Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.B.O1CCCC1.Cl>ClCCl.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: B
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of (4-trifluoromethyl-phenyl)-acetic acid (100 mg, commercially available), 6-methoxy-pyridin-3-ylamine (1.1 eq., commercially available) and 1-hydroxybenzotriazole (1.1 eq) in dichloromethane (2 mL) was added under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq) and N,N-diisopropyl ethyl amine (1.2 eq.). After stirring for 3 h at ambient temperature, the reaction mixture was concentrated and a solution of borane-tetrahydrofuran complex (1 M in THF, 3 eq.) was added and the reaction mixture was stirred for 18 h at 60° C. A further portion of the borane-tetrahydrofuran complex (1 M in THF, 3 eq.,) was added and the reaction mixture was stirred for 4 h at 80° C. An aqueous solution of hydrochloric acid (1 M, 2 mL) was carefully added and stirring was continued for 15 min. at reflux. After cooling it was diluted with ethyl acetate (15 mL) and washed with aqueous Na2CO3 (saturated, 15 mL). The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound. MS m/e: 297.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3[N:12]=[C:13]([NH2:21])[N:14]=[C:15]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[N:9]=[N:8]2)=[CH:4][C:3]=1[CH3:24].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>N1C=CC=CC=1>[NH2:21][C:13]1[N:14]=[C:15]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[C:3]([CH3:24])[CH:4]=3)[C:11]=2[N:12]=1
Reactant: Cc1cc(Cn2nnc3c(-c4ccco4)nc(N)nc32)ccc1N
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1ccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)cc1C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A suspension of 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (260 mg, 0.812 mmol) in pyridine (5 mL) at room temperature was treated dropwise with ethyl chloroformate (0.155 mL, 1.62 mmol), stirred for 30 min, poured into water (30 mL), extracted with EtOAc (2×10 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (318 mg, 100%) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:67]([N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1)(=[O:69])[CH3:68]>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([N:73]3[CH2:74][CH2:75][N:70]([C:67](=[O:69])[CH3:68])[CH2:71][CH2:72]3)=[O:11])=[CH:19][CH:18]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)N1CCNCC1
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N3CCN(C(C)=O)CC3)cc2)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
The hydrogenated compound 4 (2.0 g, 4.6 mmol) was dissolved in CH2Cl2 (20 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (0.75 mL, 5.4 mmol) and BOP reagent (2.19 g, 4.96 mmol) were added and the reaction mixture was stirred for 15 min. 1-Acetylpiperazine (1.16 g, 9.02 mmol) was added and the resulting solution was stirred at room temperature for about 2 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (75 mL). The organic layer was extracted with 1.0 N NaOH (1×10 mL), water (2×30 mL) and brine (1×30 mL). Drying and concentration of the organic layer gave the desired amide 18 (2.4 g, ˜96%). 1H NMR (400 MHz, DMSO-d6): 7.24 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 6.87 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.58 (m, 1H), 3.50 (s, 3H), 3.27-3.46 (m, 8H), 3.08-3.13 (m, 1H), 2.77-2.83 (m, 3H), 2.61 (t, J=7.2 Hz, 2H), 1.99 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[OH:13])[CH3:2].[H-].[Na+].Br[CH2:17][C:18]#[N:19]>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([CH3:12])=[CH:5][C:4]=1[O:13][CH2:17][C:18]#[N:19])[CH3:2]
Reactant: CCc1c(O)cc(C)c2sccc12
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(OCC#N)cc(C)c2sccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
4-Ethyl-7-methyl-benzo[b]thiophen-5-ol (438 mg, 2 mmol) was dissolved in 10 ml DMF, and the reaction mixture was cooled to zero degrees C. Sodium hydride (66 mg, 3 mmol) was added and the reaction mixture was stirred 30 minutes at zero C. Bromoacetonitrile (170 ul, 3 mmol) was addeed, and the reaction mixture was stirred 10 minutes at zero degrees C, then allowed to warm to room temperature. The reaction was quenched after 1 hour at room temperature with water, diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. Solvent was removed in vacuo, and the residue chromatographed (10% ethyl acetate in hexanes) to give 422 mg of (4-Ethyl-7-methyl-benzo[b]thiophen-5-yloxy)-acetonitrile as an oil, 80% .
