Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:17]([Cl:22])[CH:16]=1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Nc1ccc(O)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc(N)cc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2,4-difluorobenzoate (6.48 g) and 4-amino-2-chlorophenol (5.0 g) in diglyme (40 mL) was added K3PO4 (7.39 g). The mixture was stirred at 110° C. overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:5]=[C:6]([CH:10]=[O:11])[C:7]=1[O:8][CH3:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH:10]([C:6]1[CH:5]=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:7]=1[O:8][CH3:9])=[O:11]
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cc(S(N)(=O)=O)cc(C=O)c2OC)c1

Procedure:
Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-methoxybenzene boronic acid, gave 5-formyl-3′,6-dimethoxy-biphenyl-3-sulfonic acid amide.
Reaction SMILES: [C:1]([CH2:3][C@H:4]([NH:34]C(=O)OC(C)(C)C)[C:5]([NH:7][C@@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1)[C:13]([C@@:15]1([CH3:18])[CH2:17][O:16]1)=[O:14])=[O:10])=[O:6])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@@H:4]([CH2:3][C:1]#[N:2])[C:5]([NH:7][C@@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:9]([NH:11][C@@H:12]([CH2:19][C:20]1[CH2:24][CH2:23][CH2:22][CH:21]=1)[C:13]([C@@:15]1([CH3:18])[CH2:17][O:16]1)=[O:14])=[O:10])=[O:6]
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](CC#N)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](NC(=O)[C@@H](N)CC#N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 138.7 %

Procedure:
To a solution of tert-butyl ((S)-3-cyano-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyl oxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (0.59 g, 1.0 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 15 min at ambient temperature then concentrated to dryness to afford (S)-2-amino-3-cyano-N-((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)propanamide (650 mg, quant.) as its TFA salt, which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)(=O)C.O.[OH-].[Na+].Cl>[CH3:1][C:2]1[S:3][C:4]2[C:10]([CH2:11][OH:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1cccc2nc(C)sc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cccc(CO)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Under nitrogen atmosphere, to a solution of methyl 2-methyl-1,3-benzothiazole-7-carboxylate (6.00 g, 29.0 mmol) in tetrahydrofuran (150 mL) was added lithium aluminum hydride (1.18 g, 34.7 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and water, 1 M aqueous sodium hydroxide solution (10 mL) and 2 M hydrochloric acid (10 mL) were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (4.78 g, yield 92%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([CH3:13])([CH3:12])[C:3]1=[O:14].[N+:15]([O-])([OH:17])=[O:16].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[CH:9][CH:10]=2)[NH:5][C:4]([CH3:12])([CH3:13])[C:3]1=[O:14]
Reactant: CN1C(=O)C(C)(C)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)C(C)(C)Nc2cc([N+](=O)[O-])ccc21
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
In a 50-mL r.b. flask, a solution of 3,4-dihydro-1,3,3-trimethylquinoxalin-2(1H)-one (830 mg, 4.36 mmol) in 20 mL of conc. H2SO4 was cooled to −15° C. A solution of HNO3 (336 mg, 4.80 mmnol, 1.1 equiv) dissolved in conc. H2SO4 (1 mL) was then added dropwise via syringe in order to maintain a temperature below −5° C. After complete addition the reaction was allowed to stir at −15° C. for 15 min, warmed to rt, poured over NaOH (15 g) pellets and ice. After complete solution of the NaOH pellets, the red precipitate was filtered, redissolved in EtOAc (150 mL), washed with H2O (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated to give a orange solid. No further purification is required to obtain 960 mg (94%) of 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2(1H)-one as an orange solid. Data for 3,4-dihydro-1,3,3-trimethyl-6-nitroquinoxalin-2 (1H)-one: 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J=8.8, 2.5, 1H), 7.55 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 4.04 (bs, 1H), 3.42 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:25][C:26]1[CH:27]=[C:28]([CH:43]=[CH:44][CH:45]=1)[CH2:29][NH:30][C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([CH3:42])[CH:34]=1)=[O:32].