Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.C(Cl)[Cl:22].S(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:22][CH:11]([C:13]1[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=1)[C:9](=[O:10])[C:1]1[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)C(Cl)c2ccc(OC)cc2)cc1
Reaction time: 0.83 h

Procedure:
Anisoin (2.87 g), 100 mL of methylene chloride, and pyridine (2.02 g) are placed in a flask under nitrogen. Thionyl chloride (1.60 ml) is added dropwise over 5 minutes using a water bath to maintain the reaction temperature between 25° C. and 30° C. After allowing the mixture stir for 50 minutes the reaction is quenched by washing with water (2×100 mL) and 100 mL of brine. The organics are dried over sodium sulfate, filtered, then concentrated. The resulting oil is taken up in 25 mL of diethyl ether and filtered. The filter cake is rinsed with 25 ml of diethyl ether. To the filtrate is added 25 ml of ethanol and the solution is concentrated. Crystals are allowed to form over 24 hours. The precipitate which forms is filtered, washed with 25 mL of ethanol, and dried in vacuo at 45° C. to give 4.00 g of product. (69%). Analysis calculated for C16H14ClO3 : C, 66.10; H, 5.20; Cl, 12.19. Found: C, 66.29; H, 5.32; Cl, 12.56. MS(FD) 290.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]12[CH2:41][CH2:40][CH2:39][C:37]3[C:38]1=[C:33]([CH:34]=[CH:35][CH:36]=3)[NH:32][C:31]2=[O:42].C(=O)([O-])[O-].[K+].[K+].O>CO.Cl.CN(C)C=O>[CH:24]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]45[CH2:41][CH2:40][CH2:39][C:37]6[C:38]4=[C:33]([CH:34]=[CH:35][CH:36]=6)[NH:32][C:31]5=[O:42])[CH2:13][CH2:12]3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCCc3ccccc32)CC1
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(C2CCCCc4ccccc42)CC1)CCC3
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
1-t-Butoxycarbonyl-4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)piperazine (340 mg, 1.0 mmol) was dissolved in 10% hydrochloric acid methanol (4 ml) and stirred at 40° C. for 3.5 hours. The solvent was removed by evaporation under a reduced pressure, and the thus obtained residue was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) and potassium carbonate (490 mg, 3.5 mmol) and stirred overnight at room temperature in N,N-dimethylformamide (3 ml). This was mixed with water, the precipitate was collected by filtration and then the reaction product was extracted from the mother liquid with ethyl acetate. The extract was washed with water and saturated brine and dried with anhydrous sodium hydrogensulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography. The thus purified compound was combined with the aforementioned precipitate and thoroughly washed with ethyl acetate to obtain 370 mg (0.81 mmol, 80%) of the title compound.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([N:3]1[CH2:2][CH2:1][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)OC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using iso-propyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Example 3) and benzoyl chloride; 1H-NMR (CDCl3): δ 10.48 (1H, br s), 7.98 (1H, s), 7.47 (2H, m), 7.41 (2H, m), 7.40 (2H, m), 7.30 (1H, m), 7.15 (1H, m), 6.99 (1H, m), 5.04 (1H, m), 4.15 (2H, t), 3.2 (2H, d), 1.10 (6H, d); MS (ES): 375 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[CH:16][CH:17]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20]
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(C=O)cc3)cc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CO)cc3)cc2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A mixture of 0.90 g (2.52 mmol) of ethyl 4-chloro-6-[4-formylphenoxy)-1-methyl-2-indolecarboxylate, 0.10 g (2.52 mmol) of sodium borohydride and 20 ml of ethanol was stirred at 0° C. for 2 hours. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 0.91 g (>99%) of ethyl 4-chloro-6-[4-(hydroxymethyl)phenoxy]-1-methyl-2-indolecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([C:23](O)=[O:24])[CH:17]=3)=[C:9]([CH3:26])[CH:8]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:48][O:49][C:50]1[CH:59]=[CH:58][C:53]([C:54]([NH:56][NH2:57])=[O:55])=[CH:52][CH:51]=1>C1COCC1>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([C:54]([NH:56][NH:57][C:23]([C:18]2[CH:17]=[C:16]3[C:21]([CH:22]=[C:14]([C:10]4[C:11]([CH3:13])=[CH:12][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:8][C:9]=4[CH3:26])[NH:15]3)=[CH:20][CH:19]=2)=[O:24])=[O:55])=[CH:58][CH:59]=1