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O.S([O-])(=O)(=O)C.[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:15])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCOCCOCCOCc1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of tetrahydrofuran (140 mL) containing sodium hydride (0.43 g, 18 mmol) was added dropwise a solution of non-polydispersed tetraethylene glycol (3.5 g, 18 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred for 1 h. Then mesylate of non-polydispersed tetraethylene glycol monobenzylether 32 (6.0 g, 16.5 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed, CH2Cl2, 250 mL) and the filtrate was washed H2O, dried MgSO4, and evaporated to dryness. The resultant oil was chromatographed (silica, ethyl acetate/methanol, 10:1) and chromatographed (silica, chloroform/methanol, 25:1) to afford the non-polydispersed title compound as a clear oil (2.62 g, 34% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Treat a solution 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (5.79 g, 20.7 mmol) in dichloromethane (50 mL) at −78° C. with oxalyl chloride (1.99 mL, 22.8 mmol), DMSO (3.5 mL, 49.5 mmol), and triethylamine (8.6 mL, 62.1 mmol). Stir at −78° C. for 30 min, warm to room temperature and stir for 1 h. Quench with ice and extract with dichloromethane (100 mL). Wash with saturated aqueous NaHCO3, saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and purify (silica gel chromatography, eluting with 40:60 to 50:50 ethyl acetate:hexanes) to give the title compound (4.53 g, 78%).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:16]([NH:18][NH2:19])=O>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:19][N:18]=[CH:16][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Reactant: NNC=O
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1ncn[nH]1

Procedure:
A mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and formic hydrazide (0.21 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as a slightly green viscose oil. LCMS calculated for C10H17N6 (M+H): 221.2; found: 221.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.CC(N(C)C)=O.[OH-].[Na+].Cl[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
334 g (1 mol) of 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane, 1.2 dm3 of dimethylacetamide, 200 cm3 of toluene and 44 g of sodium hydroxide were refluxed until it was no longer possible to separate off any water of reaction using a water separator. The toluene was then removed by distillation, 164.4 g (1.1 mol) of 4-chloronitrobenzene were added, and the mixture was refluxed for 48 hours. After the mixture had been cooled to about 0° C., the solid was filtered off, washed with about 100 cm3 of dimethylacetamide and discarded. As much of the dimethylacetamide as possible was removed from the filtrate by vacuum distillation. The oily residue was taken up in 800 cm3 of methanol, a yellow solid precipitating out. The solid was separated off and dried. After the mother liquor had been worked up, a total of 325 g (71% of theory) of a yellow solid were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.FC(F)(F)C(O)=O.C(O)(C)C>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C:2]2[C:11]3[C:6](=[C:7]([N+:13]([O-:15])=[O:14])[C:8]([CH3:12])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(N[C@H](C)c3ccc(Cl)cc3)nccc2c1[N+](=O)[O-]
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 1-chloro-6-methyl-5-nitroisoquinoline (0.22 g, 1.0 mmol), (R)-1-(4-chlorophenyl)ethanamine (0.31 g, 2.0 mmol), 2,2,2-trifluoroacetic acid (0.011 g, 0.10 mmol) and isopropanol (1 mL). The reaction mixture was stirred and heated in a microwave reactor at 140° C. for 60 min. The reaction mixture was diluted with chloroform, washed with 10% sodium carbonate, dried over sodium sulfate and concentrated. The crude product was chromatographed on silica gel eluting with 20% ethyl acetate/hexane to give (R)-N-(1-(4-chlorophenyl)ethyl)-6-methyl-5-nitroisoquinolin-1-amine as a solid. MS Found: (ESI pos. ion) m/z 342 (M+H+).
