Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCl.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])([CH3:6])(C)C.[CH2:25](N(CC)CC)[CH3:26]>C(O)C>[CH2:3]([O:7][C:8]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[C@@H:12]([CH3:21])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])[CH2:6][CH2:25][CH3:26]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(CC)CC
Agent: ClCl
Solvent: CCO
Product: CCCCOC(=O)N[C@H](C(=O)O)[C@@H](C)OCc1ccccc1

Procedure:
A mixture of 20 g. of chloromethylated polystyrene resin having 1.16 mmole of chlorine per gram, and 8 g. of Nα-t-butoxycarbonyl-O-benzyl-L-threonine in 500 ml. of ethanol is treated with 2.6 g. of triethylamine and refluxed for three days in excess ethanol. The resin is separated by filtration, washed with ethanol, water, methanol, dichloromethane and ether, successively, and then dried overnight at 40° C. giving the Nα-butoxycarbonyl-O-benzyl-L-threonine resin.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:15]([CH3:21])[CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Li])CCC.[C:29](OCC)(=[O:31])[CH3:30]>O1CCCC1>[C:19]([CH:18]([CH2:17][CH2:16][CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=2)[CH:10]=1)[CH3:21])[C:29](=[O:31])[CH3:30])#[N:20]
Reactant: CCOC(C)=O
Reactant: CC(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)CCC(C)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 2.5 grams (0.008 mole) of 5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile in 20 mL of tetrahydrofuran was cooled to about -78 ° C., and 3.2 mL (0.008 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for 30 minutes, and then 1.1 grams (0.012 mole) of ethyl acetate was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 60 hours. The reaction mixture was partitioned between ethyl acetate and aqueous dilute hydro-chloric acid. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 25% ethyl acetate in hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.9 gram of 3-cyano-2-oxo-6-[3-(4-trifluoromethylphenyl)phenyl]heptane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14]([NH2:18])[C:15](=[CH2:17])[CH3:16]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][CH2:14][C:15]([CH3:17])=[CH2:16])[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: C=C(C)CN
Product: C=C(C)CNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 64 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (128 mg, 0.5 mmol) in methallylamine (0.5 ml) was stirred for 48 h at 90° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (3 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration and washed with water, to give 92 mg (64%) of the pure title compound; mp 224-226° C. (dec.); 1H-NMR (DMSO-d6): δ1.72 (s, 3H), 3.75 (d, 2H), 4.83 (s, 2H), 7.05 (s, 1H), 7.45 (br s, 1H), 11.0 (br s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)C(N)=O)#[N:2].Cl.[CH3:13][OH:14].[CH3:15][OH:16]>>[C:1]([C:3]1[CH:4]=[CH:5][C:9]([C:13]([O:16][CH3:15])=[O:14])=[CH:10][CH:11]=1)#[N:2]
Reactant: N#Cc1cccc(C(N)=O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C#N)cc1
Yield: 93 %

Procedure:
m-Cyanobenzamide (73.0 g, 0.5 mol) which has a purity of 99% or more and methanol (460.3 g) were placed in a 2 l-separable flask, and the mixture was allowed to react at 64° C. for 12 hours while a 20% hydrochloric acid/methanol solution (162.4 g) prepared in advance was added thereto with stirring. Gas chromatographic analysis revealed that the reaction mixture contained 74.9 g of methyl p-cyanobenzoate (yield 93%).
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[NH2:22][CH:23]1[CH2:26][NH:25][CH2:24]1.O>CS(C)=O>[NH2:22][CH:23]1[CH2:26][N:25]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:24]1
Reactant: NC1CNC1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(N)C4)cc3nc21
Temperature: 95 °C
Reaction time: 6 h
Yield: 51.2 %

Procedure:
A suspension of 1.16 g of 7,8-difluoro-1-methyl-4-oxo-l,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 1.38 g of 3-aminoazetidine in 15 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 6 hours. After cooling to approximately 20° C., 100 cm3 of water are added to the reaction mixture. The insoluble matter is drained, washed with 3 times 20 cm3 of water, taken up with 100 cm3 of water and treated with 4 cm3 of N methanesulphonic acid. After removal of some slight insoluble matter by filtration through diatomaceous silica and addition of 4 cm3 of N aqueous sodium hydroxide, the suspension obtained is concentrated under reduced pressure (20 kPa) at a temperature in the region of 60°C. to a volume of approximately 80 cm3. The insoluble matter is drained, washed with 100 cm3 of water and 100 cm3 of ethanol and recrystallized in 150 cm3 of dimethylformamide. 0.7 g of 8-(3-amino-1-azetidinyl)-7-fluoro-1-methyl-4-oxo1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid, which decomposes at 358° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][NH:27][CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1.[CH:31](OC1C=CC=CC=1)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([F:30])[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]3[CH2:29][CH2:28][N:27]([CH:31]=[O:32])[CH2:26][C:19]3=[N:20][C:21]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCNC2
Reactant: O=COc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCN(C=O)C2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (30.5 mg, 0.073 mmol) in THF (364 μL) at room temperature was treated with phenyl formate (140 μL, 1.09 mmol). The reaction mixture was stirred at 60° C. for 1 h. The reaction was purified by HPLC Method B using a 50% to 80% ACN gradient to give the title compound, as a TFA salt, as a pale yellow solid (9.4 mg, 23%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.29 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.66 (m, 2H), 2.00 (m, 1H), 2.10 (m, 1H), 2.77 (m, 4H), 3.49 (m, 2H), 3.76 (t, J=5.9 Hz, 1.4H), 3.82 (t, J=6.1 Hz, 0.6H), 4.12 (m, 1H), 4.48 (s, 0.6H), 4.52 (s, 1.4H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (td, J=8.3, 6.3 Hz, 1H), 8.18 (s, 0.7H), 8.24 (s, 0.3H); ESI-MS m/z [M+H]+ 447.90.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])Cl)[CH3:8].C(N(CC)CC)C.[OH2:20]>CCOCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([Si:9]([CH3:12])([CH3:11])[OH:20])[CH3:8]
Reactant: C=CCCCCC(C)[Si](C)(C)Cl
Reactant: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CCCCCC(C)[Si](C)(C)O
Temperature: 0 °C

