Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:31](I)[CH3:32]>CC(N(C)C)=O>[CH2:31]([O:2][C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:3])[CH3:32]
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O

Procedure:
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (6.0 g), sodium bicarbonate (4.0 g), and ethyl iodide (11.6 g) in dimethylacetamide (200 ml) was stirred at room temperature under nitrogen for 72 hours. The reaction mixture was filtered and evaporated under high vacuum. Water (250 ml) was added, and the resulting solution extracted with dichloromethane (2×400 ml). The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as a mixture of isomers. NMR(CDCl3) δ9.22(s, 1H), 4.10(2 superimposed quartets, 2H), 1.13(2 superimposed triplets, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[N:25]1([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C@H:11]2[CH2:15][N:14]([C:34]([C:31]3([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:32][CH2:33]3)=[O:35])[C@H:13]([C:16]([NH:18][C:19]3([C:22]#[N:23])[CH2:21][CH2:20]3)=[O:17])[CH2:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Cl)c3)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 39 %

Procedure:
The reaction of (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7F with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(3-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a white solid (39%). MS ISP (m/e): 505.2/507.3 (100/34) [(M+H)]+.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])=[C:15]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.CO>[NH2:10][CH:11]1[C:36](=[O:37])[N:13]2[C:14]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:15]([O:18][S:19]([CH3:22])(=[O:20])=[O:21])[CH2:16][S:17][C@H:12]12
Reactant: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2SC1
Reaction time: 2 h
Yield: 102 %

Procedure:
To a suspension of 4-nitrobenzyl 7-(2-phenylacetamido)-3-mesyloxy-3-cephem-4-carboxylate (11 g.) in methylene chloride (100 ml.) were added pyridine (2.37 g.) at ambient temperature and then phosphorus pentachloride (5.4 g.) at 0° C. with stirring, whereafter the mixture was stirred at -3° to 3° C. for 2 hours. After adding methanol (5.2 g.) at -20° C., the stirring was continued at the same temperature for additional an hour. The reaction mixture was poured into water and adjusted to pH 7.5 with sodium bicarbonate, followed by extraction with ethyl acetate (500 ml.). The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was pulverized with diethyl ether to give 4-nitrobenzyl 7-amino-3-mesyloxy-3-cephem-4-carboxylate (8.8 g.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH2:14])[CH:6]=1)=[O:4].[CH3:15][C:16]1[N:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:22]([C:19]2[CH:20]=[N:21][C:16]([CH3:15])=[CH:17][CH:18]=2)=[O:23])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)n(CCN)c1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccc(C)nc2)c1
Reaction time: 72 h

Procedure:
1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester (0.50 g, 2.55 mmol) was coupled with 6-methyl-3-pyridinecarboxylic acid (0.42 g, 3.1 mmol)in dimethylformamide (42.5 ml) with triethylamine (1.80 ml, 12.75 mmol) and propylphosphonic acid anhydride (0.90 ml, added as a 0.90 ml ethyl acetate solution). After 72 hours, dichloromethane and aqueous sodium bicarbonate were added. The layers were separated and the organic layer washed with brine and dried (Na2SO4). Filtration, concentration, and purification by medium pressure liquid chromotography (silica gel, 4-6% methanol/dichloromethane) gave the desired product, MP: 184°-185° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:42])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:42][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCOCC3)c2)n1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2cccc(CN3CCOCC3)c2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 550.41 [M-H]+; RT=1.40 min (HPLC System 3).
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.BrC1C=CC([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]2)=[O:49])=CC=1C>>[CH3:56][N:53]1[CH2:54][CH2:55][N:50]([CH:48]=[O:49])[CH2:51][CH2:52]1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)ccc1Br
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: CN1CCN(C=O)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-bromo-3-methyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (167 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-(4-methyl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-142) as a pale yellow powder (25 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[CH:17][S:16][C:10]=2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=1.[Cl:19]Cl.[OH-].[Na+]>CO.ClCCl>[Cl:19][C:17]1[S:16][C:10]2[N:11]=[C:12]([NH2:15])[CH2:13][N:14]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:9]=2[CH:18]=1
Reactant: ClCl
Reactant: NC1=Nc2sccc2C(c2ccccc2F)=NC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: NC1=Nc2sc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
19 g of 5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine were dissolved in 730 ml of 5% methanol in dichloromethane, treated while stirring well with 327 g of a 2.8% solution of chlorine gas in 5% methanol in dichloromethane and stirred at room temperature under argon for 5 minutes. Thereafter, the reaction mixture was poured into 600 ml of 0.2N sodium hydroxide solution while cooling with ice and extracted. The dichloromethane extracts were dried with sodium sulphate, filtered and the solvent was evaporated in a vacuum. After two fold boiling of the residue in 5% methanol in dichloromethane and filtration there were obtained 7.4 g of 7-chloro-5-(2-fluoro-phenyl)-3H-thieno[2,3-e][1,4]diazepin-2-ylamine of m.p. 215-217° C. (dec.).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)=[CH:27][CH:28]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCc2cn(-c3cccnc3)c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2cn(-c3cccnc3)c3ccccc23)cc1