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)NNC(=O)c4ccc(OC)cc4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-[4-(2-methoxycarbonylethyl)-2,6-dimethylphenyl]-1H-indole-6-carboxylic acid (200 mg, 570 μmol) and HOBT (85 mg, 630 μmol) in THF (10 mL) was added EDCI (164 mg, 860 μmol) and the solution was stirred at RT for 10 min. Then a solution of 4-methoxybenzoic acid hydrazide (104 mg, 630 μmols) in THF (5 mL) was added and the mixture was stirred at RT for 18 h. The solvent was removed under reduced pressure and the residual material was chromatographed using a 50-90% gradient of heptane/ethyl acetate to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=2)[C:38](OC)=[O:39])[C:31]1=[O:45].FC1C=CC(CN)=CC=1>>[F:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:29][N:30]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][N:44]=2)[C:38]([NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:39])[C:31]1=[O:45]
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)c1
Yield: 40 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 4-fluorobenzylamine, 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 40% yield: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, 1H), 8.37 (dd, J=5.1, 0.6 Hz, 1H), 7.41 (dd, J=5.4, 1.5 Hz, 1H), 7.37-7.26 (m, 2H), 7.13-6.97 (m, 5H), 6.80 (br s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.38 (t, J=8.1 Hz, 2H); MS (ES+) m/z 441.1 (M+1).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][O:12][N:11]=1)[CH2:4][C:5]#[C:6][CH2:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:14]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:13][O:12][N:11]=1)[CH2:4][C:5]#[C:6][CH2:7][CH3:8]
Reactant: CI
Reactant: CCC#CCCOc1nonc1-c1cccnc1
Solvent: CC(C)=O
Product: CCC#CCCOc1nonc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1.5 ml, 22 mmol) and 3-(3-(3-hexynyloxy)-1,2,5-oxadiazol-4-yl)pyridine (2.5 mmol) in acetone (20 ml) was stirred at room temperature for 18 h and evaporated to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: BrCCCCCCCCC1OCCO1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 2-(8-bromooctyl)-1,3-dioxolane (5 g, 18.85 mmol) in dimethyl formamide (100 mL) was added 3-hydroxybenzaldehyde (2.37 g, 19.42 mmol) and potassium carbonate (5.37 g, 38.83 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (4.66 g, 78%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.C(=O)([O-])O.[Na+:12].[C:13]([NH:23][C@@H:24]1[C:46](=[O:47])[N:26]2[C:27]([C:43]([OH:45])=[O:44])=[C:28]([CH2:31]OC(=O)C(C3C=CC=CC=3)O)[CH2:29][S:30][C@H:25]12)(=[O:22])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]>O>[Na+:12].[C:13]([NH:23][C@@H:24]1[C:46](=[O:47])[N:26]2[C:27]([C:43]([O-:45])=[O:44])=[C:28]([CH2:31][S:1][C:2]3[N:6]([CH3:7])[N:5]=[N:4][N:3]=3)[CH2:29][S:30][C@H:25]12)(=[O:22])[C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:15]
Reactant: O=C(O)C1=C(COC(=O)C(O)c2ccccc2)CS[C@@H]2[C@H](NC(=O)[C@H](O)c3ccccc3)C(=O)N12
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In water (5 ml) was dissolved 7β-(D-mandelamido)-3-mandelyloxymethyl-3-cephem-4-carboxylic acid (0.50 l g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.17 g). The solution was stirred at 60° C. for 30 minutes. After cooling in the air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, elution being carried out with water and a solvent mixture of water and methanol. The fractions containing the desired product were pooled, concentrated and lyophilized. The procedure provided 7β-(D-mandel-amido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (0.34 g).
