1917.
Reaction SMILES: Cl.C[O:3][C:4](C1CCN1)=[O:5].[CH2:10]([N:12]([CH2:39][CH3:40])[CH2:13][C:14]1[S:15][C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C@@H:34]4[CH2:36][O:35]4)=[C:27]([CH2:37][CH3:38])[CH:26]=3)[N:21]=2)=[CH:17][C:18]=1[CH3:19])[CH3:11].CC[N:43]([CH:47]([CH3:49])C)[CH:44](C)C.[OH-].[Na+]>CO>[CH2:10]([N:12]([CH2:13][C:14]1[S:15][C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH2:33][C@@H:34]([OH:35])[CH2:36][N:43]4[CH2:44][CH:49]([C:4]([OH:5])=[O:3])[CH2:47]4)=[C:27]([CH2:37][CH3:38])[CH:26]=3)[N:21]=2)=[CH:17][C:18]=1[CH3:19])[CH2:39][CH3:40])[CH3:11]
Reactant: COC(=O)C1CCN1
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H](O)CN1CC(C(=O)O)C1
Temperature: 70 °C
Reaction time: 22 h
Yield: 78.6 %

Procedure:
To a solution of azetidine-2-carboxylic acid methyl ester hydrochloride (51 mg, 340 μmol) in methanol (1 mL), a solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (30 mg, 68 μmol) in methanol (1 mL) followed by DIPEA (90 mg, 679 μmol) is added. The mixture is stirred at 70° C. for 22 h before it is cooled to rt and 3 M aq. NaOH (0.35 mL) is added. The mixture is stirred at rt for 18 h before it is separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia) to give the title compound (29 mg) as a resin; LC-MS*: tR=0.74 min; [M+1]+=543.09; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.21 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.33 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.62-2.69 (m, 1H), 2.73 (q, J=7.3 Hz, 2H), 3.10-3.17 (m, 1H), 3.18-3.22 (m, 1H), 3.22-3.28 (m, 2H), 3.42-3.51 (m, 2H), 3.66-3.72 (m, 1H), 3.73 (s, 2H), 3.74-3.80 (m, 2H), 7.72 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1ccsc1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A dry flask was charged with 3-Methyl-thiophene-2-carboxylic acid (0.500 g, 3.520 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (35 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.888 g, 3.517 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.940 g, 2.50 mmol, 71%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][N:11]([CH2:36][CH2:35][N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[C:25]([F:24])[CH:34]=3)[CH:29]=[CH:30][C:31]2=[O:38])[CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To cis-1,1-dimethylethyl [((3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-piperidinyl)methyl]carbamate (350 mg; 1.0 mmol) in MeOH (2 ml) and CHCl3 (8 ml) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 2(d) (200 mg; 1.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 8 hours. Na(OAc)3BH (530 mg; 2.5 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (415 mg; 78%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]1(=[O:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1>CCOCC.Cl>[F:9][C:2]([F:1])([F:8])[C:3]([CH:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:25])=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCCc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A 250 mL one necked round bottomed flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was added over about 5 minutes. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer was washed with 3N HCl, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give pure compound (32 g, 81%): mp 48°-49° C.; 1H NMR CDCl3 δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H); 19F NMR CDCl3 δ -72.0. EI GC-MS M+=242.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17]([O:20][CH2:21][C:22](Cl)=[O:23])(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][CH2:21][C:22]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:23])(=[O:19])[CH3:18]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A solution of 4-aminobenzonitrile (5 g, 42.3 mmol) and triethylamine (7.08 mL, 50.8 mmol) in dichloromethane (DCM) (40 mL) was cooled in an ice-water bath before the dropwise addition of 2-chloro-2-oxoethyl acetate (5.46 mL, 50.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM (50 mL) and the resulting solution washed with 2N HCl (50 mL). On mixing, precipitation occurred and the solid collected was filtered and dried under vacuum at 40° C. for 4 hours to yield a pale brown solid. The solid was dissolved in DCM (150 mL) and washed with 2N HCl (50 mL). The organic layer was collected via a hydrophobic frit and the solvent removed to yield the title compound as a cream solid (4.48 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[C:12](C)[CH:11]=[CH:10][N:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].[CH3:15]C1N=C(C#N)C=CC=1.C([Mg]Br)CC>>[NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(O)(CN)c1cc(C)ccn1
Reactant: Cc1cccc(C#N)n1
Agent: CCC[Mg]Br
Product: CCCC(O)(CN)c1cccc(C)n1