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][CH2:7]I.[CH:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13].C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O.C(Cl)Cl.CN(C)C=O>C(Cl)Cl>[OH:3][CH2:4][CH2:5][O:6][CH2:7][C:11]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C[Si](C)(C)OCCOCI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The iodomethyl 2-(trimethylsilyloxy)ethyl ether solution prepared in example 2 was kept in a dry ice-acetone bath and a dry solution of nitroform (76 g; 0.5 moles) in 375 ml of methylene chloride was added over 20 minutes through an addition funnel. [See Example 5 for the preparation of the nitroform solution]. After the addition of the nitroform-methylene chloride solution was complete, dry dimethylformamide (100 ml) was added and after five minutes the reaction solution was removed from the dry ice-acetone bath and allowed to warm to near 0° C. (takes about 45 minutes). The solution was then cooled in an ice bath for 15 minutes before it was poured into 600 ml of ice water. The lower organic layer was separated after which the aqueous phase was extracted with 3×25 ml of methylene chloride. The combined organic extracts were dried over sodium sulfate and then allowed to stand in a hood in a current of air to remove volatiles. The residue (approximately 150 g but depends on the amount of dimethylformamide lost) contains mainly 2,2,2-trinitroethyl 2-hydroxyethyl ether1 and dimethylformamide along with much smaller amounts of two byproducts2 (A and B). The crude ether was added to 46 ml of concentrated hydrochloric acid and the mixture was stirred well at 60°-65° C. for 1 hour. After cooling to room temperature, 30 ml of methylene chloride was added and the organic layer was separated and washed with 3×30 ml of water. The combined water extracts (90 ml) were back extracted with methylene chloride (30 ml) and the combined organic extracts were dried over sodium sulfate.
Reaction SMILES: [C:1]([OH:20])(=[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][CH2:17][CH3:18].[O-2].[Zn+2:22]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCCCC(CCC(OS([O-])(=O)=O)CC(C)C)CC.[Na+].O>[C:1]([O-:20])(=[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][CH2:17][CH3:18].[Zn+2:22].[C:1]([O-:20])(=[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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 65 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A molten stearic acid (29.5 grams, Hystrene 7018) was added gradually to a stirred mixture of zinc oxide (4.9 grams), citric acid (0.06 gram), Tergitol 15-S-7 (0.35 gram) and water (66 grams) at 65° C. The reaction mixture was stirred at 60-70° C. for one hour, cooled to 25° C., filtered and dried to give 32.6 grams (99.1% yield) of zinc stearate white powder that showed 0.08% water, 13.6% ash, 0.49% by weight of free fatty acid, and a melting point of 126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:19]([O:23][C:24]([N:26]1[C@@H:31]([C@@H:32]([OH:47])[C@@H:33]([NH:43][C:44](=[O:46])[CH3:45])[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37](Br)[CH:36]=2)[CH2:30][O:29][C@@H:28]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:27]1[CH3:54])=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:19]([O:23][C:24]([N:26]1[C@@H:31]([C@@H:32]([OH:47])[C@@H:33]([NH:43][C:44](=[O:46])[CH3:45])[CH2:34][C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH2:1][CH3:2])[CH:36]=2)[CH2:30][O:29][C@@H:28]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:27]1[CH3:54])=[O:25])([CH3:21])([CH3:22])[CH3:20]
Reactant: CCOc1ccccc1B(O)O
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(Br)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
Add 2-ethoxyphenylboronic acid (0.065 g, 0.394 mmol) and (1,1′-bis(diphenylphosphino)ferrocene) palladium(II) chloride (0.021 g) to a mixture of 2M sodium carbonate solution (0.262 g, 0.525 mmol) and (2R,3S,5R)-5-[(1S,2S)-1-hydroxy-2-acetylamino-3-(3-bromo-5-fluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.151 g, 0.262 mmol) in tetrahydrofuran (2.62 mL) in a sealed tube flushed with nitrogen. Heat the tube at 80° C. for 3 days. Add saturated aqueous sodium chloride and extract with ethyl acetate (2×50 mL). Dry over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with hexanes containing 25-50% ethyl acetate to provide the title compound (0.075 g, 46%) as a white foam.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: N#Cc1ccccc1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(NC(=N)c2ccccc2)cc1C