Procedure:
A solution of 7-oct-1-enyldimethylchlorosilane (2.56 ml) in ether (2 ml) was added dropwise over 1 hour to a stirring mixture of triethylamine (1.5 ml), water (0.18 ml) and ether (15 ml) in an ice/water bath. The resultant was stirred a further 1 hour in the ice/water bath and filtered washing the filtered solid with ether (10 ml). The filtrate was evaporated with a rotary evaporator and the residue partitioned between hexane (30 ml) and water (30 ml). The organic layer was separated, dried (MgSO4) and filtered through silica gel (70-230 mesh, 60 Å), washing with hexane (100 ml). The filtrate was evaporated with a rotary evaporator to afford a colorless oil which was vacuum dried and weighed (1.06 g).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:14]=[C:13]([CH3:15])[S:12][C:11]=2[CH:16]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[S:12][C:13]([CH3:15])=[CH:14][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:23]1[CH3:32]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: Cc1cc(S(=O)(=O)c2ccccc2)c(C=O)s1
Product: COC(=O)Cn1c(C)c(Cc2sc(C)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using 3-benzenesulfonyl-5-methylthiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: FC(F)(F)C([N:5]([C:22]1[CH:23]=[C:24]([C:27](Cl)=[O:28])[S:25][CH:26]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=O.C(N(CC)CC)C.[C:39]([O:50][CH2:51][CH3:52])(=[O:49])[CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[OH:41]>CCOCC>[CH2:6]([NH:5][C:22]1[CH:23]=[C:24]([C:27]([O:41][CH:40]([CH:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[OH:43])[C:39]([O:50][CH2:51][CH3:52])=[O:49])=[O:28])[S:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1csc(C(=O)Cl)c1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)c1

Procedure:
A mixture of 4-[N-(trifluoroacetyl)-N-(hexadecyl)amino]-2-thiophenecarbonyl chloride and 1.2 g. of triethylamine in 100 ml. of warm ether is treated with 2.5 g. of diethyl tartarate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37](C1C=C(F)C=CC=1C1NC2C(C=1C1CCCCC1)=CC=C(C(OC(C)(C)C)=O)C=2)(=O)C>>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:37])[C:17]4[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cc(F)ccc1-c1[nH]c2cc(C(=O)OC(C)(C)C)ccc2c1C1CCCCC1
Reactant: COC(=O)C1=Cc2cc(F)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Product: COC(=O)C1=C(C)c2cc(F)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Yield: 11 %

Procedure:
The title product 10-tert-butyl 6-methyl 13-cyclohexyl-3-fluoro-5-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 20a was synthesized following the procedure reported for the synthesis of 10-tert-butyl 6-methyl 13-cyclohexyl-3-fluoro-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 19a, using tert-butyl 2-(2-acetyl-4-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate 33c instead of tert-butyl 3-cyclohexyl-2-(4-fluoro-2-formylphenyl)-1H-indole-6-carboxylate 32d, and was obtained in 11% yield as a white solid; m/z 504 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].N1CC[C@H:23]([OH:26])[CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:19][CH2:22][C@H:23]([OH:26])[CH2:20]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: O[C@H]1CCNC1
Product: COc1cc(N2CCC(N3CC[C@H](O)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
(S)-1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-pyrrolidin-3-ol was prepared in an analogous fashion to [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine of Example 475a replacing Dimethylamine with (S)-Pyrrolidin-3-ol. The crude material was purified via trituration with Et2O to yield a yellow solid, MP 137-139° C. (197 mg, 51%). LC/MS (E/I+) 322.14 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:37])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)Cl>[CH:31]1([O:30][C:29]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), were added triethylamine (188 μl, 1.35 mmol) and cyclohexyl carbonochloridate (78 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(cyclohexyloxycarbonylamino)-2-phenylacetate (105 mg; 60% yield).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:11]=[CH2:12])[OH:10])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:3][C:1]1[CH2:2][CH2:12][CH2:11][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: C=CC1(O)CCCCC1C(=C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1=CCCCCC(=O)CCC1