Procedure:
A solution of crude 3-[(p-ethoxycarbonylphenoxy)methyl]-N-(3-pyridyl)-indole (6.5 g) in 60 ml of ethanol and 60 ml of 1N sodium hydroxide is heated under reflux for 3 hours. The ethanol is distilled off, the aqueous phase is washed with ether, acidified with conc. hydrochloric acid to pH=6, and the resulting solid is filtered off to yield 3-[(p-carboxyphenoxy)-methyl]-N-(3-pyridyl)indole. Treatment with ethanolic hydrogen chloride gives 3-[(p-carboxyphenoxy)methyl]-N-(3-pyridyl)indole hydrochloride.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[O:12]=[C:13]1[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH2:22][N:23]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(NCc2ccncc2NC(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2Cc3ccncc3NC2=O)CC1
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Trifluoroacetic acid (1,43 g) was a add to a solution of the material from Step A (0.47 g, 1.24 mmol) in dichloromethane (10 mL). After stirring overnight, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.62 g, 3.73 mmol) was added at room temperature. After 2 d, the acetonitrile was evaporated in vacuo, the residue partitioned between 1N NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1 to 20% methanol in methylene chloride gradient elution), which gave the title compound (0.15 g). MS 305.2.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:17][OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.O=[Mn]=O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(F)c1NCCN1CCCCC1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(F)c1NCCN1CCCCC1

Procedure:
(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)methanol (453 mg, 1.795 mmol) and MnO2 (692 mg, 7.960 mmol) were heated in toluene (15 mL) at reflux overnight. The suspension was filtered through Celite with CH2Cl2 and concentrated on a rotary evaporator. Crude 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzaldehyde was carried on to the next reaction.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:24]1[CH:3]([CH:2]([CH3:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:4]1
Reactant: C=CC(C)CCCC(C)CCCC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)C1CO1
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of 9.6 g of 3,7,11-trimethyl-1-dodecene in 200 ml of methylene chloride was added 10.8 g of meta-chloroperbenzoic acid at room temperature, and the mixture was stirred at the same temperature for 6 hours. Thereafter, the reaction mixture was filtered and the filtrate was washed successively with aqueous sodium thiosulfate, aqueous sodium hydrogen carbonate and aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was distilled under reduced pressure to give 6.8 g (yield 59%) of 1,2-epoxy-3,7,11-trimethyldodecane. The physical constants of the compound are as follows.
Reaction SMILES: [NH4+:1].[Cl-].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:20])[NH:15][C:14](=S)[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:7]=[CH:8][CH:9]=1>CCO>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:20])[N:15]=[C:14]([NH2:1])[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:7]=[CH:8][CH:9]=1
Reactant: [NH4+]
Reactant: CC1(c2cccc(Br)c2)NC(=S)Cn2nccc21
Agent: [Cl-]
Solvent: CCO
Product: CC1(c2cccc(Br)c2)N=C(N)Cn2nccc21
Temperature: 80 °C
Yield: 98.3 %

