Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6](C(C(O)=O)C)[C:5]1=[O:17])=[N+]=[N-].NC1CCCCCNC1=O.C(O)(=O)C.O=[C:33]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(O)C.[Pd]>[CH2:37]([O:36][C:34]([CH:33]([NH:1][CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:35])[CH3:38]
Reactant: CC(C(=O)O)N1CCCCCC(N=[N+]=[N-])C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Pd]
Agent: NC1CCCCCNC1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCCNC1=O

Procedure:
Reduce 3-azidoperhydroazocin-2-one (Example 3) to 3-aminoperhydroazocin-2-one using 10% Pd/C in ethanol. NMR (CDCl3, TMS): δ 1.67 (broad s, 8H), δ 2.25 (broad s, 2H), δ 3.35 (m, 2H), δ 3.8 (m, 1H), δ 7.0 (broad, 1H). Hydrogenate a solution of 1.42 g of this amine, 0.59 g acetic acid and 3.09 g ethyl 2-oxo-4-phenylbutyrate in 50 ml ethanol over 10% Pd/C catalyst. AFter filtration and concentration of the reaction, purify the product by chromatography over silica gel to isolate 3-[(1-ethoxycarbonyl-3-phenyl-1-propyl)amino]perhydroazocin-2-one.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C@@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]2=[O:33])[CH2:10][CH2:9]1>ClCCl>[NH2:25][C@@H:14]1[CH2:15][CH2:16][CH2:17][C@H:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10]2)[C:13]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@H](c2ccccc2)N(CC2CC2)C1=O
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution tert-butyl (3R,7R)-1-(cyclopropylmethyl)-2-oxo-7-phenylazepan-3-ylcarbamate (82 mg, 0.23 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichlormethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound (53 mg). 1H NMR (500 MHz, CDCl3) δ 7.40–7.37 (m, 2H), 7.34–7.31 (m, 3H), 4.97 (dd, J=9.3, 3.7 Hz, 1H), 4.05 (dd, J=9.8, 4.2 Hz, 1H), 3.24 (dd, J=14.4, 7.1 Hz, 1H), 2.69 (dd, J=14.2, 7.1 Hz, 1H), 2.16–2.10 (m, 2H), 2.03–1.97 (m, 1H), 1.92–1.85 (m, 2H), 1.65–1.56 (m, 1H), 0.69–0.63 (m, 1H), 0.34–0.23 (m, 2H), 0.09–0.04 (m, 1H), −0.10–0.15 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])C.[Br:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:16]=[C:15]([O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)[N:14]([CH2:26][CH3:27])[N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:28]O>>[Br:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:16]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([CH:22]([O:3][CH3:1])[O:23][CH3:28])=[CH:24][CH:25]=3)[N:14]([CH2:26][CH3:27])[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: CC(=O)Cl
Reactant: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C=O)cc1
Product: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(OC)OC)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Acetyl chloride (0.023 ml, 0.323 mmol, 0.1 equiv) was added to a stirring solution of 4-{[3-(3-bromophenyl)-1-ethyl-1H-pyrazol-5-yl]oxy}benzaldehyde (1.2 g, 3.23 mmol, 1.0 equiv) in methanol (7 mL). 4A molecular sieves were added and the mixture was stirred at 50° C. for 3 hours. The sieves were filtered and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (0-70% ethyl acetate:hexanes) to give 3-(3-bromophenyl)-5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H-pyrazole (1.2 g, 2.88 mmol, 89% yield). Calc'd (M+1)+419.0. Found: 419.19 (minor peak), 373.18 (major peak). Major peak is aldehyde seen because of deprotection occurring on LCMS.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][NH2:35]>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:35][CH3:34])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: CN
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: CNc1ccc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(COC)C2)cn1

