Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
N,N'-carbonyldiimidazole (1.13 g) is added to a solution, cooled to +5° C., of [2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetic acid (1.85 g) in dry dichloromethane (30 cc). The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenylperhydro-4-isoindolone hydrochloride (2.29 g) and triethylamine (1.9 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 2 hours, then washed with water (2×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4 cm, height 50 cm), eluting under a nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (30:70 by volume) and collecting 125-cc fractions. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-{[2-(N-tert-butoxycarbonyl-N-methylamino)phenyl]acetyl}-7,7-diphenylperhydro-4-isoindolone (2.8 g) in the form of a white meringue-like product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])=[O:4].[CH2:14]([N:26]([CH2:28][CH2:29]O)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:14]([N:26]([CH2:28][CH2:29][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCN(C)CCO
Reactant: O=C(c1ccccc1O)C(F)(F)F
Product: CCCCCCCCCCCCN(C)CCOc1ccccc1C(=O)C(F)(F)F
Yield: 61.2 %

Procedure:
2-Trifluoroacetylphenol (Matsumoto, S.; Kobayashi, H. and Ueno, K. Bull. Chem. Soc. Jpn. 1969, 42, 960) (490 mg, 2.57 mmol) and 2-[N-dodecyl-N-methylamino] ethanol (627 mg, 2.58 mmol) were reacted by the general procedure as described in example 1 and afforded the title compound (654 mg, 61%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[O:4].[OH:7][CH2:8][C:9](=[O:12])[CH2:10][OH:11]>>[OH:4][CH2:3][C:2]([C@@H:1]([C@H:8]([C@H:9]([CH2:10][OH:11])[OH:12])[OH:7])[OH:6])=[O:5]
Reactant: O=CC(O)CO
Reactant: O=C(CO)CO
Product: O=C(CO)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
Recently, L-fructose was prepared by aldol condensation. See S. Morgenlie, Carbohydr. Res., 107 (1982) 137-141. DL-Glyceraldehyde condensed with 1,3-dihydroxy-2-propanone catalyzed by Dowex 1 (OH-) resin to give a hexulose mixture. Crystallization of the mixture from methanol yielded 54% of DL-fructose. Treatment of the DL-fructose mixture with baker's yeast gave a product from which 62% of 2,3:4,5-di-O-isopropylidene-β-L-fructopyranose was isolated after acetonation. When L-glyceraldehyde was used as starting material, 2,3:4,5-di-O-isopropylidene-β-L-fructopyranose was isolated in 60-65% yield after acetonation of the hexulose mixture.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)C(C)C)(C)C.[C:21]([NH:24][CH2:25][CH2:26][NH2:27])(=[O:23])[CH3:22]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][CH2:26][CH2:25][NH:24][C:21](=[O:23])[CH3:22])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)NCCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (15.5 mmol) 2,6-dichloro-3-nitropyridine in 50 mL of THF at −78° C. under Ar atmosphere was added 2.7 mL (15.5 mmol) of N,N-diisopropylethylamine followed by 1.6 mL (15.5 mmol) of N-acetylethylenediamine. The mixture was stirred at −78° C. for 30 min, allowed to warm to room temperature, and stirred for 72 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography eluting with MeOH/dichloromethane gradient (1→10%) to provide N-(2-(6-chloro-3-nitropyridin-2-ylamino)ethyl)acetamide as pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:30])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])(=[O:22])=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.[Li+].[OH-]>C1COCC1.O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([NH:19][CH2:18][CH2:17][C:16]([C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[C:14]=1[CH3:15])=[CH2:30])(=[O:21])=[O:22]
Reactant: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCNS(=O)(=O)c1ccccc1Cl)c1c(C)c(CC(=O)O)cc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 92 %