Reaction SMILES: OC1C=CC=CC=1/C=[N:5]\[C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]1[N:30]([CH3:37])[NH:31][C:32](=[O:36])[C:33](=[O:35])[N:34]=1)=[C:11]2[C:15]([O:17]CC1C=CC(OC)=CC=1)=[O:16].O.CS(O[C:48](=[O:59])/[C:49](/[C:53]1[N:54]=[C:55]([NH2:58])[S:56][CH:57]=1)=[N:50]\[O:51][CH3:52])(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:58][C:55]1[S:56][CH:57]=[C:53](/[C:49](=[N:50]/[O:51][CH3:52])/[C:48]([NH:5][C@@H:6]2[C:13](=[O:14])[N:12]3[C@@H:7]2[S:8][CH2:9][C:10]([CH2:27][S:28][C:29]2[N:30]([CH3:37])[NH:31][C:32](=[O:36])[C:33](=[O:35])[N:34]=2)=[C:11]3[C:15]([OH:17])=[O:16])=[O:59])[N:54]=1
Reactant: CO/N=C(\C(=O)OS(C)(=O)=O)c1csc(N)n1
Reactant: COc1ccc(COC(=O)C2=C(CSc3nc(=O)c(=O)[nH]n3C)CS[C@@H]3[C@H](/N=C\c4ccccc4O)C(=O)N23)cc1
Solvent: COC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(=O)c(=O)[nH]n3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (6R,7R)-4-methoxybenzyl 7-((Z)-(2-hydroxybenzylidene)amino)-3-(((2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C[Al](C)C.[F:17][C:18]1[C:23]([C:24]2[CH:25]=[C:26]([C:36](OC)=[O:37])[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:28][CH:29]=2)=[CH:22][C:21]([CH3:40])=[CH:20][N:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][C:36]([C:26]1[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:28][CH:29]=[C:24]([C:23]2[C:18]([F:17])=[N:19][CH:20]=[C:21]([CH3:40])[CH:22]=2)[CH:25]=1)=[O:37]
Reactant: COC(=O)c1cc(-c2cc(C)cnc2F)cnc1-c1ccccn1
Reactant: COc1ccc(CN)cc1OC
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cnc3F)cnc2-c2ccccn2)cc1OC
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,4-dimethoxybenzylamine (0.15 g, 0.89 mmol, 8.0 equiv) in toluene (2.2 mL) was added a solution of trimethylaluminum (0.39 mL, 0.78 mmol, 7.0 equiv, 2 M in toluene) at ambient temperature and the reaction mixture was stirred for 45 minutes. To the reaction mixture was added a solution of methyl 2″-fluoro-5″-methyl-2,2′:5′,3″-terpyridine-3′-carboxylate (0.036 g, 0.11 mmol, 1.0 equiv) in toluene (2 mL) and the reaction mixture was heated to 100° C. for 15 h. The reaction mixture was cooled and diluted with ethyl acetate (30 mL) and quenched with Rochelle's salts (20 mL, saturated solution). The organic phase was washed with Rochelle's salts (3×20 mL, saturated solution), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (15 to 100% EtOAc in hexanes, silica) to afford the desired product (11-4) as a white solid after concentration. 1H NMR (500 MHz, CDCl3) δ 8.92-8.90 (m, 1H), 8.35 (d, J=4.0 Hz, 1H), 8.25 (bs, 1H), 8.07 (bs, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.82 (td, J=7.6, 1.6 Hz, 1H), 7.78 (dd, J=9.6, 2.0 Hz, 1H), 7.70 (bs, 1H), 7.30-7.27 (m, 1H), 6.83-6.79 (m, 3H), 4.51 (d, J=5.6 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.41 (s, 3H). HRMS [M+H] C26H23FN4O3 calc'd 459.1827. found 459.1827.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[N:14][NH2:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)C(N(C)C)=N.II.C(OO)(=O)C>ClCCCl>[N+:14](=[C:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N-:15]
Reactant: NN=C1c2ccccc2-c2ccccc21
Agent: CC(=O)OO
Agent: CN(C)C(=N)N(C)C
Agent: II
Solvent: ClCCCl
Product: [N-]=[N+]=C1c2ccccc2-c2ccccc21
Reaction time: 0.25 h

Procedure:
To 9-fluorenone hydrazone (9.7 g, 0.05 moles) in 1,2-dichloroethane (50 ml) together with 1,1,3,3-tetramethylguanidine (26.4 ml) and iodine (2 ml, 1% w/v solution) was added peracetic acid solution (11.4 ml, 1.27 × 0.05 moles) over 25 minutes at 10° - 15°. The orange solution was stirred for 15 minutes at 15°, washed with water (5 × 250 ml) and made up to 250 ml in a volumetric flask. An aliquot (50 ml) treated with excess acetic acid yielded 193 ml gas corrected to NTP which corresponded to a 86.2% yield of diazoalkane.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])C.[OH-].[Li+]>O1CCCC1>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)CCCCCCCC=Cc1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCC=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.7 %

Procedure:
To a solution of 10-(2-fluoro-phenyl)-dec-9-enoic acid ethyl ester (420 mg, 1.44 mmol) in tetrahydrofuran (2 mL) was added 2 M aq. lithium hydroxide solution (2 mL, 4 mmol). The reaction mixture was stirred at room temperature for 16 h, then partitioned between 1 M aq. hydrochloric acid solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated, to afford 10-(2-fluoro-phenyl)-dec-9-enoic acid (250 mg, 66%).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([CH3:20])[CH3:19].[H-].[Na+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13](=[O:18])[C:12]2([CH3:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C(=O)C(C)(C)c2cc(C3=NNC(=O)SC3C)ccc21
