Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([O:35][C:36]([O:38][CH2:39][CH:40]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)=O)C(=O)C1>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]([C:36]([O:38][CH2:39][CH:40]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=2[C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:35])[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Product: CC(C)N1CCC(CN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Yield: 113.5 %

Procedure:
Using coupling method B, N-[(R)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-1-phenylethyl]carbamic acid tert-butyl ester (1.1 g, 2.8 mmol) and 9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-OSu, 962 mg, 2.9 mmol) afforded 1.9 g of the title compound as a crude residue, that was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[NH3:17]>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:17])=[O:6]
Reactant: N
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A suspension of 3-iodobenzoic acid (4.04 g, 16.2 mmol) in dichloromethane (30 mL) was treated with 2M oxalyl chloride (16 mL, 32 mmol, hexane) followed by two drops of N,N-dimethylformamide and stirred at ambient temperature for 2 hours. After this time the solvent was removed in vacuo and the residue dissolved in tetrahydrofuran (30 ml). The solution was cooled to 0° C. and treated with 2M ammonia (20 mL, 40 mmol, methanol) and the mixture stirred for 30 minutes. The mixture was then filtered and the solvent removed in vacuo. Recrystallization of the residue from methanol afforded 3.5 g (87%) of 3-iodobenzamide, as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)[C:5]([Cl:30])=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O.C(O)(=O)C>ClCCl>[Cl:30][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:16][C:9]=23)=[CH:7][C:2]([NH:1][CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)=[N:3][CH:4]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(N)ncc4Cl)ccnc3[nH]2)CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cc(NCc5cccc(F)c5)ncc4Cl)ccnc3[nH]2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 307A (74 mg, 0.17 mmol) and 3-fluorobenzaldehyde (107 mg, 0.86 mmol) in dichloromethane was added acetic acid (0.05 mL, 0.86 mmol) and MP-CNBH3 (2.49 mmol/g) (278 mg, 0.69 mmol). The mixture was stirred overnight and the insoluble material was filtered off. The filtrated was concentrated. The residue was purified by flash chromatograph eluting with a gradient of 10%-50% ethyl acetate in hexanes to provide the title compound. LCMS: 537 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[N+](=[CH2:18])=[N-].C(O)(=O)C>CO>[CH3:18][O:14][C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH2:2][OH:1])=[C:7]([CH3:8])[C:6]=2[CH:9]=1)=[O:15]
Reactant: C=[N+]=[N-]
Reactant: Cc1c(CO)oc2ccc(C(=O)O)cc12
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2oc(CO)c(C)c2c1

Procedure:
A solution of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.69 g) in methanol (250 ml) was treated with an excess of an ethereal solution of diazomethane. The solution was allowed to stand for 11/2 hours at 0° and then the excess of diazomethane was decomposed by dropwise addition of acetic acid until no further effervescence was apparent. The solution was evaporated and the residue was dissolved in ether. The solution was washed with sodium bicarbonate, dried (Na2SO4) and evaporated to give a quantitative yield of 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid methyl ester, m.p. 96°-98° (from ethyl acetate/petrol).
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C(Cl)Cl.F[B-](F)(F)F.C([O+](CC)CC)C.Cl.[NH2:38][OH:39]>CO.C(N(CC)CC)C>[OH:39][N:38]=[C:5]1[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:15])[C:2]([CH3:1])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1
Reactant: NO
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2ccccc2)SC(=NO)N(Nc2ccccc2)C1=O
Yield: 70.2 %

Procedure:
5-Methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (0.3 g) was added to a 1M methylene chloride solution of triethyloxonium tetrafluoroborate (1 ml) at room temperature with stirring. After stirring the mixture for 24 hrs hydroxylamine hydrochloride (0.1 g) and triethylamine (0.3 g) in methanol (10 ml) were added at 0° C. The reaction mixture was again stirred for 2 hrs at room temperature followed by evaporation of the solvents under reduced pressure. The residue was added to ice water and then extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous ethyl acetate and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate-n-hexane, 1/2) to yield 2-hydroxyimino-5-methyl-5-phenyl-3-phenylaminothiazolidine-4-one (0.21 g) having a melting point of 62-63° C.
Reaction SMILES: [OH:1][C:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:19][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[CH:3]=[C:2]([OH:1])[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:14]=1)=[O:20]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)Sc1ccc(F)cc1C(O)=C2
Yield: 78 %