Procedure:
NH4Cl (0.15 g, 2.79 mmol) was added to a stirred solution of rac-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazine-6-thione (0.45 g, 1.40 mmol) in EtOH (50 mL) and the mixture was heated at 80° C. for 28 hours. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in AcOEt 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield rac-4-(3-bromo-phenyl)-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (0.42 g, 99% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18].CCN(CC)CC>O.O1CCOCC1.CCOCC>[C:21]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)([O:20][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:22]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
To a stirred suspension of 50.45 g (240 mmole) of 4-nitro-L-phenylalanine in 140 ml water was added a solution of 65.11 g (264.4 mmole; 1.1 eq) of BOC-ON in 140 ml dioxane and 53 ml (380.3 mmole; 1.58 eq) of Et3N. The gradually cleared solution was stirred at room temperature for 4 hours. The reaction mixture was poured into 410 ml water and extracted with ether (5×330 ml). The aqueous layer was acidified to pH 1.15 with 6N HCl and then extracted with EtOAc (5×330 ml). The EtOAc extracts were pooled and dried over with MgSO4, filtered and evaporated under reduced pressure to give a crude residue. This residue was dissolved in 300 ml ether, the solvent was removed under reduced pressure to give 67.61 g (90.8%) product (1) as a pale yellow foam. 1HNMR (CDCl3, δ)=8.17 & 7.38 (d & d, 4H), 5.15 & 4.55 (m & m, 2H), 3.20 (m, 2H), 1.38 (2s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([CH3:13])[C:11]3[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=[C:17]([O:18][CH3:19])[C:10]=3[O:9]2)=[CH:4][C:3]=1[O:23][CH3:24].[CH2:25]([N:28]1[CH2:32][CH2:31][O:30][CH2:29]1)[CH:26]=[CH2:27]>>[CH3:19][O:18][C:17]1[C:10]2[O:9][C@@H:8]([C:5]3[CH:4]=[C:3]([O:23][CH3:24])[C:2]([OH:1])=[C:7]([CH2:29][N:28]([CH2:32][CH2:31][OH:30])[CH2:25][CH:26]=[CH2:27])[CH:6]=3)[C@H:12]([CH3:13])[C:11]=2[CH:14]=[C:15](/[CH:20]=[CH:21]/[CH3:22])[CH:16]=1
Reactant: C=CCN1CCOC1
Reactant: C/C=C/c1cc(OC)c2c(c1)[C@@H](C)[C@H](c1ccc(O)c(OC)c1)O2
Product: C=CCN(CCO)Cc1cc([C@@H]2Oc3c(OC)cc(/C=C/C)cc3[C@H]2C)cc(OC)c1O
Yield: 53.5 %

Procedure:
20.0 g of trans-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-3-methyl-5-(E)-propenylbenzofurane and 13.6 g of 3-allyl-1,3-oxazolidine are held in 240 ml of absolute alcohol for 48 hours at 70° C. and subsequently the solvent and excess 3-allyl-1,3-oxazolidine are removed in vacuum. After purification by means of a chromatographic column there is obtained 14.4 g of N-(5-(trans-2,3-dihydro-7-methoxy-3-methyl-5-(E)-propenyl-benzofuran-2-yl)-2-hydroxy-3-methoxyphenyl-methyl)-N-(2-hydroxyethyl)-N-allylamine, a colourless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[C:24]([C:40](O)=[O:41])=[N:25][C:26]([CH2:30][C:31]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[N:27][C:28]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O=P(Cl)(Cl)Cl>O.N1C=CC=CC=1>[CH2:15]([O:22][C:23]1[C:24]([C:40]([N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:12]([CH3:14])[CH3:13])=[O:41])=[N:25][C:26]([CH2:30][C:31]([CH3:32])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:39])=[N:27][C:28]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(Cc1nc(O)c(OCc2ccccc2)c(C(=O)O)n1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: -10 °C
Yield: 26 %

