Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 100 °C

Procedure:
25 g of 2-amino-3-benzyloxypyridine (124.8 mmol, 1 equivalent) were dissolved in 781 ml of ethanol, and 102.7 g of ethyl 2-chloroacetoacetate (624.2 mmol, 5 equivalents) and 15 g of 4 Å molecular sieve were added. The mixture was heated at reflux for 2 d (bath temperature 100° C.). The mixture was then concentrated and excess ethyl 2-chloroacetoacetate was distilled off on a rotary evaporator with dry ice-cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate 9:1, 4:1). This gave 20.81 g of the title compound (54% of theory).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:18]=4)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:30][N:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:19]2[CH:18]=[C:17]([C:15]3[CH:16]=[C:11]4[CH:10]=[CH:9][NH:8][C:12]4=[N:13][CH:14]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:29][CH2:28]1
Reactant: COc1ccc(Cn2ccc3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN1CCN(Cc2cccc(-c3cnc4[nH]ccc4c3)c2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine (151) (30 mg) in CHCl3 (8 mL) was added trifluoroacetic acid (5 mL) and heated at 50° C. for 12. After completion of the reaction the solvents were removed, diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with CHCl3 twice. The organic layer was washed with brine solution and dried over sodium sulphate and the solvent completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound in 2% MeOH/CHCl3 gave pale yellow solid compound 5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridine 152.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2([CH:17]([F:19])[F:18])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]2)[CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>CO.C1COCC1.[Pd]>[F:19][CH:17]([F:18])[C:8]1([C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[F:20])[NH:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[O:10][CH2:9]1
Reactant: [H][H]
Reactant: CC1(C)OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OCC(c2ccccc2F)(C(F)F)NC1=O
Yield: 99.3 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-morpholin-3-one (3.14 g, 8.92 mmol) and sodium acetate (1.46 g, 17.83 mmol) were suspended in 100 mL methanol and 10 mL THF. Eventually, 10% Pd on charcoal (315 mg) was added and the reaction mixture was treated with hydrogen (balloon) at rt. After 60 minutes the reaction mixture was filtered over celite and evaporated. The residue was partitioned between aqueous Na2CO3 solution and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated to give 2.42 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:3](F)=[O:4].C[Si](C)(C)[O-:16].[K+:19]>CCOCC>[F:1][C:2]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:3]([O-:16])=[O:4].[K+:19]
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Perfluoroisobutyryl fluoride (17.76 g, 82 mmol) was distilled into a 3-neck flask (equipped with a cold finger condenser, mechanical stirrer and a nitrogen inlet) containing a slurry of potassium trimethylsilanolate (10.26 g, 80 mmol) in dry ether (500 mL). The mixture was stirred 3 h at room temperature with the condenser maintained at -40°; then it was cooled to -40° and stirred overnight. The solid was filtered under nitrogen, washed with dry ether, and dried under a stream of nitrogen to afford potassium perfluoroisobutyrate (12.29 g, 61% yield) as a white solid: 19F NMR (D2O) δ -72.2 (d, J=7.5 Hz, CF3, 6F), -171.8 ppm (sp, J=7.5 Hz, CF, 1F). Anal. Calcd. for C4F7KO2 : C, 19.05; F, 52.75. Found: C, 19.12; F, 52.70.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=O)[O:16]CC)=[C:4]([F:20])[CH:3]=1.C(O[C:24]([CH3:33])([CH3:32])[CH:25]([OH:31])[C:26]([O:28]CC)=O)C.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:26](=[O:28])[C:25](=[C:24]([CH3:32])[CH3:33])[O:31][C:15]2=[O:16])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCOC(=O)C(O)C(C)(C)OCC
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 205 °C
Yield: 46.1 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (10.0 g, 33.1 mmol), ethyl 3-ethoxy-2-hydroxy-3-methylbutanoate (9.44 g, 49.7 mmol), ferric chloride hexahydrate (90.2 mg, 0.03 mmol) and tributylamine (309.5 mg, 1.7 mmol) were introduced into a two-necked eggplant type flask (200 cc) equipped with a Dean Stark and a Dimroth condenser and heated at 205° C. (oil bath) for 10 hours with stirring. After completion of the reaction, the reaction solution was cooled to room temperature, toluene (60 mL) was added, and the reaction solution was washed with water (100 mL). The organic layer was concentrated under reduced pressure, and ethanol (35 mL) acidified with hydrochloric acid was added to the resulting oily substance to form a homogeneous solution. The solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with ethanol acidified with hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione as white crystals (5.40 g, yield 46.1%).
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=O.[Cl:11][C:12]1[CH:20]=[CH:19][NH:18][C:17]2[C:13]=1[CH:14]=[CH:15][N+:16]=2[O-].COS(OC)(=O)=O.[NH3:29]>C(C#N)(C)=O.CCO>[Cl:11][C:12]1[CH:20]=[C:19]([NH2:29])[N:18]=[C:17]2[NH:16][CH:15]=[CH:14][C:13]=12
Reactant: N
Reactant: [O-][n+]1ccc2c(Cl)cc[nH]c1-2
Agent: CC(=O)C#N
Agent: O=C(O)c1cccc(Cl)c1
Solvent: COS(=O)(=O)OC
Solvent: CCO
Product: Nc1cc(Cl)c2cc[nH]c2n1
Temperature: 57.5 °C
Reaction time: 8 h