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and methylamine. LCMS (Method C): 484 (M+H)+, Retention time 9.8 minutes.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.[C:47](Cl)(Cl)([Cl:49])[Cl:48]>>[Cl:48][C:47]([Cl:49])=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)c1ccc(C=C(Cl)Cl)cc1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
In 260 ml of carbon tetrachloride were dissolved 60 g of ethyl 2-(4-formylphenyl)propionate and 122 g of triphenylphosphine, followed by stirring in a stream of nitrogen gas at 50° C. for 4.5 hours. After cooling, the mixture was poured into 1 l of cold n-hexane and filtered. The filtrate was concentrated under reduced pressure to give an oily substance, which was subjected to silica gel column chromatography (eluent: n-hexane--ethyl acetate=40:1) to obtain 29 g of ethyl 2-[4-(2,2-dichlorovinyl)phenyl]propionate (ST-5) as an oily substance, b.p.0.2-0.3 128°-129° C.
Reaction SMILES: C1(CN2C3C=C(F)C(F)=CC=3N=C2C2C(OCC3CCCC3)=NC=CC=2)CCCCC1.[CH3:32][O:33][C:34](=[O:71])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][N:44]2[C:48]3[CH:49]=[C:50]([F:54])[C:51]([F:53])=[CH:52][C:47]=3[N:46]=[C:45]2[C:55]2[C:56]([O:61]CC3C=CC(OC)=CC=3)=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:39][CH:38]=1>>[CH3:32][O:33][C:34](=[O:71])[CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:43][N:44]2[C:48]3[CH:49]=[C:50]([F:54])[C:51]([F:53])=[CH:52][C:47]=3[N:46]=[C:45]2[C:55]2[C:56]([OH:61])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)CCc1ccc(Cn2c(-c3cccnc3OCc3ccc(OC)cc3)nc3cc(F)c(F)cc32)cc1
Agent: Fc1cc2nc(-c3cccnc3OCC3CCCC3)n(CC3CCCCC3)c2cc1F
Product: COC(=O)CCc1ccc(Cn2c(-c3cccnc3O)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was synthesized in analogy to Example 5, intermediate b, from 3-(4-{5,6-difluoro-2-[2-(4-methoxy-benzyloxy)-pyridin-3-yl]-benzoimidazol-1-ylmethyl}-phenyl)-propionic acid methyl ester. Colorless solid (69%). MS (Turbo Spray): m/z=424.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:26].[Cl:26][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:18]=2[C:8]=1[S:7][CH2:6][C:5]1[CH:27]=[CH:28][C:2]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:3]([F:29])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Reactant: C1CCNC1
Product: Cl
Product: Fc1cc(CSc2c(Cl)ccc3c2CCNCC3)ccc1N1CCCC1

Procedure:
Use a method similar to the Example 419 to react 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine with pyrrolidine. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 391 (M+H)+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH:12]2[CH2:17]OC(C)(C)[O:14][CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S(OC[C@@H]2COC(C)(C)O2)(=O)=O)=CC=1.[F:40][C:41]1([F:85])[CH2:46][CH2:45][CH:44]([C:47]2[C:56]3[CH:55]([OH:57])[CH2:54][C:53]([CH3:59])([CH3:58])[CH2:52][C:51]=3[N:50]=[C:49]([CH:60]3[CH2:65][CH2:64][N:63]([C:66]4[N:71]=[CH:70][C:69]([OH:72])=[CH:68][N:67]=4)[CH2:62][CH2:61]3)[C:48]=2[CH:73]([F:84])[C:74]2[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][CH:75]=2)[CH2:43][CH2:42]1>>[F:85][C:41]1([F:40])[CH2:42][CH2:43][CH:44]([C:47]2[C:56]3[CH:55]([OH:57])[CH2:54][C:53]([CH3:58])([CH3:59])[CH2:52][C:51]=3[N:50]=[C:49]([CH:60]3[CH2:61][CH2:62][N:63]([C:66]4[N:71]=[CH:70][C:69]([O:72][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][OH:10])=[CH:68][N:67]=4)[CH2:64][CH2:65]3)[C:48]=2[CH:73]([F:84])[C:74]2[CH:75]=[CH:76][C:77]([C:80]([F:82])([F:81])[F:83])=[CH:78][CH:79]=2)[CH2:45][CH2:46]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)OC2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCC(CO)CO)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Example 39 were performed except for using (2,2-dimethyl-1,3-dioxan-5-yl)methyl p-toluenesulfonate, which was synthesized with the method described in J. Dubois et al., Tetrahedron, 1991, Vol. 47, pp. 1001-1012, instead of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate, and from 4.04 g (6.23 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 2.73 g of the title compound was obtained as a white solid (yield: 59%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[O:16][CH2:17][CH2:18][OH:19].O>C(Cl)Cl>[F:11][C:12]([F:23])([F:24])[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[O:16][CH2:17][CH:18]=[O:19]
Reactant: OCCOc1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCOc1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of oxalyl chloride (0.49 ml; 5.821 mmol) in anhydrous DCM (25 ml) was treated dropwise with a solution of dimethyl sulfoxide (0.91 ml; 11.641 mmol) in anhydrous DCM (4 ml). After 10 min., a solution of 2-(3-trifluoromethyl-phenoxy)-ethanol (0.800 g; 3.880 mmol) in DCM (8 ml) was added dropwise, and the reaction mixture was further stirred at −78° C. for 30 min. TEA (2.70 ml; 19.402 mmol) was then added dropwise, and after 10 min. the resulting mixture was allowed to warm-up to 0° C. before a mixture of water (2.5 ml) and DCM (25 ml) was added. The aq. layer was extracted with DCM (2×25 ml), and the mixed organic layers were then washed with aq. sat. NaHCO3 (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give (3-trifluoromethyl-phenoxy)-acetaldehyde as a yellow oil (0.792 g; 99%). This aldehyde was used for the next step without additional purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:25](=[O:26])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:25](=[O:26])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csnn1
Yield: 65.3 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(3.74 g) and 7-amino-3-methyl-3-cephem-4-carboxylic acid (4.3 g) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer)(5.0 g), mp 111° to 116° C. (dec.).
Reaction SMILES: C(#N)C.[CH:4]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)=[O:5].[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH:4]([C:6]1[N:7]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:8]=[CH:9][N:10]=1)=[O:5]
Reactant: O=Cc1ncc[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1C=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.2 %