Procedure:
The title material was prepared as described for the synthesis of 1-amino-2-(4-methylpyridin-2-yl)pentan-2-ol (Example L) in using 6-methylpicolinonitrile and propyl magnesium bromide. LC/MS (M+H)+: 195. HPLC ret. time (Condition E): 1.068 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Yield: 61.4 %

Procedure:
In 1.5 mL of DMF were combined 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.059 g, 0.14 mmol), DIEA (0.15 mL, 0.84 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.049 g, 0.21 mmol) and allowed to proceed at ambient temperature with stirring. After 2 hours the DMF was removed under reduced pressure with heating and the crude was purified by means of silica gel chromatography eluting with 1:1 EtOAc/hexanes containing 0.25% NH4OH to afford 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (0.034 g, 0.086 mmol, 62% yield). MS (apci) m/z=396.1 (M+H).
Reaction SMILES: [O:1]1[CH2:5][CH:2]1[CH:3]=[CH2:4].[C:6]([O:9]C(=O)C)(=[O:8])[CH3:7].[C:13](O)(=[O:15])[CH3:14]>COCCOCCOC>[C:6]([O:9][CH:2]([CH2:5][O:1][C:13](=[O:15])[CH3:14])[CH:3]=[CH2:4])(=[O:8])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: C=CC1CO1
Solvent: COCCOCCOC
Product: C=CC(COC(C)=O)OC(C)=O
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A 300-mL autoclave was charged with 40 mL (0.50 mol) of 3,4-epoxy-1-butene, 67.3 g (0.66 mol) acetic anhydride, 5.82 g (0.097 mol) of acetic acid and 4.2 mL of diglyme. The autoclave was purged with nitrogen twice, then the vessel was pressurized to 8 bars (100 psig) with nitrogen. The agitator was started and an initial sample was taken. The mixture was heated to 125° C. During the course of 2.5 hrs, samples were taken every 15 min for analysis by GC. GC analysis of the crude mixture after 2.5 hrs revealed 11% yield of 3,4-diacetoxy-1-butene with a 13% selectivity, 21% 3,4-epoxy-1-butene and numerous high boiling components. The reaction was observed to be first order in 3,4-epoxy-1-butene with a first order rate constant (Kfirst) of 0.0025 min-1 (Table A). This example illustrates low yield and selectivity in the absence of a tertiary amine and the inefficient catalysis of the reaction in the presence of the carboxylic acid alone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>CO.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccc(Cl)cc3Cl)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 47.2 mg, 0.150 mmol) in methanol (6.0 mL) was added neat 2,4-dichlorophenyl isocyanate (56.4 mg, 0.300 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred at room temperature for 15 minutes. The reaction mixture was diluted with water (˜25 mL) and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to a colorless film. Silica gel chromatography (20-25% ethyl acetate in hexanes) provided {4-[1-(2,4-dichloro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (74.8 mg, 99%) as a colorless film. MS cald. for C26H26Cl2FN2O3 [(M+H)+]: 503, obsd. 503.1.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8].[CH3:13]O>>[ClH:3].[NH:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([O:9][CH3:13])=[O:8]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCCN1
Product: Cl
Yield: 99.6 %

Procedure:
Thionyl chloride (65 ml, 0.89 mol) was added dropwise at ice-cooling for 45 min to a solution of L-proline (57.6 g, 0.50 mol) in 500 ml MeOH. The temperature was raised to reflux. After 4 h at reflux the mixture was cooled and the solvent evaporated in vacuo. MeOH was added to the residue and then evaporated repeatedly three times to give 86 g crude methyl (S)-2-pyrrolidinecarboxylate hydrochloride (99.6% purity by GLC) as a thick syrup. The ester (1.65 g, 0.01 mol) was transferred to a flask containing acetaldehyde (2.21 g, 0.05 mol) 10% Pd/C (0.15 g) and 15 ml MeOH. The mixture was shaken in a Parr apparatus at 55 psi hydrogen pressure for 4 h at room temperature, filtered and evaporated to give 2.1 g crude hydrochloride of the title ester. (91% purity by GLC). This material was subjected to aminolysis in Example 7D.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.[S:39]1[CH:43]=[C:42]([CH2:44][CH2:45][NH2:46])[N:41]=[CH:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:46][CH2:45][CH2:44][C:42]1[N:41]=[CH:40][S:39][CH:43]=1)=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCc1cscn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1cscn1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), 2-(thiazole-4-yl)ethylamine (11.89 mg, 0.093 mmol), and BOP (41.0 mg, 0.093 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(thiazol-4-yl)ethyl)acetamide (11.8 mg, 0.022 mmol, 47.0% yield): LCMS=542.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.82 (1 H, d, J=2.01 Hz), 8.13 (2 H, d, J=8.28 Hz), 7.46-7.69 (7 H, m), 7.08 (1 H, d, J=2.01 Hz), 5.08 (1 H, s), 3.50-3.69 (2 H, m), 3.03 (2 H, t, J=6.90 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][C:18]1=O>ClCCl.N1C=CC=CC=1>[Cl:8][C:18]1[N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[C:25]2[C:20]([C:19]=1[CH:3]=[O:4])=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2N1c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1c(Cl)n(-c2ccccn2)c2ccccc12
Reaction time: 0.25 h
Yield: 23 %