Yield: 77.8 %

Procedure:
The title compound was prepared from benzonitrile (4.25 g, 41 mmol) and 3,4-dimethylaniline (5 g, 41 mmol) by following the procedure described in preparation 10 (7.2 g, yield 77.8%, purity 99.8% by HPLC). 1H-NMR (CDCl3):δ 2.24-2.25 (d, 6H), 4.84 (bs, 2H, D2O exchangeable), 6.73-6.75 (d, 1H), 6.79 (s, 1H), 7.1-7.11 (d, 1H), 7.41-7.49 (m, 3H), 7.86-7.88 (d, 2H). MS m/z:225.2 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[CH:18]([C:5]1[O:4][C:3]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[CH:6]=1)=[O:19]
Reactant: Cc1ccoc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)oc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Under N2, a solution of 3-methyl-2-furoic acid (2.0 g, 15.9 mmol) in THF (80 mL) was cooled to −78° C. and n-BuLi (1.6 M in hexane) (20.8 mL, 33.3 mmol, 2.1 equiv) was added dropwise. The mixture was kept for 30 min at −78° C., then a solution of DMF (6.11 mL, 79.4 mmol, 5 equiv) in THF (20 mL) was added. After being stirred for 3 h at −78° C., the reaction mixture was allowed to warm to rt. The reaction was quenched with saturated aqueous ammonium chloride then the reaction mixture was partitioned between water and ether. The ether layer was washed with water, and then dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by chromatography over silica gel (0 to 30% EtOAc in heptane over 30 min) to give 5-formyl-3-methyl-2-furoic acid (0.9 g, 37%). 1H NMR (400 MHz, CD3OD) δ ppm 2.39 (s, 3H) 7.29 (s, 1H) 9.67 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2].[CH3:12]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[CH:1]([C:3]1[N:7]([CH3:12])[CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1c[nH]c(C=O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(C=O)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a solution of methyl 5-formyl-1H-pyrrole-3-carboxylate (60.0 g, 0.360 mol) in DMF (60 mL) was added potassium tert-butoxide (72.0 g, 0.576 mol). After stirring at rt for 30 min, the mixture was cooled to 0° C. and methyl iodide (132 mL, 1.45 mol) was added. The solution was then stirred at rt overnight. Water was added to quench the reaction and the solution was extracted with DCM (3×200 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and concentrated to give methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (45.0 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 12.62 (s, 1H), 9.48 (s, 1H), 7.66 (s, 1H), 7.30 (s, 1H), 3.67 (s, 3H).
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH2:5][CH3:6].[Br:14]Br.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:14][CH:5]([CH3:6])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CCC(=O)c1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccccc1
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a CH2Cl2 solution (5 mL) of propiophenone (4.93 g, 36.82 mmol), a CH2Cl2 solution (5 mL) of bromine (6.49 g, 40 mmol) was gradually added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated NaHCO3 solution and 40 mL of EtOAc were added to conduct extraction. The organic layer was washed with 20 mL of a 20 wt % sodium thiosulfate aqueous solution and then with 20 mL of saturated brine, dried (MgSO4), and subjected to distillation under reduced pressure to remove the solvent. The title compound (7.7 g) was obtained as a yellow oil. LC-MS (ES) m/z=214 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].O[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[C:15]([C:12]1[CH:11]=[CH:10][C:9]2[O:5][CH:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][CH:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[C:14]=2[CH:13]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Product: CCC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chloral hydrate (36.4 g.) was added in portions to a stirred solution of p-hydroxypropiophenone (15 g.) in concentrated sulphuric acid (100 ml.). After the addition was completed, the mixture was stirred at room temperature for 3 hours and then kept for 5 days. The reaction mixture was poured onto ice, and the resulting solid product was filtered off, dissolved in diethyl ether (200 ml.) and filtered to remove any metachloral and unreacted starting material. The filtrate was dried, and evaporated to dryness under reduced pressure. Trituration of the residue with petroleum ether (b.p. 60°-80° C.) gave a solid product, which was crystallised from aqueous ethanol to give 6-propionyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 96°-97° C.