Procedure:
To a suspn. of 4-chloro-7-azaindole-N-oxide m-chlorobenzoic acid salt [J. Org. Chem. 1980, 45, 4045] (1.60 g, 4.92 mmol) in AcCN (10 ml) was added dimethylsulfate (0.50 ml, 1.05 eq.) at RT. The suspn. was stirred under N2 at 55-60° C. overnight. After cooling to RT, a solution of NH3 in dry EtOH (2M, Aldrich, 20 ml) under cooling in an ice bath. The greenish mixture was stirred in a sealed vial at RT for 4 h, then at 45° C. for 60 h. After evaporation of the solvent and aq. workup as in the previous examples, the crude was purified by silica gel chromatography to give a yellowish-tan cryst. solid. HR-MS calculated for [MH]+: 168.03230, found: 168.03218.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7]O.[N:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O.FC(F)OC1C=C(C=CC=1OC(F)F)CCl.[C-]#N.[Na+]>C(Cl)(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: OCc1ccc(OC(F)F)c(OC(F)F)c1
Reactant: c1ccncc1
Agent: FC(F)Oc1ccc(CCl)cc1OC(F)F
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 45 °C
Yield: 98.5 %

Procedure:
A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argon atmosphere was treated with thionyl chloride (9.62 mL, 130 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a purple oil. To a solution of this 3,4-Bisdifluoromethoxybenzyl chloride in dimethylflormamide (200 mL) under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol). The resulting mixture was stirred and gently heated at 45° C. for 3 h, was cooled and was concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and was extracted five times with ether. The organic extract was washed once with brine, was dried (sodium carbonate) and the solvent was removed in vacuo to provide an oil (27 g).
Reaction SMILES: [C:1](OCC(CO)O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.CCCCCCCCCC(O)=O.CCCCCCCC(O)=O.C(O)C(O)CO>>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCC(=O)O
Solvent: OCC(O)CO
Solvent: CCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCO

Procedure:
Sodium Acrylate Acryloyl Dimethyl Taurate Copolymer (30%); Glyceryl Monostearate (15%); Caprylic/Capric Triglyceride (5%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[CH:7].I[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[C:12](=[O:18])[NH:13]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCOCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCOCCO)c21

Procedure:
Using Method C above, 3-(2-hydroxyethoxy)-1-propyne (53 mg, 0.53 mmol) (from Example 21 above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-[3-(2-hydroxyethoxy)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 68 mg, 49%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1>CN(C)C=O>[N:52]1([CH2:57][C:58]2[CH:66]=[CH:65][C:61]([C:62]([NH:16][C:14]3[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:12]([CH3:17])[N:13]=3)=[O:63])=[CH:60][CH:59]=2)[CH:56]=[CH:55][CH:54]=[N:53]1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)c1ccc(Cn2cccn2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)c2ccc(Cn3cccn3)cc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 136.8 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.47 g, 1.88 mmol), and N-methylmorpholine (0.23 mL, 2.08 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.42 g, 2.09 mmol) and 4-pyrazol-1-ylmethyl-benzoic acid (0.42 g, 2.09 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (0/100 to 30/70) to afford the title compound (1.11 g); MS (ES+) m/z 432 (M+1).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1OCC(O)=O>ClCCl.CN(C)C=O>[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: Cc1ccccc1OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1OCC(=O)Cl
Reaction time: 16 h

Procedure:
Oxalyl chloride (2.2 mL, 25 mM) was added to a stirred solution of (2-methylphenoxy)acetic acid (3.32 g, 20 mM) in dichloromethane (10 mL). Dry N,N-dimethylformamide (1 drop) was added to catalyse the reaction and the mixture was stirred for 16 hours. The solvent was removed by evaporation to leave (2-methylphenoxy)acetyl chloride as a pale yellow oil, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[C:18]2[C:19](=[C:23]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[N:25]=2)[N:20]=[CH:21][N:22]=1>CN(C)C=O.C(OC)(C)(C)C>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[C:18]3[C:19](=[C:23]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[N:25]=3)[N:20]=[CH:21][N:22]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Clc1ccc(-c2c3ncnc(OC4CCN(Cc5ccccc5)C4)c3nn2-c2ccccc2Cl)cc1
Reaction time: 2 h
Yield: 31.3 %

Procedure:
Sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.6 mmol) was added to a solution of 1-benzylpyrrolidin-3-ol (0.1 ml, 0.6 mmol) in dimethylformamide (1 ml), and the resultant mixture was stirred at room temperature for 5 min. Next, 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 1-2A-1c (50 mg, 0.13 mmol) was added in one portion, and the mixture was stirred for 2 hours. The reaction mixture was diluted with methyl tert-butyl ether and washed with water (3×). The organic phase was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate in hexanes) provided the title compound 7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine 7A-1 (21 mg): MS: 516.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.6 (s, 1H), 7.5 (m, 6H), 7.3 (m, 7H), 5.8 (m, 1H), 3.7 (s, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.2 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[NH:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:34])([F:35])[F:36])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([N:38]1[CH2:41][CH:40]([C:42]([O:44][CH3:45])=[O:43])[CH2:39]1)=[O:9])=[O:4]
Reactant: COC(=O)C1CNC1
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)CCNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1 h
Yield: 40 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Int-V, 25 mg, 0.050 mmol), methyl azetidine-3-carboxylate-HCl (7.54 mg, 0.050 mmol), 4-methylmorpholine (20.13 mg, 0.199 mmol), and HATU (24.60 mg, 0.065 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was 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 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-methyl 1-(3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoyl)azetidine-3-carboxylate (11.9 mg, 0.020 mmol, 39.9% yield): LCMS=600.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14-8.26 (2 H, m), 7.54-7.77 (7 H, m), 5.12 (1 H, s), 4.00-4.34 (4 H, m), 3.73 (3 H, d, J=5.27 Hz), 3.39-3.56 (3 H, m), 2.36 (2 H, q, J=6.44 Hz); HPLC peak RT=2.5 min (Method E).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([C:31]2[O:35][C:34]([CH3:36])=[N:33][N:32]=2)[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:29]4[CH:30]=[CH:25][CH:26]=[C:27]([C:31]5[O:35][C:34]([CH3:36])=[N:33][N:32]=5)[CH:28]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(-c4nnc(C)o4)c3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 45.2 %

Procedure:
A stirred mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.100 g, 0.32 mmol) and 5-(3-iodophenyl)-2-methyl-[1,3,4]oxadiazole (0.0915 g, 0.32 mmol) in dry triethylamine (3.5 mL) was treated under argon with a mixture of tetrakis(triphenylphosphine)palladium (0.016 g, 0.013 mmol), cuprous iodide (0.0033 g, 0.017 mmol), and triphenylphosphine (a small crystal) at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue was extracted into methylene chloride and the organic phase was washed with cold dilute hydrochloric acid, water, brine and was dried (sodium sulfate). Purification by chromatography (silica, 10 to 20% ethyl acetate in methylene chloride) followed by drying at 50° C. in vacuo afforded the titled compound as a white powder (0.068 g, 45%), mp 139°-141° C. Anal. (C29H30N2O4.1/3H2O) calcd: C 73.09, H 6.49, N 5.88, found: C 73.07, H 6.35, N 5.79. 1H-NMR (400 MHz, CDCl3) δ 8.15 (t, J=1.6 Hz, 1H), 8.01 (d-t, J=1.4 Hz, J=7.9 Hz, 1H), 7.62 (d-d, J=1.5 Hz, J=7.8 Hz, 1H), 7.49 (t, J=7.9 Hz), 7.21 (d, J=2.3, 1H), 7.14 (d-d, J=8.5 Hz, J=2.4 Hz, 1H), 6.88 (d, J=8.5, 1H), 4.82 (p, J=4.2 Hz, 1H), 3.86 (s, 3H), 3.04 (d-t, J=6.1 Hz, J=14.2, 2H), 2.64 (s, 3H), 2.51 (d,br, J=15.0, 2H), 2.42-2.32 (m, 2H), 2.27 (d-t, J=2.8 Hz, J=14.2 Hz, 2H), 2.00-1.5 (m, 9H with H2O).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH2:17].C(N(CC)CC)C>O1CCCC1>[CH3:14][C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:16]=1[NH:17][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 25 g of 4-trifluoromethylbenzoyl chloride in tetrahydrofuran was added to 14.5 g of 2,6-dimethylaniline and 16.7 ml of triethylamine in tetrahydrofuran. The reaction was stirred at ambient temperature overnight, chilled, and filtered. The filtrate was evaporated in vacuo and the residue therefrom was dissolved in chloroform, washed sequentially with 1M hydrochloric acid, 1M sodium hydroxide, water, and a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. Crystallization from methanol provided the desired title product in 85% yield, m.p. 206-207° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[C:15]2([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[C:15]3([CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:14][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cnc(Cl)nc1NC1CN(C(=O)OC(C)(C)C)CC12CCCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (0.5 g, 3.07 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (0.77 g, 3.22 mmol) in EtOH (15 mL) was added Et3N (0.62 g, 6.13 mmol) and the mixture was stirred at rt for 24 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the product as colourless oil (0.23 g, 21%).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22](O)=[O:23].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:23]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (5.63 g, 23.3 mmol), (R)-tetrahydrofuran-2-carboxylic acid (2.24 mL, 23.3 mmol), DIPEA (10.2 mL, 58.3 mmol), and HOBt (3.15 g, 23.3 mmol) in dry dichloromethane (100 mL) at 25° C. was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (4.45 g, 23.3 mmol) in one portion. The mixture was stirred at 25° C. for 16 h then 1N HCl (50 mL) was added. The organic phase was separated, washed with saturated sodium bicarbonate solution, dried with Na2SO4, filtered and concentrated to afford intermediate (S)-benzyl 1-((R)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxylate as a yellow oil which was carried forward directly.