Procedure:
10-Hydroxy-8-fluoro-dibenzo[b,f]thiepin-3-carboxylic acid (4 g; 13.8 mmoles) dissolved in methanol (100 mL) and treated with excess diazomethane in ether. The volatiles removed under vacuum and the residue, taken up in chloroform, is purified by chromatography in Silica Gel. Elution with 20% ethyl acetate in toluene yielded 3.26 g (78%) of the title compound, m.p. 85°-88° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]S(O)(=O)=O>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([NH:20][CH3:21])([C:18]([NH2:19])=[O:22])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A vigorously stirred solution of 1-benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-3A-2a; 2.10 g, 7.57 mmol) in methylene chloride (25 ml) cooled in an ice bath was treated with H2SO4 (4.0 ml, 76 mmol), dropwise. After the reaction mixture was allowed to warm to room temperature and stir overnight, it was cooled in an ice bath and then carefully quenched with concentrated NH4OH to pH 11. The mixture was extracted with methylene chloride, the combined organic layers were dried (Na2SO4) and then concentrated, in vacuo, to afford I-3A-2b (1.2 g, 54%) as an off-white solid: +ESI MS (M+1) 296.3; 1H NMR (400 MHz, CD3OD) δ 7.41 (d, J=7.5 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16 (t, J=7.1 Hz, 2H), 4.48 (s, 1H), 3.41 (d, J=8.7 Hz, 2H), 3.09 (d, J=8.7 Hz, 2H), 2.24 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=O)[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C>[CH:2]1([N:7]2[CH2:12][CH2:11][CH2:10][C:9]3([CH2:21][C:20](=[N:30][OH:31])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NO
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C3CCCC3)C1)O2)NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccc2c(c1)C(=NO)CC1(CCCN(C3CCCC3)C1)O2)NO
Temperature: 80 °C
Yield: 12.6 %

Procedure:
A mixture of (E)-3-(1′-cyclopentyl-4-oxospiro[chroman-2,3′-piperidine]-6-yl)-N-hydroxyacrylamide hydrochloride (80 mg, 0.197 mmol), hydroxylamine hydrochloride (27.3 mg, 0.393 mmol) and pyridine (0.032 ml, 0.393 mmol) in ethanol (2 ml) was heated at 80° C. The solvent was removed in vacuo and the crude was purified by preparative LC-MS to give the title compound (9.56 mg) as trifluoroacetate
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>C1COCC1>[F:14][C:15]1[CH:20]=[C:19]([C:2](=[O:1])[CH2:6][CH2:5][CH2:4][NH:3][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
In a round-bottomed flask was charged tert-butyl 2-oxopyrrolidine-1-carboxylate (2.2 g, 11.9 mmol) and THF (25 mL). The mixture was cooled down to −78° C. first, followed by slow addition of (3-fluorophenyl)magnesium bromide (17.8 mL, 17.8 mmol, 1.0 M solution in THF) over 15 minutes. The mixture was stirred for 3 hours, during which time the bath temperature rose from −78° C. to −10° C. The reaction was quenched by drop-wise addition of 1N HCl (2 mL) and warmed up to ambient temperature, followed by addition of EtOAc and water. After separating the organic layer, the aqueous layer was extracted with EtOAc three times. The combined organic layers was dried over Na2SO4 and concentrated to yield the product as a clear oil.
Reaction SMILES: [OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11](O)=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3].[Cl-].[NH4+].F[B-](F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][C:2]([CH:6]1[CH2:9][CH:8]([CH2:10][C:11]([NH2:23])=[O:12])[C:7]1([CH3:15])[CH3:14])([C:4]#[CH:5])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C#CC(C)(O)C1CC(CC(=O)O)C1(C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(C)(O)C1CC(CC(N)=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a mixture of Example 29A (84 mg, 0.4 mmol), ammonium chloride (32 mg, 0.6 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (154 mg, 0.48 mmol) in N,N-dimethylformamide was added N,N-diisopropylethylamine (348 μL, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. It was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine twice, dried (MgSO4), filtered and concentrated in vacuo to provide the title intermediate as a white solid (50 mg, 60% yield).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25]>C1(C)C=CC=CC=1>[C:6]1([C:2]2([CH2:3][C:4]#[N:5])[O:25][CH2:24][CH2:23][O:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCO
Reactant: N#CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CCC1(c2ccccc2)OCCO1
Temperature: 150 °C

Procedure:
To a solution of 3-oxo-3-phenylpropanenitrile (10 g, 68.8 mmol) and PTSA (0.027 g, 1.37 mmol) in toluene (120 mL) is added ethylene glycol (120 mL, 2057 mmol). The mixture is heated at 150° C. for 14 h. The solvent is evaporated under reduced pressure and the residue is washed with 10% NaOH solution. The aqueous layer is extracted with diethyl ether (2×100 mL) and the combined organic layers are dried (Na2SO4) and evaporated to provide the crude compound. The crude material is purified over neutral alumina eluting with 1% of ethyl acetate/hexane to afford the title compound as an off white solid (10 g, 77%).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[F:46][CH:47]([F:55])[C:48]1[O:52][C:51]([CH2:53][NH2:54])=[CH:50][CH:49]=1>>[F:46][CH:47]([F:55])[C:48]1[O:52][C:51]([CH2:53][NH:54][C:40]([C:36]2[S:35][C:34]([N:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=4)[C:30]3=[O:43])=[N:38][C:37]=2[CH3:39])=[O:41])=[CH:50][CH:49]=1
Reactant: NCc1ccc(C(F)F)o1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C(F)F)o1
Yield: 47 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with (5-(difluoromethyl)furan-2-yl)methylamine, the title compound was obtained as a white powder in 47% yield: mp 173-174° C. (diethyl ether): 1H NMR (300 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.05-6.99 (m, 2H), 6.59-6.56 (m, 1H), 6.55 (t, JH-F=54.4 Hz, 1H), 6.32-6.29 (m, 1H), 6.01 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.43 (s, 2H), 4.08-4.02 (m, 2H), 3.46-3.40 (m, 2H), 2.58 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 164.2, 162.3, 160.9, 157.5, 155.4, 153.6, 153.3, 146.2, 130.3, 116.9, 115.8, 111.3, 108.4, 105.3, 47.3, 42.0, 41.7, 36.6, 17.3: MS (ES+) m/z 465.3 (M+1).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Br:12]Br.O>CO>[Br:12][C:10]1[C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=[C:3]([CH:11]=1)[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrBr
Solvent: O
Solvent: CO
Product: COc1cc(C=O)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of vanillin (7.6 g, 50 mmol) in MeOH (60 mL) was added dropwise Br2 (2.8 mL, 50 mmol) over a 2 h period at 0° C. The mixture was warm to room temperature for another 1 h. Then cooling to 0° C., water (25 mL) was poured over a 20 min period and resulted in the precipitation of white solid. The mixture was stirred for further 15 min. The precipitate was filtered, washed with ice water and dried to give 10.7 g of white solid. Spectrum analysis verified the compound is 5-Br-vanillin.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[N:18](CC4C=CC=CC=4)[CH:19]([CH3:21])[CH2:20][C:10]=3[C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]1[CH:32]=[C:33]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][N:45]=3)[C:40]([OH:47])=[C:39]([CH2:48][CH:49]([OH:51])[CH3:50])[C:38]2=[O:52])[CH:34]=[CH:35][CH:36]=1.[OH:53][C:54]1C2C(=NC=CC=2)NC(=O)C=1>>[CH3:40][O:47][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[N:18]([OH:53])[CH:19]([CH3:21])[CH2:20][C:10]=3[C:9]2=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH:47][C:40]1[C:41]2[C:46](=[N:45][CH:44]=[CH:43][CH:42]=2)[N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:53][CH3:54])[CH:32]=2)[C:38](=[O:52])[C:39]=1[CH2:48][CH:49]([OH:51])[CH3:50]
Reactant: CC(O)Cc1c(O)c2cccnc2n(-c2cccc(Cl)c2)c1=O
Reactant: CC1Cc2c(c3cccnc3n(-c3cccc(Cl)c3)c2=O)N1Cc1ccccc1
Reactant: O=c1cc(O)c2cccnc2[nH]1
Product: COc1cccc(-n2c(=O)c(CC(C)O)c(O)c3cccnc32)c1
Product: COc1cccc(-n2c(=O)c3c(c4cccnc42)N(O)C(C)C3)c1

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-5-(3-chlorophenyl)-2-methyl-I-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one when 1-(3-chlorophenyl)-3-(2-hydroxypropyl)-4-hydroxy-[1,8]naphthyridin-2-one is substituted for 1-phenyl-3-(2-hydroxyethyl)-hydroxyethyl)-4-hydroxy-[1, 8]naphthyridin-2-one. Furthermore, 1,2,3,5-tetrahydro-5-(3-methoxyphenyl)-1-hydroxy-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one is produced by this procedure when 4-hydroxy-1-(3-methoxyphenyl)-3-(2-hydroxypropyl)-[1,8]naphthyridin-2-one is substituted for 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one and hydroxylamine hydrochloride is substituted for benzylamine hydrochloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)c1

Procedure:
The title compound was prepared from 2′-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.94) (0.350 g, 1.0 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.283 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.426 g, 81%). MS (ISP) 526.2 [(M+H)+]; mp 189° C.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28]4(C)[CH2:30][O:29]4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:33])[CH2:4][CH2:5][C:6](=[O:32])[CH:7]=1.I(O)(=O)(=O)=O>O1CCCC1.O.C(Cl)(Cl)Cl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][C:28](=[O:29])[CH3:30])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:33])[CH2:4][CH2:5][C:6](=[O:32])[CH:7]=1
Reactant: CC1(CO[C@@H]2C[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@@]2(O)C(=O)CO)CO1
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 22 %

