Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](C)=[N:7][C:6]=2[CH:11]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:9]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:11][C:6]=2[N:7]=[CH:8]1
Reactant: Cc1nc2cc(Cl)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: c1ccc2ocnc2c1
Temperature: 100 °C

Procedure:
To form 5-vinyl-2-methylbenzoxazole (4aa), the general procedure was followed using 5-chloro-2-methylbenzoxazole (3d) (167 mg, 1.01 mmol), vinyl MIDA boronate (2g) (218 mg, 1.19 mmol), SPhos (42 mg, 0.10 mmol) and Pd(OAc)2 (11 mg, 0.050 mmol). The reaction time and temperature were modified so that the reaction mixture was heated to 100° C. for 2 h. Benzoxazole 4aa was isolated as a pale golden liquid (152 mg, 96%). TLC (hexanes:EtOAc 3:1) Rf=0.46, visualized by UV (254 nm).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1>[Cl-].[Zn+2].[Cl-]>[C:2]1([CH:1]=[CH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnnc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: C(=Cc1ccnnc1)c1ccccc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 4-methylpyridazine (2.83 g, 30 mmol) and the resulting mixture heated for 20 hours at 150° C. The cool reaction mixture was partitioned between dichloromethane (40 ml) and 2M aqueous sodium hydroxide solution (20 ml), then the organic phase separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residual pale brown oil was purified by column chromatography on silica gel, using dichloromethane:methanol (99:1) as eluant, to give the title compound (3.65 g) as a pale brown solid. Found: C, 78.95; H, 5.52; N, 15.39. C12H10N2 requires C, 79.10; H, 5.53; N, 15.37%. δ (CDCl3): 6.96 (1H, d), 7.45 (5H, m), 7.55 (2H, m), 9.12 (1H, d), 9.30 (1H, s). LRMS: m/z 183 (M+1)+.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27]/[CH:28]=[C:29](\[Cl:31])/[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([CH:23]=[CH:24][CH:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([Cl:31])[CH3:30])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: C/C(Cl)=C/CC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(Cl)=CCC(C)C(O)C=C[C@H]1C(O)CC(Cl)[C@@H]1CC=CCCCC(=O)O
Yield: 59.1 %

Procedure:
Under argon, 427 mg of (5Z,13E,18Z)-(8R,9R,11R,12R,15S,16RS)-9,19-dichloro-16-methyl-11,15-bis(tetrahydropyran-2-yloxy)-5,13,18-prostatrienoic acid was stirred at room temperature for 16 hours with 9 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then evaporated under vacuum and the residue purified by column chromatography on silica gel with hexane/20-80% ethyl acetate, thus producing 180 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].C1CCCCC1.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:47]([C:44]3[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=3)(=[O:49])=[O:48])[CH:13]=2)=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)c3cccc([N+](=O)[O-])c3)c3cc(-c4cccnc4)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To (3-nitro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (536, 291 mg, 0.85 mmol) in tetrahydrofuran (7 mL) was added 1.5 M of lithium diisopropylamide in cyclohexane (676 μl , 1.59 mmol) at −78° C. under an atmosphere of nitrogen. After 30 minutes, p-toluenesulfonyl chloride (209 mg, 1.10 mmol) was added in tetrahydrofuran and the reaction was stirred for three hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. All solids were filtered and purified by silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the compound (537, 182 mg, 43%). MS (ESI) [M+H+]+=499.2.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6].O.Cl>C1COCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 98.3 %