Procedure:
To an acetonitrile (500 mL) solution of 2-formylimidazole (64 g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added at room temperature. The reaction solution was stirred at 50° C. for 16 hours. The reaction solution was cooled to room temperature and the precipitated crystal was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain a crude compound. The wash solution was washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to obtain a crude product. The crude product was combined with the crude product obtained previously, followed by washing with ether to obtain the title compound (88.3 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][OH:11])[CH:5]=[N:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35]>>[OH:11][CH2:10][C@H:9]([NH:8][C:6]1[N:7]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([OH:35])=[C:20]([O:19][CH3:18])[CH:25]=2)[CH:3]=[N:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2cncc(N[C@@H](CO)c3ccccc3)n2)ccc1O
Yield: 37.7 %

Procedure:
In a procedure analogous to Example 2, reaction of (2R)-2-[(6-chloropyrazin-2-yl)amino]-2-phenylethanol (137 mg, 0.55 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (151 mg, 0.60 mmol) furnished the product (70 mg, 38%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:13][OH:14]>CO>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:14][CH3:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C#N)cc1
Yield: 93.9 %

Procedure:
p-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 75.7 g of methyl p-cyanobenzoate (yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.Cl.[N:32]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33]1>O1CCCC1.CO.C(N(CC)CC)C>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][N:32]3[CH2:33][CH2:34][CH2:35]3)[CH2:43][CH2:42]2)=[O:21])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CN(CCN2CCNCC2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCN(CCN2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Triethylamine (0.101 ml) and phenyl chloroformate (0.0908 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 25 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, N,N-dimethylformamide (3 ml) was added thereto. Then an 1.0 M solution of 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride in methanol (0.819 ml) and triethylamine (0.343 ml) were added to the mixture, followed by stirring for 4 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (114 mg) as a pale yellow oil.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][CH2:21][CH3:22])[C:14]=2[CH:23]=1)(=O)=O.[C:26]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CO.CC(C)=O>[CH3:25][O:24][C:11]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:35]2[CH2:36][CH2:37][CH:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:33][CH2:34]2)=[CH:23][C:14]2[C:15]([CH2:20][CH2:21][CH3:22])=[CH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1
Reactant: CCCc1cc(=O)oc2cc(OC)c(OCCCOS(C)(=O)=O)cc12
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CO
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CCCc1cc(=O)oc2cc(OC)c(OCCCN3CCC(c4ccccc4)CC3)cc12
Yield: 54 %

Procedure:
Method A (20 h at 60° C.); starting materials: 6-[3-(methanesulfonyloxy)propoxy]-7-methoxy-4-propyl-2H-1-benzopyran-2-one (example 76) and 4-phenylpiperidine; yield 54%; fusion point 101°-102° C. (from TBME and petroleum ether). Fumarate: method E; yield 62%; fusion point 191°-194° C. (from acetone and methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccc(Cl)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a solution of ethyl 2-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.18 g, 0.61 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.088 g, 0.61 mmol) in ethanol (10 mL), piperidine (0.0044 mL, 0.044 mmol) was added at ambient temperature. The mixture was refluxed for 6 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound (0.061 g, y. 23%).
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br-:9].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][N+:15]([CH3:29])([CH3:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[Br-:9].[Cl-:10].[CH3:28][N+:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2+:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])([CH3:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCCl
Reactant: C=CCC(N)CC=C
Agent: [Br-]
Solvent: CO
Product: C=CCC(CC=C)[NH2+]CCCC[N+](C)(C)CCCCCCCCCCCC
Product: [Cl-]
Temperature: 65 °C
Reaction time: 48 h
Yield: 67.2 %

Procedure:
A mixture of 22 g diallylmethylamine and 75 g 4-chlorobutyldimethyldodecylammonium bromide were dissolved in 100 mL methanol and the reaction mixture was stirred at 65° C. for 48 hours. The progress of the reaction was monitored by the disappearance of the diallylmethylamine by thin layer chromatography (TLC). After cooling to room temperature, the solvent was removed under reduced pressure. The residual viscous oil was precipitated into 800 mL dry ether with rapid stirring. The ether layer was decanted and the residue was again treated with 500 mL dry ether. After stirring for 15 minutes the solvent was removed and the oily residue was dried under vacuum at 35° C. for 48 hours, yielding 65 g of the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8](CC)[CH:9]([C:11]#N)O)([CH3:4])([CH3:3])[CH3:2].C1([O:22]C)C=CC=CC=1.Cl.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[O:40]1[CH2:45][CH2:44][O:43]CC1>>[C:1]([O:5][C:6]([NH:7][CH:8]([CH2:9][CH3:11])[CH:44]([OH:43])[C:45]([OH:40])=[O:22])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C#N
Reactant: C1COCCO1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1S)-(2-Cyano-1-ethyl-2-hydroxyethyl)carbamic acid tert-butyl ester (10 g, 46.7 mmol) was dissolved in 1,4-dioxane (100 mL). Anisole (5 mL) was added and then concentrated HCl (100 mL). The mixture was heated under reflux for 24 hours. The mixture was evaporated to dryness under vacuum and re-dissolved in 100 mL water. The solution was washed with ether and then neutralized with saturated aqueous NaHCO3. Di-tert-butyl dicarbonate (10 g, 46 mmol) was added with 1,4-dioxane (200 mL), and the mixture was stirred at ambient temperature for 24 hours. The dioxane was removed under vacuum and the remaining aqueous solution was washed with ether. The solution was acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and evaporated to yield 3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (4.5 g) as yellowish oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16]([N:3]([CH2:4][CH2:5][N:6]([CH3:8])[CH3:7])[CH2:1][CH3:2])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CCNCCN(C)C
Solvent: ClCCl
Product: CCN(CCN(C)C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of N′-ethyl-N,N-dimethylethane-1,2-diamine (0.62 mL, 4.4 mmol) in methylene chloride (10 mL) was added 6-chloropyridine-3-sulfonylchloride (0.85 g, 4 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred for 30 min at room temperature followed by the extraction with aqueous HCl (5%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.7 gram (60% yield) of the title compound: MS (ES) m/z 292 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.[Li]CCCC.CO[N:18](C)[C:19](=O)[CH3:20]>C1COCC1>[CH:8]([C:4]1[CH:3]=[C:2]([C@@H:19]([NH2:18])[CH3:20])[CH:7]=[CH:6][CH:5]=1)([CH3:10])[CH3:9]
Reactant: CON(C)C(C)=O
Reactant: CC(C)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc([C@H](C)N)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-3-isopropylbenzene (10 g, 0.05 mol) in THF was added dropwise with BuLi (47 mL, 0.075 mol) at −60° C. After stirred 30 minutes, N-methoxy-N-methylacetamide (6.22 g, 0.06 mol) was added. The mixture was stirred at −30° C. for 3 hours. Then the mixture was quenched with H2O, the mixture was partitioned between EtOAc and water. The layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to obtained the titled compound.