Procedure:
A solution of 1.54 g of 9-fluoro-11β ,17,21-trihydroxy-16α-[(2-methyl-oxiranyl)methoxy]pregn-4-ene-3,20-dione, 21-acetate in 50 ml of tetrahydrofuran is stirred for 270 minutes with a solution of 2.6 g of periodic acid in 20 ml of water. The solution is poured into water and extracted with chloroform. The chloroform solution is washed with 10% sodium bicarbonate solution, dried, and evaporated in vacuo to give an oily residue. This is dissolved in chloroform and chromatographed on a 40 g-silica gel column. Elution with chloroform gives 400 mg of slightly impure product followed by 990 mg of TLC homogeneous solid. The 990 mg is recrystallized twice from acetone-hexane to give 328 mg of 9-fluoro-11β ,17,21-trihydroxy-16α-(2-oxopropoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 203°-208°C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C@@H:18]([C:30](=[O:41])[NH:31][C@H:32]([CH2:36][O:37][CH2:38][CH:39]=C)[CH:33]([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]=C)=[CH:22][CH:21]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C@@H:18]3[CH2:19][C:20]4=[CH:21][CH:22]=[C:23]([CH:24]=[CH:25]4)[O:26][CH2:27][CH:28]=[CH:39][CH2:38][O:37][CH2:36][C@H:32]([CH:33]([CH3:35])[CH3:34])[NH:31][C:30]3=[O:41])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCOC[C@@H](NC(=O)[C@@H](Cc1ccc(OCC=C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N1
Yield: 86.6 %

Procedure:
A solution of 1.25 g (2.20 mmol) of 9H-fluoren-9-ylmethyl[(R)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)-2-(4-allyloxyphenyl)ethyl]carbamate and 0.40 g (0.659 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 610 ml of dichloromethane was stirred at 40° C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 1.03 g of the desired compound were obtained as a colorless solid.
Reaction SMILES: C(=O)([O-])O.[Na+].[Br-].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH2:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:16]1([C:15]2[CH:7]=[C:8]3[N:9]([CH:14]=2)[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc[n+]1CC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: c1ccc(-c2cc3ccccn3c2)cc1
Yield: 69.1 %

Procedure:
A solution of sodium hydrogen carbonate (10.5 g, 119.8 mmol) in water (125 ml) was added to 2-methyl-1-(2-oxo-2-phenyl-ethyl)-pyridinium bromide (35.0 g, 119.8 mmol) and the reaction heated to reflux for 30 min. The resultant solid was filtered, washed with water and then dried under vacuum to yield 2-phenyl-indolizine (16.0 g, 70%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To a solution of 12.2 mmol 2-fluoro-5-nitrobenzoic acid (CAS 7304-32-7; commercially available, e.g. from Fluorochem) in 40 ml THF was added 18.2 mmol morpholine and the mixture was stirred at room temperature for 16 h. The volatiles were removed in vacuo and the residue was resuspended in 25 ml water and acidified to pH 4 by dropwise addition of aqueous HCl. The resulting mixture was stirred at room temperature for 30 min, and the resulting crystals were then collected by filtration and dried in vacuo at 50° C. to afford the title compound as a yellow solid (yield 32%). MS (m/e): 251.0 ([M−H]−, 100%)
Reaction SMILES: CS[C:3]1[S:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10].CS>[Cl-].[Zn+2].[Cl-].CCOCC.C(O)(C)C>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][S:4]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:11])=[O:10]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCCS1
Agent: CS
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 1.25 h

Procedure:
To a mixture of 235 g of 5,6-dihydro-2-(methylthio)-4H-1,3-thiazine (A. F. McKay et al., J. Am. Chem. Soc., 80, 3339 (1950)) and 2 g of zinc chloride at approximately 115° in a nitrogen atmosphere, 263 g of ethyl nitroacetate (S. Zen et al., Kogyo Kagaku Zosshi, 74, 70 (1971)) was added dropwise over a 1.5 hour period. The mixture was held at 110°-120°. When evolution of methyl mercaptan ceased after 45 minutes further stirring of the heated mixture, 1 g of zinc chloride was added and the mixture was stirred at about 115° for 1.25 hours. An additional 1 g of zinc chloride then was added and stirring of the mixture at about 115° was continued for 1.5 hours. The mixture then was poured into a cooled 2/1 ether/isopropyl alcohol mixture. The crystallized product was collected, washed with ether and dried under reduced pressure to leave a tan solid, m.p. 100°-102°, which on recrystallization from methanol gave ethyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate as a pale yellow solid, m.p. 105°-106°.