Procedure:
A mixture of 2-isopropenyl-1-vinylcyclohexan-1-ol (0.166 g; 10-3 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.038 g; 10-4 mol) in tetrahydrofuran (5 cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 24 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying over magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 5-methylcyclodec-5-en-1-one (0.070 g) is obtained, which has the following characteristics:
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[N:22]1[C:26](=[O:27])[C:25](Br)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1.O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[C:15]=1[N:22]1[C:26](=[O:27])[C:25]([N:10]2[C:11](=[S:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9]2)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1
Reactant: Sc1nnnn1-c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3-n3nnn(-c4ccccc4)c3=S)c2)c(C(C)(C)CC)c1

Procedure:
According to the method disclosed in Pharmazle, 29 (2) page 90, a mercuric salt of 1-phenyl-5-mercaptotetrazole and 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone were reacted in dimethylformamide. The reaction mixture was poured into water, was extracted with ethyl acetate and washed. After evaporating off the ethyl acetate under reduced pressure, the remaining substance was recrystallized from ethanol to provide 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-(4-phenyl-5-thioxotetrazolin-1-yl)-5-pyrazolone having a melting point of 169° to 171° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(O)cc1O
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(O)cc1O

Procedure:
A mixture of 2,4-dihydroxy-5-nitrobenzoic acid (14.2 g, 92.1 mmol), thionyl chloride (100 mL, 1.15 mol) and dimethylformamide (4 drops) is refluxed for 4 h. The solvents are removed under reduced pressure and the resulting gum is stripped once with toluene and dried under reduced pressure to afford 2,4-dihydroxy-5-nitrobenzoyl chloride as a gum, which is used without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([N:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:32][CH2:33]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:10]([CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]2([CH3:24])[CH2:23][O:22]2)[CH2:15]1)=[N+:11]=[N-:12].C([O-])(=O)C.[Na+]>C(O)C>[N:10]([CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([OH:22])([CH3:23])[CH2:24][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])[CH2:15]1)=[N+:11]=[N-:12]
Reactant: CC1(CN2CC(CN=[N+]=[N-])OC2=O)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)(CN1CC(CN=[N+]=[N-])OC1=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (350 mg, 2.37 mmol), 5-azidomethyl-3-(2-methyloxiran-2-ylmethyl)oxazolidin-2-one (500 mg, 2.37 mmol), sodium acetate (214 mg, 2.61 mmol) and ethanol (5 ml) was stirred at 70° C. for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 5-azidomethyl-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]oxazolidin-2-one (640 mg, yield 75%) as a light yellow oil.
Reaction SMILES: C(OC(C1CCCN1C(=O)C(NC(=O)[C:18]1[CH:23]=[CH:22][C:21](N)=[C:20]([Cl:25])[CH:19]=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35]CC2C=CC=CC=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[Cl:25][C:20]1[CH:21]=[CH:22][C:23]([CH2:35][O:34][CH:32]2[CH:31]([NH:43][C:44]([CH:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=3)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]2)=[CH:18][CH:19]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccc(Cl)cc1
Yield: 65 %

Procedure:
Prepared from 97a and syn-[2-(4-chloro-benzyloxy)-5-oxo-tetrahydro-furan-3-yl]-carbamic acid allyl ester following the method used for 98a to afford 154 mg (65% yield) of the title compound as a pale pink solid. HPLC (C18 column) 10.597 min; 1H-NMR (500 MHz, CDCl3) δ 1.14 (d, J=6.8 Hz, 0.75H), 1.34, (d, J=6.8 Hz, 2.25H), 1.6 (br, 0.25H), 1.91 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.29 (m, 0.75H), 2.40 (dd, J=17.3, 10.3 Hz, 0.75H), 2.51 (m, 0.25H), 2.82 (dd, J=17.3, 8.5 Hz, 0.75H), 3.08 (dd, J=17.9, 10.9 Hz, 0.25H), 3.58 (m, 1H), 3.72 (dd, J=16.5, 8.7 Hz, 0.75H), 4.10 (m, 0.25H), 4.22 (d, J=8.0 Hz, 0.25H), 4.39 (d, J=10.8 Hz, 0.25H), 4.54 (dd, J=9.1, 2.9 Hz, 0.75H), 4.60 (d, J=11.9 Hz, 0.75H), 4.68 (m, 1H), 4.85 (d, J=11.7 Hz, 0.75H), 4.86 (m, 1H), 5.49 (d, J=5.2 Hz, 0.75H), 5.81 (d, J=5.2 Hz, 0.25H), 6.2 (br, 0.25H), 6.74 (m, 2H), 7.05 (d, J=8.5 Hz, 0.5H), 7.17 (d, J=8.4 Hz, 0.5H), 7.30 (m, 3.25H), 7.48 (dd, J=8.4, 2.0 Hz, 0.75H), 7.56 (d, J=1.9 Hz, 0.25H), 7.73 (d, J=1.9 Hz, 0.75H), 8.42 (d, J=5.7 Hz, 0.25H) ppm; LC-MS (ES+) m/e=563, 565 (M+H).