[CH3:46][O:47][C:48](=[O:57])[CH:49]([P:51]([O:55][CH3:56])([O:53][CH3:54])=[O:52])[NH2:50].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:46][O:47][C:48](=[O:57])[CH:49]([P:51]([O:53][CH3:54])([O:55][CH3:56])=[O:52])[NH:50][C:37](=[O:39])[C:36]1[CH:40]=[CH:41][C:33]([C:31]([NH:30][CH2:29][C:28]2[CH:43]=[CH:44][CH:45]=[C:26]([OH:25])[CH:27]=2)=[O:32])=[CH:34][C:35]=1[CH3:42]
Reactant: Cc1cc(C(=O)NCc2cccc(O)c2)ccc1C(=O)O
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.50 g, 9.2 mmol) was added to a solution of 4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoic acid (Example 90; 2.40 g, 8.4 mmol), rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125; 1.80 g, 9.1 mmol) and diisopropylethylamine (1.50 g, 11.6 mmol) in N,N-dimethylformamide (50 mL). The solution was stirred overnight at room temperature. Ethyl acetate (200 mL) was added and the solution was washed with 1N hydrochloric acid solution, water and brine (200 mL each), dried (MgSO4), filtered and evaporated to give crude rac.-2-(dimethoxyphosphinyl)-N-[4-[[(3-hydroxybenzyl)amino]carbonyl]-2-methylbenzoyl]glycine methyl ester (2.47 g, 63% yield). This material was used in subsequent reactions without flrther purification.
Reaction SMILES: C[O:2][C:3](=[O:48])[CH:4]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:25]=1)[O:5][P:6]([C@@H:9]([NH:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7].[Li+].[OH-].Cl>CO.O>[C:36]([O:35][C:33]([N:32]=[C:31]([NH:40][C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[NH:30][C:26]1[CH:25]=[C:24]([CH:4]([O:5][P:6]([C@@H:9]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH:10]([CH3:12])[CH3:11])([OH:8])=[O:7])[C:3]([OH:48])=[O:2])[CH:29]=[CH:28][CH:27]=1)=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)C(OP(=O)(O)[C@@H](NS(=O)(=O)Cc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 6 h

Procedure:
To a slurry of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (0.53 mmol) in 6 mL of methanol and 3 mL of H2O was added LiOH (124.3 mg, 5.3 mmol). After stirring for 6 hours, the solution was acidified to pH 2 with concentrated HCl and extracted with methylene chloride (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid as a yellow oil that was used without further purification in the following step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][OH:15])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.N1C(=O)CC[C@H]1C(O)=O>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]=[O:15])[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CO)OC1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of (3R,6S)-(6-hydroxymethyl-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (37.5 g, 162.13 mmol) in DCM (310 mL) cooled to −10° C. was added DIPEA (84.75 mL, 495.06 mmol). Then a solution of Pyr.SO3 complex (50%, 69.47 g, 218.25 mmol) in DMSO (225 mL) was slowly added. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture was partitioned between water (150 mL) and DCM (220 mL). The two layers were separated and the aq. layer was extracted twice with DCM (2×150 mL). The combined org. layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was co-evaporated 3 times with toluene and purified over a short pad of silica gel (EA-Hept. 2-1) to afford the title aldehyde as a white solid (33.58 g, 90% yield).