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
1.16 g 5-(3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (Example 3) in 30 ml DMF were cooled to 0° C. 0.175 g sodium hydride from a 55% dispersion in mineral oil was added and the mixture was successively stirred for 0.5 hr at 0° C. and 0.5 hr at 20° C. After cooling to 0° C. a solution of 0.43 g ethyl chloroformate in 2 ml DMF was added dropwise. The reactional mixture was stirred at room temperature for 16 hrs, 250 ml ethyl acetate were added and the organic solution was washed with water. The aqueous phase was extracted with 2×100 ml methylene chloride and the organic solutions were mixed, dried on magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on silica (methylene chloride-ethyl acetate: 4/1) then washed with isopropyl ether to yield 1.11 g of crystals.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[NH2:19][C:20]1[C:21]([CH2:26][CH2:27][CH2:28][CH2:29]N)=[N:22][CH:23]=[CH:24][CH:25]=1>>[NH2:19][C:20]1[C:21]([CH2:26][CH2:27][CH2:28][CH2:29][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][N:6]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: NCCCCc1ncccc1N
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1cccnc1
Product: Nc1cccnc1CCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
Using a procedure similar to that of Example 16, 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone was reacted with 1.1 molar equivalents of 4-(3-amino-2-pyridyl)butylamine, to give 2-[4-(3-amino-2-pyridyl)butylamino]-5-(3-pyridylmethyl)-4-pyrimidone, m.p. 130°-1.5°.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1([CH2:21][C:22]([NH2:24])=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1>C1COCC1>[NH2:24][CH2:22][CH2:21][C:8]1([OH:7])[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: NC(=O)CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of LiAlH4 (1.8 g, 0.048 mmol) in THF (40 mL) at 0° C. was added dropwise via addition funnel a solution of 2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetamide (4 g, 0.016 mmol) in THF (40 mL). The solution warmed to 25° C. and was then heated to reflux for 12 h. After cooling, the solution was then carefully quenched with a saturated solution of sodium potassium tartrate and extracted several times with DCM. The combined organic fractions were dried (Na2SO4) and the resulting residue was used directly without further purification: LCMS (ES) m/e 236 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]3[OH:19])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].I[CH2:29][CH3:30]>>[CH2:29]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][CH:17]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]2[OH:19])=[N:12]1)[CH3:30]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCc1ccc(Cc2c(OC3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC)c2C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodopropane.
Reaction SMILES: Br[C@H:2]([C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)[CH3:18])[C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])=[O:4].[N-:26]=[N+:27]=[N-:28].CN(C)C(=[NH2+])N(C)C>C(#N)C>[N:26]([C@@H:2]([C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)[CH3:18])[C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])=[O:4])=[N+:27]=[N-:28]
Reactant: C[C@@H](c1ccc(Br)cc1)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Solvent: CC#N
Product: C[C@@H](c1ccc(Br)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step C (2.71 g, 6.39 mmol) in acetonitrile (40 mL) was added tetramethylguanidinium azide (3.51 g, 22.2 mmol). The reaction was stirred at room temperature for 12 h. The solid was filtered off, and the filtrate was evaporated. The crude product was purified by flash chromatography (83:17 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: [Na].S(O)(O)(=O)=[O:3].[CH2:7]([NH:14][C:15](N)=N)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]C>>[CH2:7]([N:14]=[C:15]=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCNC(=N)N
Reactant: O=S(=O)(O)O
Agent: [Na]
Product: CCCCCCN=C=O

Procedure:
Proceeding in a manner similar to that described above in part A of Example 18, and using 3.44 g. of sodium, 30.9 g. of n-heptylguanidine sulfate, and 19.1 g. of n-hexylisocyanate, there was obtained 26.2 g. of 1-n-heptylamidino-3-n-hexylurea having the structural formula ##STR63## as a white crystalline solid which melted at 68°-72° C. The solubility of this base in a dilute acidic solution (prepared by mixing 0.36 ml. of N/2 hydrochloric acid and 9.64 ml. of water) at 25° C. was less than 0.25 percent. In 95 percent ethyl alcohol at 25° C. it was soluble to the extent of 5 percent (w/v); a precipitate formed when the 5 percent alcoholic solution was diluted with four volumes of water.