Procedure:
The title compound is prepared following the procedure of Andreani, A. et al., J. Med. Chem. 20, (1977) 1344-1346 as follows. To a mixture of dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) is added phosphorus oxychloride (0.50 mL) at 0° C. After stirring for 15 min, a solution of 1-(pyridin-2-yl)-1,3-dihydroindol-2-one (Le Baunt, G. et al., EP 0 580 502) (250 mg, 1.2 mmol) in dichloromethane (2.0 mL) and pyridine (0.25 mL) is added and the resulting dark-red solution is stirred for 36 hr. The reaction mixture is poured onto ice water and extracted with dichloromethane. The combined organic layer is washed with water, with saturated sodium bicarbonate, with brine, dried over sodium sulfate, filtered and concentrated. The dark residue is purified by chromatography eluting with dichloromethane-0 to 3% methanol. Product containing fractions are combined and concentrated to afford 2-chloro-1-(pyridin-2-yl)-1H-indole-3-carboxaldehyde (70 mg, 23% yield) as a beige solid. TLC (dichloromethane) Rf=0.18; ESI/MS 257 (M+H); RT=2.99 min; NMR 10.16 (1H, s); 8.79 (1H, d); 8.25 (2H, m); 7.84 (1H, d, J=9 Hz); 7.73 (1H, m); 7.40 (3H, m).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[S:22]1[CH:23]=[C:19]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]1=2
Reactant: Brc1csc2ccccc12
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1csc3ccccc13)O2
Reaction time: 96 h
Yield: 45.5 %

Procedure:
A mixture of 4.6 g (20 mmol) of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 6.4 g (30 mmol) of 3-bromobenzo[b]thiophene, 0.4 g of triphenylphosphine, 95 mg of cuprous iodide, 6 ml of triethylamine and 150 ml of acetonitrile was degassed with argon for 15 minutes. Palladium acetate, 110 mg, was then added and stirring at room-temperature was continued for 4 days. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was chromatographed over 200 g of silica gel using methylene chloride/hexane 1:1(v/v) for elution. Crystallization of the combined clean fractions from ether/hexane yielded 3.3 g (45.5%) of colorless crystals with m.p. 123°-124° C. A lower melting modification with m.p. 88°-91° C. was also observed.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:17]=[CH:16][C:15]=1[N+:31]([O-:33])=[O:32].[H][H]>C1COCC1.C(O)C>[CH2:7]([O:6][C:4](=[O:5])[C:3](=[O:9])[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[CH:16][C:15]=1[N+:31]([O-:33])=[O:32])[CH3:8]
Reactant: [H][H]
Reactant: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 72.2 %

Procedure:
To a suspension of sodium hydride (1.62 g, 60%, 40.5 mmol) in 20 ml of anhydrous THF at room temperature was added ethanol (2.5 ml) slowly. Diethyl oxalate (5.5 ml, 40.50 mmol) and 2-methyl-1-nitro-4-[2-(phenylmethoxy)ethoxy]benzene (10.19 g, 35.49 mmol) was added to the solution slowly after hydrogen evolution subsided. The reaction was heated at 60° C. for 2 h. The deep red solution was cooled to 0° C. and quenched with 50 ml of 3N HCl solution. Brine (50 ml) was added and the mixture was extracted with EtOAc (2×100 ml). The combined organic layers was dried with MgSO4, filtered and concentrated. The brown oil was chromatographed on silica gel with 20% ethyl acetate in hexanes to elute out starting material and then with 35% ethyl acetate in hexanes to give 9.93 g (72%) of 3-[5-(2-benzyloxy-ethoxy)-2-nitro-phenyl]-2-oxo-propionic acid ethyl ester as a yellow oil. 1H NMR (CDCl3) 8.18 (1H, d, J=9.29), 7.35-7.25 (5H, m), 6.91 (1H, dd, J=9.29, 2.69), 6.77 (1H, d, J=2.69), 4.59 (2H, s), 4.44 (2H, s), 4.35 (2H, q, J=7.32), 4.19 (2H, m), 3.81 (2H, m), 1.37 (3H, t, J=7.32).