Procedure:
To a solution of {4-[3-(2-Chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (140 mg, 0.294 mmol) in THF (6 mL) was added a solution of LiOH (141 mg, 5.88 mmol) in water (1.5 mL). The resulting mixture was warmed with a heat gun to produce a clear solution, which was stirred for 15 hours at room temperature. At this time, LCMS analysis indicated the complete conversion of starting material. The THF was evaporated and the aqueous layer was diluted with water and slowly neutralized with 1.0 N HCl to obtain a white precipitate which was collected by filtration and washed with water and hexanes. After air drying, 125 mg of {4-[3-(2-chloro-benzenesulfonylamino)-1-methylene-propyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (bs, 1H), 7.96 (t, J=5.6 Hz, 1H), 7.87-7.93 (m, 2H), 7.73 (s, 1H), 7.59-7.62 (m, 2H), 7.45-7.51 (m, 1H), 7.29-7.38 (m, 2H), 5.50 (dd, J=3.3, 1.2 Hz, 1H), 4.93 (d, J=1.0 Hz, 1.2H), 3.72-3.80 (m, 2H), 3.00-3.12 (m, 2H), 2.30-2.39 (m, 2H), 2.17 (s, 3H). MS cald. for C23H22ClFNO4S [(M+H)+] 462.1, obsd. 462.0.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([NH2:29])[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.Cl.CI.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:31][C:2]([F:1])([F:30])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([NH:29][CH3:35])[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(N)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNC1(C(=O)Nc2ccc(OC(F)(F)F)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 42 mg (0.08 mmol) 4-Amino-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide; hydrochloride (example 80) and 96 mg (0.68 mmol) methyl iodide and 17.6 mg (0.128 mmol) potassium carbonate in 2 mL DMF was heated to 40° C. for 1.5 h. The mixture was filtered and the filtrate was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 9.6 mg (24%) of the title compound. MS (m/e): 472.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([OH:30])([CH2:27][O:28][CH3:29])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:32][CH3:33])[C:16]=1[F:34].C(O)(=O)C.[F-].[NH4+]>C1(C)C=CC=CC=1.O1CCOCC1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti].C(OCC)(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[N:1][C:2]2[CH:11]=[C:10]([F:12])[CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:13])[NH:7]3)[C:22]([OH:30])([CH2:27][O:28][CH3:29])[C:23]([F:26])([F:25])[F:24])=[C:17]([O:32][CH3:33])[C:16]=1[F:34]
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Reactant: COCC(O)(C(=O)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Agent: [Ti]
Agent: [F-]
Agent: [NH4+]
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COCC(O)(C(=Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml 1,4-dioxane are added 33 μl acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5° C. and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride, 30%) yields 9.5 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[C:11]3([O:13][CH2:12]3)[C:10]([CH3:15])([CH3:14])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([CH3:15])([CH3:14])[C:11]2([CH2:12][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[OH:13])=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=Cc2ccc(F)cc2)C12CO2
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C=CC(=Cc2ccc(F)cc2)C1(O)Cn1ccnc1

Procedure:
A mixture of 7-(4-fluorobenzylidene)-4,4-dimethyl-1-oxaspiro[2.4]hept-5-ene (5.5 g), produced according to the previous example, with imidazole (2 g) and potassium carbonate (6.6 g) is heated in N,N-dimethyl-formamide (50 cc) for 4 hours. The mixture is poured into water and extracted with ethyl acetate. The organic phase is washed, dried and recrystallized to obtain the product indicated, m.p. 172° C., compound no. 32
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:19][C@@H:20]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:21]#[N:22].[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.O>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:29][C:24]([CH2:23][C@H:20]([NH:19][C:45]([C@@H:44]2[CH2:48][CH2:49][CH2:50][N:43]2[C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[O:46])[C:21]#[N:22])=[CH:25][CH:26]=1
Reactant: N#C[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(-c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of propane phosphonic acid anhydride (T3P, 50% in DMF, 344 mg) was added to a stirred solution of (S)-2-amino-3-(biphenyl-4-yl)propanenitrile (100 mg), N-tert-butoxycarbonyl-(L)-proline (107 mg) and triethylamine (0.314 mL) in DMF (3 mL) at 20° C. The resulting solution was stirred at 20° C. for 1 hour. Water (15 mL) was added and the mixture extracted with ethyl acetate (3×5 mL). The organics were washed with saturated brine (5×5 mL), dried over sodium sulfate and evaporated to afford the subtitle compound (178 mg).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]([O:40][CH3:41])=[O:39])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.O>[C:42]1([CH:37]([CH:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:10]4[CH:11]=[CH:12][C:7]([C:6]([F:5])([F:22])[F:23])=[CH:8][CH:9]=4)=[O:20])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)[C:38]([O:40][CH3:41])=[O:39])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 59.9 %