Procedure:
N-(2-(tert-Butyldimethylsilyloxy)ethyl)propan-2-amine (8b) (98.0 mg, 451 μmol, Eq: 1.1, prepared as previously described) was added to 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylic acid (56) (155 mg, 410 μmol, Eq: 1.00), then pyridine (2.5 ml) was added, and the reaction mixture was cooled to −10° C. with stirring. POCl3 (188 mg, 115 μl, 1.23 mmol, Eq: 3) was added dropwise, then the reaction mixture was stirred at −10° C. for 1 hour, allowed to warm to 0° C. and stirred for one hour. 10 drops of water were added at 0° C., the reaction mixture was stirred for 5 min and the solvent was removed on a rotary evaporator to almost dryness. The mixture was placed on 12 g silica gel column and eluted with 5% to 50% ethyl acetate/hexane over 20 min. to give 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-hydroxy-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (57) (62 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N+:15]([O-:17])[CH3:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:9][N:10]3[CH:14]=[N:13][CH:12]=[N:11]3)[CH2:35][CH:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[O:17][N:15]2[CH3:16])=[CH:4][CH:3]=1
Reactant: C=CCCCCCCCCCCCCCCCC
Reactant: C[N+]([O-])=C(Cn1cncn1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1CC(Cn2cncn2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 25 °C

Procedure:
A solution of 32.8 g (0.131 mol) of 1-(4-chlorophenyl)-N-methyl-2-(1H-1,2,4-triazol-1-yl)ethanimine N-oxide (1: R=4-Cl) [prepared by reacting 2-(1H-1,2,4-triazol-1-yl)-4'-chloroacetophenone (35.38 g, 0.160 mol) with N-methylhydroxylamine hydrochloride (20.0 g, 0.240 mol) and NaHCO3 (20.12 g, 0.240 mol) in 500 ml ethanol] and 62.8 ml (0.196 mol) of 1-octadecene (2: n=15) in 400 ml toluene is refluxed for 48 hours under a nitrogen atmosphere. Upon cooling to room temperature the solvent is removed under reduced pressure. The residual dark solid is collected and washed sequentially with acetonitrile and ether. Crystallization from ethyl acetate gave 9.0 g (14%) of isomer A (3: R=4-Cl, n=15), melting at 100°-102° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([S:6]([OH:9])(=[O:8])=[O:7])[C:3]1=[O:10].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+:25].P(=O)(O)(O)O>O.O1CCCC1>[C:11]1([CH2:17][C:18]([NH:1][CH:2]2[CH2:5][N:4]([S:6]([O-:9])(=[O:8])=[O:7])[C:3]2=[O:10])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+:25]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CN(S(=O)(=O)O)C1=O
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 45.6 %

Procedure:
In 1 ml of water is dissolved 50 mg of the above 3-amino 2-oxoazetidine-1-sulfonic acid, followed by addition of a solution of 69 mg phenylacetyl chloride in 1 ml tetrahydrofuran and 101 mg of sodium hydrogen carbonate in alternate portions with ice-cooling and stirring. After stirring at room temperature for 30 minutes, the mixture is adjusted to pH 5.8 with phosphoric acid. The tetrahydrofuran is then distilled off under reduced pressure. The water layer is washed with ethyl acetate and purified by XAD-II chromatography, whereby 42 mg of sodium 3-phenylacetamido-2-oxoazetidine-1-sulfonate is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].C[O-].[Na+]>CO>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]([N+:15]([O-:17])=[O:16])=[CH:8][C:9]=1[OH:14]
Reactant: O=[N+]([O-])c1cc2c(cc1NCCCO)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(NCCCO)c([N+](=O)[O-])cc1O

Procedure:
A mixture consisting of 0.013 mol (3.12 g) of 2-(γ-hydroxypropyl)amino-4,5-methylenedioxy-1-nitrobenzene, prepared according to Example 5, and 22 ml of a 30% strength solution of sodium methylate in methanol are brought to the refluxing temperature of the methanol for 10 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([NH:1][S:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20])=[CH:11]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cnc2c(Br)cccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
3-Amino-8-bromoquinoline (300 mg, Production Example 5b) was dissolved in pyridine (5 ml), to which was then added 3-pyridinesulfonyl chloride (254 mg), followed by stirring at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: ClC1C=CC=C([N+]([O-])=[O:9])C=1C.Cl[C:13]1[C:18]2[C:19](=[O:24])[NH:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1>>[OH:9][C:13]1[C:18]2[C:19](=[O:24])[NH:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C1NS(=O)(=O)c2cccc(Cl)c21
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2cccc(O)c21

Procedure:
Starting from the 2-chloro-6-nitro toluene, the preparation of the starting compound, 4-chloro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide, was carried out by one of the following processes: