Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.C[Si](C)(C)Cl.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(N(CC)CC)C.O.CO>[NH2:10][C@@H:11]1[C:21](=[O:22])[N:13]2[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.955 g of 7β-(N-phenylacetyl-amino)ceph-3-em-4-carboxylic acid in 60 ml of absolute methylene chloride is treated with 0.720 g of trimethylchlorosilane and 0.474 g of absolute pyridine. The mixture is stirred for 60 minutes at room temperature and then cooled to -20° C., and a solution of 3.20 g of absolute pyridine in 30 ml of absolute methylene chloride, and 23.4 ml of an 8% solution of phosphorus pentachloride in absolute methylene chloride, are then added successively. The mixture is stirred for 60 minutes at -10° C. to -12° C. and is again cooled to about -20° C., and 15 ml of absolute methanol are then allowed to run in. The whole is stirred for 25 minutes at -10° C. and then for 35 minutes at room temperature, 15 ml of water are added, the pH value of the reaction mixture is increased from 1.8 to 2.2 by dropwise addition of triethylamine and the mixture is stirred for 20 minutes at room temperature. The pH value is raised to 3.8 by renewed addition of triethylamine and the two-phase mixture is stirred for 90 minutes whilst cooling in an ice bath and is then filtered. The filter residue is washed with methanol, methylene chloride and diethyl ether and is dried in a vacuum desiccator. 7β-amino-ceph-3-em-4-carboxylic acid of the formula ##STR27## is thus obtained in an amorphous form; the product is further processed without purification.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>O1CCCC1>[C:16]1([CH2:15][CH2:14][S:10][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [S-2]
Reactant: BrCCc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CCSCCc2ccccc2)cc1
Reaction time: 24 h

Procedure:
A solution of 7.65 g (32 mmol) of sodium sulfide nonahydrate and 8.7 ml (64 mmol) of 2-bromoethylbenzene in 150 ml of 1:1 tetrahydrofuran:methanol was heated at reflux under inert atmosphere. After 24 h, the solution was allowed to cool and concentrated in vacuo to give the crude desired compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=S)[NH2:9])=[C:5]([C:11]([NH2:13])=[O:12])[N:4]=[CH:3]1.O>[OH-].[Na+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu]=S>[CH3:1][N:2]1[CH:3]=[N:4][C:5]2[C:11](=[O:12])[NH:13][C:8]([NH2:9])=[N:7][C:6]1=2
Reactant: Cn1cnc(C(N)=O)c1NC(N)=S
Agent: S=[Cu]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Product: Cn1cnc2c(=O)[nH]c(N)nc21
Yield: 95.8 %

Procedure:
1-Methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (3.98 g, 20 mM) was dissolved in 1N sodium hydroxide (160 ml). Copper acetate, H2O (4.6 g, 23 mM) was added and the reaction mixture as then refluxed for 1 hour. After cooling to 50° C. the formed copper sulphide was filtered off. The filtrate was acidified with acetic acid to pH 5.0. The resulting product was filtered off at 25° C. washed with water and dried. Hereby was isolated 3.16 g (96%) of the title compound as a white powder, mp. >300° C. 13C-NMR(1N NaOD) δppm: 170.7; 163.6; 154.0, 141.4; 120.0; 32.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[CH3:52])[NH2:48]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:48][C:47]1[CH:49]=[CH:50][C:51]([CH3:52])=[C:45]([I:44])[CH:46]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1I
Yield: 89.5 %

Procedure:
2-Chloroisonicotinic acid (3.3 g, 21 mmol), HATU (8.75 g, 23 mmol), diisopropylethyl amine (10.9 ml, 63 mmol) and 3-iodo-4-methylaniline (5.00 g, 21 mmol) in dimethylformamide (50 ml) were heated under nitrogen for 16 hours. The reaction was cooled, solvent removed in vacuo and the residue taken up in dichloromethane (150 ml). The organic solution was washed with water (3×100 ml) and brine (100 ml), dried over magnesium sulfate, filtered and solvent removed in vacuo. The residue was purified by column chromatography (40:60 ethyl acetate:cyclohexane) to give 2-chloro-N-(3-iodo-4-methylphenyl)-isonicotinamide as a white solid (7.00 g, 18.8 mmol).
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.[N:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][NH:2][C:18]([C:9]1[N:8]=[CH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)=[O:20]
Reactant: CN
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a stirred solution of MeNH2.HCl (173 mg, 5.12 mmol) in toluene (5 mL) at 0° C., was added AlMe3 (2 M solution in Hexanes, 1.28 mL, 2.56 mmol). After 30 minutes the solution was canulated into a stirred solution dimethyl pyridine-2,5-dicarboxylate (500 mg, 2.56 mmol) in DCM (5 mL) at 0° C. before stirring over night at room temperature. An aliquot was taken and analysed by NMR, indicating that there was a 0.8:1 ratio of product to starting material. MeNH2.HCl (173 mg, 5.124 mmol) and AlMe3 (2M solution in Hexanes, 1.28 mL, 2.56 mmol) were added and the reaction stirred for 12 hours. The reaction was quenched by addition of H2O (2 mL) and extracted with EtOAc (2×10 mL). The organics were combined, dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (520 mg, quant. yield) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([CH3:19])[N:8]=1.CN(C)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([CH3:19])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(O)nc1C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(Cl)nc1C
Temperature: 0 °C
Yield: 63.3 %

Procedure:
Phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 6a (1.47 g, 7.5 mmol), benzyltriethylammonium chloride (1.71 g, 7.5 mmol) and N,N-dimethylaniline (1.82 g, 15 mmol) in acetonitrile (30 ml). The mixture was reflux for 5 hours. The mixture was poured into ice water and neutralized with NaHCO3. The solution was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO4, concentrated and chromatographed to obtain 6b, (1.02 g, 4.75 mmol, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH:19](OCC)=[O:20].[H-].[Na+].O>CCOCC>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:19]=[O:20])[C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 24 g biphenylacetic acid ethyl ester and 8.2 g ethyl formate is added dropwise while stirring to a suspension of 2.4 g sodium hydride in 250 ml ether. The reaction mixture is stirred for 2 hours at room temperature and cold water is carefully added. The aqueous phase is acidified to pH 2 and the product is extracted with ether. The extract is dried and concentrated by evaporation.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8](Cl)([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[OH-:25].[Na+]>Cl>[CH2:1]([N:3]([CH2:23][CH3:24])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:25])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CC)CCNC(=O)C(Cl)(c1ccccc1)C1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCN(CC)CCNC(=O)C(O)(c1ccccc1)C1CCCCC1
Temperature: 55 °C

Procedure:
A mixture of N-[2-(diethylamino)ethyl]-2-chloro-2-cyclohexyl-2-phenylacetamide (6.35 g) and 1N hydrochloric acid (100 ml) was heated at 55 ° C. for 2 hours. After being cooled, the solution was made alkaline with 6N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was dried over magnesium sulfate, evaporated under reduced pressure. And the residue was triturated with a mixture of n-hexane and diisopropyl ether to give N-[2-(diethylamino)ethyl]-2-cyclohexyl-2-hydroxy-2-phenylacetamide (4.98 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:19][C@@H:20]([CH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])[C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22].C(N[C@H](C(O)=O)[C@@H](C)OC(C)(C)C)(OC(C)(C)C)=O.N1CCOCC1>C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:19][C@@H:20]([CH:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH3:30])[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(OC(C)(C)C)[C@H](N)C(=O)N1CCOCC1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: C1COCCN1
Solvent: ClC(Cl)Cl
Product: CC(OC(C)(C)C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)N1CCOCC1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and 4-[(S)-2-amino-3-tert-butoxybutyryl]-morpholine (prepared from N-BOC-O-tert-butyl-L-threonine (Sigma) and morpholine (Aldrich) using General Procedure M, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 96:4 CHCl3/MeOH as the eluent.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30]([CH3:32])C)#N.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:32]([NH:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)=[N:30][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])=[CH:18][CH:17]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1nncs1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)cc1
Yield: 40 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol) with 2-amino-1,3,4-thiadiazole (23 mg, 0.22 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 40% yield (38 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:40][C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (3.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (230 ml), and to the suspension was added potassium carbonate (4.0 g), and the mixture was stirred at room temperature for 30 minutes. 3-picolylchloride hydrochloride (1.9 g) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and the precipitated crystals were recovered by filtration to obtain the title compound (2.9 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Cl[CH2:23][C:24]1[N:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]2[N:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1cccnc1CCl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol (2.70 g), ethyl 2-chloromethylnicotinate (1.74 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.42 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]nicotinate as a colorless oil (2.45 g, 63%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12](OCC)=[O:13])=[CH:8][C:6]=2[N:7]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc2oc(CC)nc2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1nc2cc(CO)ccc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A stirred solution of 8.0 grams (0.037 mole) of ethyl (2-ethylbenzoxazol-5-yl)carboxylate in 100 mL of anhydrous tetrahydrofuran was cooled to 0° C., and 20 mL (0.02 mole) of a 1.0 molar solution of lithium aluminum hydride in tetrahydrofuran was added portionwise from a syringe. Upon completion of the addition the reaction mixture was stirred at 0° C. for 15 minutes, then was allowed to warm to ambient temperature, where it stirred for about 18 hours. The reaction mixture was poured into a mixture of 250 mL of an aqueous solution saturated with ammonium chloride and ice. The mixture was then extracted with two 250 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.1 grams of (2-ethylbenzoxazol-5-yl)methanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:19])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)Cl>[Cl:22][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:19])[CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc2nc(-c3ccc(Cl)cc3)cc(Cl)c2c1

Procedure:
A mixture of 25 g (91 mmol) of 2-(4-chlorophenyl)-6-fluoro-4-hydroxyquinoline and 50 ml of phosphorus oxychloride was stirred and heated under reflux for 2 hr. It was then cooled, poured onto ice and diluted with 500 ml of methylene chloride. This mixture was then made alkaline with 3N sodium hydroxide. The organic phase was separated, and the aqueous phase was extracted with 2×200 ml of methylene chloride. The organic extracts were combined, washed with water and with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was collected and washed with hexane to give 22.2 g of product as a brownish solid, mp 169°-172°.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH2:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1](=[O:4])[CH2:2][CH3:3])[CH3:10]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)CC(=O)CC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)c1ccccc1)C(=O)CC
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Ethyl propionylacetate 18 (10 g, 69.4 mmol) was added slowly to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 3.33 g, 83.3 mmol, 1.2 equiv) in THF (100 ml) at 0° C. and the mixture was stirred for 30 min. 2-Bromoacetophenone 19a (15.2 g, 76.34 mmol, 1.1 equiv) in THF (10 ml) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. Saturated aqueous ammonium chloride (60 ml) was added and the mixture was subsequently extracted with diethyl ether (3×70 ml). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a dark yellow oil that was purified by flash column chromatography (10% EtOAc/hexane) to give the diketoester 20a (14.8 g, 82%) as a yellow oil: TLC Rf=0.50 (silica gel, 25% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=8.4 Hz, 2H), 7.58 (m, 1H), 7.46 (m, 2H), 4.22 (q, J=7.2 Hz, 3H), 3.74 (dd; J=8.4 Hz, 18.4 Hz, 1H), 3.53 (dd, J=5.2 Hz, 18.4 Hz, 1H), 2.91-2.70 (m, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.4, 197.4, 169.3, 136.3, 133.6, 128.8, 128.3, 61.9, 53.2, 37.7, 36.6, 14.2, 7.8; HRMS calcd for C15H18O4+Na+ 285.1103; found 285.1093 [M+Na+].
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[K+]>C(O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH:6]([CH3:7])[CH2:5][C:4]([OH:22])=[O:3])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
3.04 g. of 3-(2',4'-difluoro-4-biphenylyl)butyric acid ethyl ester and 1 g. of KOH in 25 ml. of ethanol are heated under reflux for 2 hours. The mixture is evaporated. The residue is dissolved in water and the solution is washed with ether and acidified to pH 3 with hydrochloric acid and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-butyric acid, m.p. 109°-110°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]=[CH:39]1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]1[NH:27][C:26]2[CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[S:30][C:25]=2[C:24]=1[CH:43]1[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)cc2s1
Reactant: BrC1C=CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3OCc3ccccc3)c(C3C=CCCC3)c2s1
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
To a solution of methyl 5-(2,4-bisbenzyloxyphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.36 g, 2.90 mmol) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in oil, 127 mg, 3.19 mmol) under ice-cooling and the mixture was stirred for 20 min. 3-Bromocyclohexene (0.34 ml, 2.95 mmol) was added and the mixture was stirred under ice-cooling for 50 min. Ethyl acetate (20 ml) was added to the reaction mixture, and the organic layer was washed successively with water (20 ml×3) and saturated brine (10 ml) and dried over sodium sulfate. After filtration and concentration, a mixed solvent (10 ml) of hexane:ethyl acetate (10:1) was added. The precipitated solid was collected by filtration. The solid was washed with a mixed solvent (5 ml×3) of hexane:ethyl acetate (10:1), and dried under reduced pressure to give methyl 5-(2,4-bisbenzyloxyphenyl)-6-(cyclohex-2-enyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1.35 g, yield 85%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([CH2:15][CH3:16])=[N:4]1)[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH2:17]([N:12]1[CH2:13][CH:14]=[C:9]([C:6]2[C:5]([CH2:15][CH3:16])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH3:8])[CH2:10][CH2:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1nn(CC)c(C)c1-c1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1nn(CC)c(C)c1C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.55 g (35.0 mmol) of 1,3-diethyl-4-(4-pyridyl)-5-methylpyrazole (from Step E) and 4.20 mL (35.0 mmol) of benzyl bromide in 50 mL of MeOH was heated at reflux for 30 min. The mixture was cooled to 0° C. and treated with 2.65 g (70.0 mmol) of sodium borohydride in portions so as to maintain the internal at ˜0° C. The resulting mixture was stirred cold for 30 min, then concentrated. The residue was partitioned between 300 mL of CH2Cl2 and 150 mL of 1.0 N NaOH and the layers were separated. The organic layer was dried over MgSO4. The organic layer was extracted with 300 mL of ether; the extract was dried over MgSO4. The organic layers were combined and concentrated. Chromatography on a Biotage 75L using 9:1 v/v heptane/acetone as the eluant affforded the title compound. 1H-NMR (400 MHz) δ 1.19 (t, J=7.6, 3H), 1.37 (t, J=7.6, 3H), 2.17 (s, 3H), 2.31–2.35 (m, 2H), 2.58 (q, J=7.6, 2H), 2.66 (t, J=5.6, 2H), 3.13 (app q, J=2.8, 2H), 3.65 (s, 2H), 4.01 (q, J=7.6, 2H), 5.46–5.48 (m, 1H), 7.26–7.39.