Procedure:
Thionyl chloride (3.6 ml) was added to a clear solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.025 mol) in DMF (1 ml) and DCM (100 ml). The mixture was stirred and refluxed for one hour. The solvent was evaporated. DCM (50 ml) was added to the residue, then evaporated. The residue was dissolved in DCM (50 ml) and the solution was added dropwise to a solution of intermediate (18) (0.025 mol) in DCM (150 ml) and DIPEA (0.049 mol). The reaction mixture was stirred for 2 hours at room temperature. Water was added and this mixture was extracted twice. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in DIPE, filtered off, dried, and crystallized from 2-propanol (150 ml; later, 300 ml was added). The mixture was stirred for 2 hours at room temperature. The precipitate was filtered off, washed with 2-propanol and dried, yielding 8.58 g of methyl α-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetate (intermediate 23).
Reaction SMILES: N[CH:2]1[N:6]2[C:7](=[O:20])[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:5]2[C:4]2[S:21][CH:22]=[CH:23][C:3]1=2.O>C(O)(=O)C.[Zn]>[O:20]=[C:7]1[N:6]2[CH2:2][C:3]3[CH:23]=[CH:22][S:21][C:4]=3[C:5]2=[C:10]([C:11]([OH:13])=[O:12])[CH:9]=[C:8]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC1c2ccsc2-c2c(C(=O)O)cc(-c3ccccc3)c(=O)n21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1C2
Yield: 97.3 %

Procedure:
A suspension of 45.7 g of 4-amino-4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]pyrrolo[1,2-a]pyridine-9-carboxylic acid in 915 ml of acetic acid was treated with 27.6 g of zinc powder and heated to boiling under reflux for 2 hours. The suspension was then cooled and poured into 3000 ml of water. The excess zinc was for the most part removed by decantation. The separated crystals were filtered off under suction and dried in a vacuum. There was obtained 42.4 g of 4,6-dihydro-6-oxo-7-phenylthieno[2',3':3,4]-pyrrolo[1,2-a]pyridine-9-carboxylic acid with a m.p. of >300° (purity 85-90%). This material was purified further by recrystallization from methanol/N,N-dimethylformamide.
Reaction SMILES: [CH:1]([C:4]1([C:10]#[N:11])[CH2:8][CH2:7][NH:6][C:5]1=[O:9])([CH3:3])[CH3:2].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:12][C:13]1[N:18]=[C:17]([N:6]2[CH2:7][CH2:8][C:4]([CH:1]([CH3:3])[CH3:2])([C:10]#[N:11])[C:5]2=[O:9])[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)C1(C#N)CCNC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of 3-isopropyl-2-oxopyrrolidine-3-carbonitrile (120 mg) obtained in Step B, 2,4-dichloropyrimidine (240 mg), cesium carbonate (510 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg) in tetrahydrofuran (3 mL) was added tris(dibenzylideneacetone)dipalladium(0) (14 mg), and the mixture was stirred overnight at 100° C. To the reaction mixture was added water, 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 (hexane/ethyl acetate) to give the title compound (160 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1B1OC(C)(C)C(C)(C)O1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>ClCCCl.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>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: Oc1ccccc1Br
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: Cn1cccc1-c1ccccc1O
Temperature: 80 °C
Yield: 33.7 %

Procedure:
1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole (5.0 g, 24 mmol), tetrakis(triphenylphosphine)palladium (0) (1.4 g, 1.2 mmol), 2-bromophenol (4.2 g, 24 mmol), and potassium carbonate (24 mL of 2.0 M, 48 mmol) were combined in 1,2-dichloroethane (291 mL). The mixture was heated at 80° C. for 16 h. The mixture was cooled to 25° C. before it was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, and concentrated. Column chromatography (0-100% ethyl acetate/hexanes) on the residue gave 2-(1-methylpyrrol-2-yl)phenol (1.4 g, 34%). ESI-MS m/z calc. 173.2. found 174.2 (M+1)+; Retention time: 1.76 minutes (3 min run).
Reaction SMILES: [NH2:1][C:2]1[N:6](CC2C=C(C)C(C(=O)C3C=CC(C(F)(F)F)=CC=3)=C(Cl)C=2)[N:5]=[N:4][C:3]=1[C:28]([NH2:30])=[O:29].CI.[C:33](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:33][NH:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:28]([NH2:30])=[O:29]
Reactant: Cc1cc(Cn2nnc(C(N)=O)c2N)cc(Cl)c1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CNc1[nH]nnc1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-(4-[4-trifluoromethylbenzoyl]-3-chloro-5-methylbenzyl)-1,2,3-triazole-4carboxamide (438 mg, 1.00 mmole), methyl iodide (142 mg, 1.00 mmol), and potassium carbonate (138 mg, 1.00 mmole) in N,N-dimethylformamide (2.0 mL) is stirred 48 hours at ambient temperature, poured into water (15 mL), and filtered. Chromatography provides 1-4-[4-trifluoromethylbenzoyl]-3-chloro-5-methyl-benzyl)-5-methylamino-1,2,3-triazole-4-carboxamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43]4[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][N:44]=4)=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.2 %

Procedure:
A mixture of 59 mg (0.1 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1 (4-hydroxybenzyl)propylcarbamate, 42 mg (0.3 mmol) of 2-chloro-5-nitropyridine and 65 mg (0.2 mmol) of cesium carbonate in 0.5 mL of dimethyl formamide was stirred at rt for 12 h. The mixture was diluted with ethyl acetate and extracted with water. Evaporation of the solvent and chromatography on silica gel (1:1 ethyl acetate/hexane) gave the title compound (38 mg) as a white foam.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)(=[O:9])[CH3:8].CN(C)C=O.[NH2:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31]>ClCCl.N1C=CC=CC=1>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][CH3:21])=[C:14]([CH:18]=1)[C:15]([NH:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31])=[O:17])(=[O:9])[CH3:8]
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(C(C)=O)cc1C(=O)Nc1c(C)cccc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 436.6 %

Procedure:
Oxalyl chloride (3.66 g, 0.0288 mol) was added dropwise to a stirred solution of 5-acetyl-2-ethoxybenzoic acid (3 g, 0.00144 mol) and dimethylformamide (0.1 ml) in dichloromethane (15 ml). The mixture was stirred at room temperature for 3 hours, then the solvent evaporated under vacuum and the residue azeotroped with hexane (3×50 ml). The crude acyl chloride was dissolved in dichloromethane (20 ml) and the solution added dropwise to a stirred solution of 2-amino-3-methylbenzamide (2.16 g, 0.0144 mol) in pyridine (40 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for a further 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (50 ml) and this solution then washed with saturated aqueous sodium carbonate solution (50 ml), 2N hydrochloric acid (50 ml) and brine (50 ml), then dried (Na2SO4) and evaporated under vacuum. Trituration of the residue with diethyl ether gave the title compound as a white solid (2.14 g, 44%), m.p. 214°-216° C. Found: C,66.81; H,5.98; N,8.16. C19H20N2O4 requires C,67.04; H,5.92; N,8.23%.