Procedure:
1 N NaOH (148.5 mL, 148.5 mmol) was added under nitrogen to a solution of 4′-methoxy-biphenyl-4-carboxylic acid methyl ester (12.0 g, 49.5 mmol), prepared in the previous step, in 1 L of THF plus 250 mL of water at room temperature. After the addition the reaction was refluxed for 16.5 h (overnight). After cooling to approximately room temperature the reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration and dried under reduced pressure to give 4′-methoxy-biphenyl-4-carboxylic acid (11.11 g, 98%) as a white solid, mp 245-250° C.; MS (ESI) m/z 227 [M−H]−. Elemental Analysis for C14H12O3: Calc'd: C, 73.67; H, 5.30; N, 0.00; Found: C, 69.52; H, 5.01; N, 0.04.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH:13]=O.[CH:21]1([N+:27]#[C-:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl(O)(=O)(=O)=O>CO>[CH:21]1([NH:27][C:28]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[NH:1][C:13]=2[C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[O:10][CH3:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: N#Cc1cn[nH]c1N
Reactant: [C-]#[N+]C1CCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCCC2)c(OC)c1
Reaction time: 15 h
Yield: 29.8 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (491 mg, 4.54 mmol) and 2,4-dimethoxybenzaldehyde (754 mg, 4.54 mmol) in a vial under nitrogen atmosphere were added methanol (20 mL) followed by cyclohexyl isonitrile (500 mg, 581 μL, 4.54 mmol) and perchloric acid (91.2 mg, 81.4 μL, 0.908 mmol) at RT. Then, the resulting brown solution was stirred for 15 h by which time lots of solid was formed. These solids were collected by filtration and washed with methanol. After air drying, 495 mg (30% yield) of 3-(cyclohexylamino)-2-(2,4-dimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as a white solid. LC/MS calcd. for C20H23N5O2 (m/e) 365.43, obsd. 366.0 (M+H, ES+).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(C)C=CC=CC=1.[CH3:24][OH:25]>C(OC)(OC)OC>[CH3:24][O:25][CH:13]([O:14][CH3:17])[C:12]1[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:16][CH:15]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1ccc(C=O)cc1
Reactant: CO
Solvent: COC(OC)OC
Product: COC(OC)c1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two g (9 mmol) of 4-(tert.-butoxycarbonyloxy)-benzaldehyde were dissolved at room temperature in 10 ml of methanol and 1.2 ml of trimethyl orthoformate. To obtain complete solution, 1.5 ml of toluene were added. This was followed by the addition of 3.75 mg of RhCl3 [CH3C(CH2PPh2)3 ] as catalyst. The mixture was then stirred overnight at room temperature. The solvents were separated off by steam distillation and the oily residue was taken up in a little toluene. The rhodium catalyst was filtered off over a G-4 frit. After the toluene had been stripped off under reduced pressure, the product was dried in an oil pump vacuum.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C#N)ccn1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccn(Cc2ccccc2)c1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of ethyl 1-benzyl-3-cyano-1H-pyrrole-2-carboxylate (8.7 g, 34.1 mmol) in Methanol (40 mL) and Tetrahydrofuran (THF) (40 mL) was treated with 2M LiOH (40 mL, 80 mmol) and then stirred at 50° C. for 1 hour. The mixture was adjusted to pH<2 by adding HCl (1M) and then concentrated to afford 1-benzyl-3-cyano-1H-pyrrole-2-carboxylic acid as a white solid (7.3 g, 32.4 mmol, 95% yield) which was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6) ppm 7.54 (d, J=6.4 Hz, 1H), 7.45-7.27 (m, 4H), 7.12 (d, J=7.2 Hz, 1H), 6.76-6.69 (d, J=7.2 Hz, 1H), 5.64 (s, 2H); LCMS (m/z) ES+=227 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(O)noc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12

Procedure:
A solution of 3-hydroxy-6-benzyloxy-7-propyl benz[4,5]isoxazole (195 mg) in acetone (3 mL) was treated with methyl iodide (0.067 mL) and potassium carbonate (100 mg). The mixture was refluxed for 8 hours. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was dried over magnesium sulfate, filtered and concentrated to a solid, which was chromatographed over silica gel to afford the product.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[CH:37]([N:40]([CH:48]([CH3:50])[CH3:49])[P:41](Cl)[O:42][CH2:43][CH2:44][C:45]#[N:46])([CH3:39])[CH3:38].CO>C(Cl)Cl>[CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][P:41]([N:40]([CH:48]([CH3:50])[CH3:49])[CH:37]([CH3:38])[CH3:39])[O:42][CH2:43][CH2:44][C:45]#[N:46])=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: CC(C)(C)C(=O)Oc1ccc2c(CC(=O)NCCCCCCO)cc(=O)oc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N(C(C)C)P(OCCC#N)OCCCCCCNC(=O)Cc1cc(=O)oc2cc(OC(=O)C(C)(C)C)ccc12
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 33a (0.6 g, 1.5 mmol) in 10 mL of anhydrous CH2Cl2 was added triethylamine (0.4 mL) followed by 2-cyanoethyl diisopropylchlorophosphoramidite (0.35 mL, 1.6 mmol). The solution was kept at room temperature for 1 h and treated with 0.1 mL of MeOH. The solvent was evaporated and the residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated. The crude product was chromatographed on silica eluting with 5% triethylamine in ethyl acetate. Concentration of the pure product fractions and drying under vacuum afforded 0.59 g (65%) of 34 as a colorless, viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]#N)[C:11]3=[CH:10][CH:9]=2)=[S:7])=[CH:4][CH:3]=1.[OH2:21].[OH-:22].[K+]>C(O)CO>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[N:12]3[CH2:13][CH2:14][CH2:15][CH:16]([C:17]([OH:22])=[O:21])[C:11]3=[CH:10][CH:9]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Cc1ccc(C(=S)c2ccc3n2CCCC3C#N)cc1
Reactant: O
Agent: [K+]
Solvent: OCCO
Product: Cc1ccc(C(=S)c2ccc3n2CCCC3C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of the resulting nitrile (1.5 g., 0.005 moles) in ethylene glycol (20 ml.) containing water (1.6 ml.) and potassium hydroxide (1.65 g.) is heated in an oil bath at 110°-120°, in a nitrogen atmosphere, for 2.5 hours. The solution is cooled to room temperature, it is poured into water (60 ml.) and extracted with ether (2×30 ml.). The aqueous alkaline phase is cooled to 5° C. and made acidic to pH-4. The product is extracted into ethyl acetate (3×100 ml.), the extract is washed with water, dried, and evaporated in vacuo. The residue is crystallized from dichloromethane-methanol to give 3-p-methylthiobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid, m.p. 174°-175°.
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([O:11]C)[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.C(Cl)(Cl)Cl>[F:1][C:2]1[N:3]=[C:4]([OH:11])[C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1nc(F)cnc1C(N)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ncc(F)nc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.1 %

Procedure:
In a nitrogen atmosphere, 0.09 g of 5-fluoro-3-methoxy-2-pyrazinecarboxamide is suspended in 3.6 mL of acetonitrile. Then, 0.16 g of sodium iodide and 0.11 g of chlorotrimethylsilane are successively added to the suspension, which is then stirred at ambient temperature for 20 hours. Then, 2 mL of water and 40 mL of chloroform are added to the reaction mixture and separated into layers. The organic layer is separated, washed successively with 5% (w/v) aqueous solution of magnesium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform) to obtain 0.01 g of 5-fluoro-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]([CH:10](O)[CH3:11])[NH2:9].C(=O)([O-])[O-:14].[K+].[K+]>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:8]([CH2:10][CH2:11][OH:14])[NH2:9]
Reactant: O=C([O-])[O-]
Reactant: CC(O)NN
Reactant: Clc1ncccn1
Agent: [K+]
Solvent: CCO
Product: NN(CCO)c1ncccn1

Procedure:
4.8 g (41.9 mmol) of 2-chloropyrimidine in 100 ml of ethanol and 3.6 g (47 mmol) of hydrazinoethanol and 9 g (64.2 mmol) of potassium carbonate were heated under reflux for 5 h. The mixture was filtered off with suction and the filtrate was concentrated by evaporation.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:8]=2[CH:26]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg]Br.[NH4+].[Cl-]>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:17])=[O:18])[C:8]=2[CH:26]([OH:27])[CH3:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Br
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C(C)O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde (2.11 g, 5.62 mmol) in THF (30 mL) at −78° C. and under a nitrogen atmosphere, was added 3.0M methylmagnesium bromide in diethyl ether (2.6 mL). The mixture was stirred at 0° C. for 30 min then additional 3.0M methylmagnesium bromide in diethyl ether (0.3 mL) added. After 15 min, the reaction mixture was poured into a saturated solution of NH4Cl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The crude material was combined with a second portion of crude reaction mixture obtained following the same method (starting from 140 mg, 3.73 mmol of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbaldehyde) and the combined batches were purified by column chromatography (Si—PCC, gradient 20-100% DCM in pentane) affording the title compound as a gum which solidified on standing (2.02 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 8.07 (1H, d, J=8.35), 7.80-7.75 (2H, m), 7.51-7.38 (5H, m), 7.33-7.26 (2H, m), 7.20-7.14 (3H, m), 5.25-5.15 (1H, m), 4.06 (1H, d, J=11.01 Hz), 2.31 (3H, s), 1.70 (3H, d, J=6.88 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)=[C:4]([F:22])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C