Reaction SMILES: [OH:1][CH:2]1[C:17](=O)[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Na].[SiH3]O[SiH3]>O1CCOCC1.CO>[C:2]1(=[O:1])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: O=C1CCC=CCCCCCCC=CCCC1O
Agent: C[Si](C)(C)Cl
Agent: O=C1CC/C=C/CCCCCC/C=C/CCC1
Agent: O=C1CC/C=C/CCCCCC/C=C/CCC1O
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1CCC=CCCCCCCC=CCCC1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a flask containing a solution of 16-hydroxycyclohexadeca-4E,12E-dien-1-one (2.5 g, 10 mmole), triethylamine (2.02 g, 20 mmole) in 1,4-dioxane (20 ml) was added chlorotrimethylsilane (2.17 g, 20 mmole) in one portion at room temperature. The reaction was stirred for 18 hours and then quickly filtered through a fritted glass fimnel. The resultant solution of the silyl ether was transferred to a pressure-equalizing dropping funnel and used directly in the following operations. A 2-neck round bottomed flask was charged with sodium (460 mg, 20 mmole), chlorotrimethylsilane (2.17 g, 20 mmole) and 1,4-dioxane (15 ml) and the mixture was warmed to 45° C. The solution of the silyl ether prepared above was added slowly (30 minutes via a pressure-equalizing dropping funnel) while gradually increasing the reaction temperature to 110° C. The mixture was stirred at 110° C. for 16 hours, cooled to room temperature, and to the mixture was added methanol. The reaction mixture was poured onto water, extracted with ether, dried with sodium sulfate, filtered and evaporated to give the crude ketone product. This material was purified by chromatography (CH2Cl2) to afford cyclohexadeca-4E,12E-dien-1-one (1.24 g, 53% yield) as a colorless liquid. C16H26O (234.39 g/mole). 1HNMR (500 MHz, CDCl3): 1.21 (m, 4H), 1.34 (m, 4H), 1.61 (m, 2H), 1.97 (m, 4H), 2.03 (q, 2H), 2.28 (m, 2H), 2.39 (m, 4H), 5.28 (m, 1H), 5.34 (m, 3H) ppm. 13CNMR (125 MHz, CDCl3): 22.3, 26.8, 27.0, 27.6, 28.1, 28.9, 30.8, 30.9, 31.4, 41.4, 42.8, 128.9, 129.3, 131.4, 132.1, 211.6 ppm. IR (νmax(cm−1)): 2950(s), 2920(s), 2860(s), 1715(s), 1440(m), 1260(s), 980(s), 800(s). MS (m/z): 234(M+), 216, 205, 191, 177, 163, 149, 135, 123, 109, 95, 81, 67, 55, 41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13](=[O:26])[NH:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.N1C=CC=CC=1.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([O:26][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(F)ccc43)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc(F)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (150 mg, 0.43 mmol) in dichloromethane (30 mL) was added pyridine (136 mg, 1.72 mmol) and then Tf2O (243 mg, 0.86 mmol) was added dropwise with stifling at 0° C. The resulting solution was stirred for 4 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (200 mg, crude).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH2:6][C:7](F)([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1)[NH2:4].[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24]2[CH:31]=[C:30]([C:32](O)=[O:33])[NH:29][C:25]2=[N:26][C:27]=1[CH3:28])=[O:21].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[CH3:28][C:27]1[N:26]=[C:25]2[NH:29][C:30]([C:32](=[O:33])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=3)[C:2]([F:17])([F:16])[F:1])=[CH:31][C:24]2=[CH:23][C:22]=1[C:20]([O:19][CH3:18])=[O:21]
Reactant: COC(=O)c1cc2cc(C(=O)O)[nH]c2nc1C
Reactant: NC(C1=CC=CC(F)(C(F)(F)F)C1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoro-1-[3-fluoro-3-(trifluoromethyl)phenyl]ethanamine (2.07 g, 8.54 mmol) was dissolved in N,N-dimethylformamide (6 ml), and 5-(methoxycarbonyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.60 g, 6.83 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (2.56 g, 6.83 mmol) and 4-methylmorpholine (2.53 ml, 20.50 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water was added. The aqueous phase was extracted three times with ethyl acetate and the extract was dried over sodium sulphate, adsorbed on silica gel and chromatographed with ethyl acetate. This gave 1.74 g (55% of theory) of methyl 6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate. HPLC-MS: log P=3.37; mass (m/z): 460.1 (M+H)+; 1H-NMR (D6-DMSO): δ 2.79 (s, 3H), 3.87 (s, 2H), 6.29-6.32 (m, 1H), 7.50 (s, 1H), 7.70-7.74 (m, 1H), 7.82-7.84 (m, 1H), 8.05 (d, 1H), 8.18 (s, 1H), 8.66 (m, 1H), 9.72-9.74 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[K].[OH-:13].[Na+].[Mg+2].[Cl-].[Cl-].[Cl-].[Na+]>O>[CH2:8]([CH:7]1[C:2]([OH:6])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:13])[CH:9]=[CH2:10]
Reactant: [OH-]
Reactant: Cc1ccc(C=CCCO)o1
Agent: [Cl-]
Agent: [K]
Agent: [Mg+2]
Solvent: O
Product: C=CCC1C(=O)C=CC1(C)O
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
In a reaction vessel, water (750 ml) was charged, and the temperature was elevated up to 100° C. to reflux. Then, 5-methyl-2-furylallylcarbinol (24 g) and a solution of MgCl2.6H2O (31.5 g) in water (160 ml) were dropwise added thereto in 2.5 hours and 3.5 hours, respectively. During the addition, the pH value of the reaction mixture was maintained at 5.7 to 5.3 by the addition of an aqueous 10% potassium primary phosphate solution and an aqueous 1 N NaOH solution. After about 1.5 hours from the start of the reaction, the pH value stabilized and remained within said range. After completion of the addition of the aqueous MgCl2 solution, the reaction mixture was stirred at pH 5.5 under reflux at 100° C. for an additional 4.5 hours. Then, the reaction mixture was cooled to 40° C. and neutralized with an aqueous 1 N NaOH solution. After addition of sodium chloride (320 g), the mixture was extracted with toluene (250 ml) four times. The extract was dried over anhydrous magnesium sulfate, and toluene was removed therefrom by distillation at 60° C. under reduced pressure to give an oily substance (21.6 g), which was subjected to distillation under reduced pressure to obtain 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (20.4 g). Yield, 85%. B.P., 88°-90° C./0.5 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])(O)[CH:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[H-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 48.5 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-3,4-dihydro-3-hydroxy-2H-1-benzopyran (3.53 g, 0.0107 mol) in tetrahydrofuran (150 ml) was treated with sodium hydride (80%, 0.32 g). The mixture was heated at reflux for sixteen hours. Water and ethyl acetate were added to the cooled solution and the organic layer separated, dried and evaporated under reduced pressure to afford 1.62 g of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 200° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:27][C:28](Cl)=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1>[C:28](=[O:29])([O:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 0.90 g. of chloroformic acid n-pentyl ester as in Example 1. The 1.5 g. of yellow, partially crystallized oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.479 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-pentyl carbonate obtained melts at 50.1°-51.0° and has a clearing point of 61.1°. UV (EtOH): ε270 = 26,800.
Reaction SMILES: C[C@@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=O.O.[C:12]1(C)[CH:17]=[CH:16]C(S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>>[C:7]([O:9][CH2:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C@H:6]([CH3:10])[OH:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Solvent: OCc1ccccc1
Solvent: O
Product: C[C@H](O)C(=O)OCc1ccccc1

Procedure:
Commercially available L-lactide 1 (16 g, 0.14 mol) and p-toluenesulfonic acid monohydrate (catalytic amount) in benzyl alcohol (40 mL, 0.38 mol) was heated to 110° C. overnight. Excess benzyl alcohol was removed under vacuum to obtain a light yellow oil. The desired product was distilled under vacuum (0.9 mm Hg, 85-95° C.) to obtain 50.3 g of 2 as a clear oil. The distilled oil was used without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.N#N.[CH3:13][N:14]([C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMSO (1.47 mL, 20.8 mmol) in 60 mL of CH2Cl2 was cooled to −78° C. and treated with oxalyl chloride dropwise under N2 atmosphere for 10 min. The resulting mixture was treated with a solution of 2-[methyl(trityl)amino]ethanol (3.0 g, 9.45 mmol) in 10 mL of CH2Cl2 dropwise and stirred for additional 15 min. Triethylamine (6.6 mL, 47.3 mmole) was added to the mixture and warmed up to room temperature. The reaction was quenched by adding water and diluted with 100 mL of CH2Cl2. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with ether to give the product as white solid.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1
Reactant: CC(=O)Cl
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(C)=O)CC1

Procedure:
from trans-N-benzyl-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)cyclohexylamine and acetylchloride. Oil. Rf value: 0.66 (alumina, ethyl acetate/petroleum ether= 1:3, v:v).