Procedure:
8-(4-Chloro-2-fluorophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (0.8 g) was added to a mixture of concentrated nitric acid (60%, d=1.38; 1 ml) and concentrated sulfuric acid (10 ml) under ice-cooled condition. The mixture was reacted for 30 minuets at 0° C., poured into ice water (150 ml) and then extracted with ether. The extract layer was washed with water, an aqueous saturated sodium hydrogencarbonate solution and water in this order, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the compound of interest (0.65 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C.CC(=O)OCC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([NH:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]5[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=5[CH:75]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)c4cccn34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (23 mg, 0.052 mmol), HATU (30 mg, 0.078 mmol) and Et3N (0.02 mL, 0.104 mmol) in DMF (10 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (24 mg, 0.104 mmol). The mixture was stirred at rt overnight. EA (50 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)indolizine-5-carboxamide (13 mg, yield 40%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (t, J=6.0 Hz, 1H), 9.05 (s, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.67 (s, 3H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.94 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.48 (d, J=18.0 Hz, 1H), 4.38 (d, J=18.0 Hz, 1H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=616.0 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10]([N+:12]([O-])=O)[CH3:11].[N+](CC)([O-])=O.ClC1C=CC=C(Cl)C=1C=O.[C:30](OC)(=[O:36])[CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH:10]([CH3:11])[NH:12][C:30](=[O:36])[CH:31]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=Cc1c(Cl)cccc1Cl)[N+](=O)[O-]
Agent: O=Cc1c(Cl)cccc1Cl
Solvent: CC[N+](=O)[O-]
Product: COC(=O)C1C(=O)NC(C)C1c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-2-nitropropylene (m.p. 49°-50° C., b.p. 90°-102° C./0.33 mm. Hg.)is prepared from nitroethane and 2,6-dichlorobenzaldehyde by a similar process to that described in the second and third parts of Example 4. This compound is reacted with dimethyl malonate and the product hydrogenated by a similar process to that described in the fourth and fifth parts of Example 4, and the 4-(2,6-dichlorophenyl)-3-methoxycarbonyl-5-methylpyrrolidin-2-one thus obtained is separated into two geometrical isomers thereof by repeated chromatography on a silica gel column, using a 2:1 v/v mixture of toluene and ethyl acetate as eluant. The two isomers have m.p. 157°-158° C. (first isomer) and 143°-144° C. (second isomer). These two esters are separately hydrolysed and decarboxylated by a similar process to that described in the sixth part of Example 4, and there are thus obtained a first isomer, m.p. 182°-184° C., and a second isomer, m.p. 173.5°-175° C., of 4-(2,6-dichlorophenyl)-5-methylpyrrolidin-2-one, the isomers differing by cis- and trans- relationship of the 4-(2,6-dichlorophenyl)- and 5-methyl-substituents.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13](Cl)=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2].[C:31]([NH:41][NH2:42])(=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([N:41]([C:31](=[O:40])[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[NH2:42])=[N:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[NH:22][C:23]=1[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)Nc2c(c(Cl)nc(=O)n2-c2ccccc2)C1c1ccccc1
Reactant: COc1cccc(C(=O)NN)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2c(c(N(N)C(=O)c3cccc(OC)c3)nc(=O)n2-c2ccccc2)C1c1ccccc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
The compound of step 6 (100 mg, 0.237 mmol) was taken in 2 ml EtOH and treated successively with m-anisic hydrazide (99.6 mg, 0.6 mmol) and TEA (Triethylamine) (35 microl, 0.25 mmol) at room temperature and stirred at 60° C. for 72 h.