Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O1CCOCC1>[N:14]1([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (4.86 g, 26.2 mmol) in dioxane (50 ml) was added morpholine (11.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in water and the mixture was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide the title compound (6.2 g, 93%) as a yellow solid, MS (m/e): 251.2 (M−H, 100%).
Reaction SMILES: C(OCC)(=O)C.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[O:19][C:18]([CH3:21])([CH3:20])[N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:16]2[CH2:29][F:30])=[CH:11][CH:10]=1)#[CH:8].Cl/[C:32](=[N:38]/[OH:39])/[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:25]([O:24][C:22]([N:17]1[C@H:16]([CH2:29][F:30])[C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:39][N:38]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:8]=3)=[CH:14][CH:13]=2)[O:19][C:18]1([CH3:21])[CH3:20])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To an ethyl acetate (20 ml) solution of (4S,5R)-tert-butyl 5-(4-ethynylphenyl)-4-(fluoromethyl)-2,2-dimethyloxazolidine-3-carboxylate (1.35 g, 4.0 mmol) is added a dimethylformamide solution of (E)-ethyl 2-chloro-2-(hydroxyimino)-acetate (12.5 ml, 1.5 g, 2.5 equiv). Sodium hydrogen carbonate (3.5 g) is added to the solution and it is allowed to stir overnight at room temperature. The mixture is filtered and diluted with ethyl acetate (100 ml). After washing with water (4×25 ml) the organic phase is concentrated to give the crude product, which is purified on silica gel using a gradient of ethyl acetate in hexanes (0% to 20% ethyl acetate) to give the title compound (567 mg): 1H NMR (400 MHz, CDCl3) 1.43-1.56 (m, 14 H) 1.62 (s, 3 H) 1.74 (br. s., 3 H) 4.50 (q, J=7.24 Hz, 3 H) 5.20 (d, J=7.33 Hz, 1 H) 6.96 (s, 1 H) 7.60 (d, J=8.34 Hz, 2 H) 7.86 (d, J=8.59 Hz, 2 H), m/z (Cl) 449 ([M+H]+.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17]O.[OH-].[K+]>>[CH3:17][C:16]1([CH3:20])[CH2:19][O:14][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:15]1
Reactant: CC(C)(N)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCC1=NC(C)(C)CO1
Reaction time: 4 h
Yield: 86.9 %

Procedure:
64 g (320 mmoles) of dodecanoic acid and 61.1 ml (640 mmoles) of 2-amino-2-methylpropanol was placed in a two neck flask equipped with a vigreux column, distillation condenser and a thermometer. The temperature of the reaction mixture was slowly brought to 180° C. and maintained there for 9 hours. After cooling, a 10% alcoholic KOH solution (2 g, 3.6 mmoles) was added and the reflux was continued at 180° C. for 4 hours. The excess 2-amino-2-methylpropanol was distilled at aspirator pressure (86°C./ 18 mm). When the vapor temperature reached 103° C., the distillation was discontinued and the residue was taken in petroleum ether and filtered. The filtrate was washed with dilute KOH, water, dried and concentrated. The oil was distilled at 120° C./ 1.2 mmHg to give 70.5 g (87%) of product.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][C:4](=O)[CH2:5]Cl.ClC=CC(=O)C(C)C.[NH2:16][C:17]1[N:21]=[CH:20][NH:19][N:18]=1>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[N:18]2[N:19]=[CH:20][N:21]=[C:17]2[N:16]=[CH:5][CH:4]=1
Reactant: O=C(C=CCl)CCl
Reactant: Nc1nc[nH]n1
Agent: CC(C)C(=O)C=CCl
Solvent: CC(=O)O
Product: ClCc1ccnc2ncnn12

Procedure:
1,4-Dichloro-1-buten-3-one (10.9 g) (prepared in a manner analogous to the preparation of 1-chloro-4-methyl-1-penten-3-one described in Example 20 below), 3-amino-1,2,4-triazole (6.5 g) and glacial acetic acid were heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent was evaporated to give a solid. The crude product was purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol (in the ratio 97:3 respectively), followed by recrystallisation from tetrachloromethane, to give 7-chloromethyl-1,2,4-triazolo[1,5-a]pyrimidine. Yield 10.15 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][C:20]=2[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:34]([O:33][C:20]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:19]=1[CH:17]1[CH2:18][NH:15][CH2:16]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COc2ccc(C3CNC3)c(OCc3ccccc3)c2)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
In a 25 ml round-bottomed flask, 1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid tert-butyl ester is dissolved in 10 ml of dichloromethane and then 2.5 ml of trifluoroacetic acid are added. The reaction mixture is stirred for 2 hours. The solvents are evaporated off and the residue is then taken up in isopropyl ether. 0.92 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is obtained. Yield=90%.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].F[C:26](F)(F)[CH:27]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[C:16]([F:17])=[C:15]([N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH3:26])[CH2:28]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: FC(F)(F)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ncnc(N2CCCC(C)C2)c1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 108.6 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 0.2 g of 4-(2-butynyloxy)-5-fluoro-6-chloropyrimidine, 0.28 g of potassium carbonate and 0.15 g of 3-trifluoromethylpiperidine was added therein, and the mixture was stirred for 5 hours at 70° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.28 g of 4-(2-butynyloxy)-5-fluoro-6-(3-methylpiperidino)pyrimidine (hereinafter, referred to as Compound (26)).
Reaction SMILES: [Na].[CH:2]1[C:7]([CH:8]([OH:11])[CH2:9][NH2:10])=[CH:6][CH:5]=[C:4]([OH:12])[CH:3]=1.[CH2:13]([C:17]1[CH:32]=[CH:31][C:20]([O:21][CH2:22][C:23]2[O:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=2)=[CH:19][CH:18]=1)[C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>CO>[OH:11][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([OH:12])=[CH:3][CH:2]=1)[CH2:9][NH:10][CH:14]([CH3:16])[CH2:13][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]2[O:24][CH:25]=[C:26]([OH:30])[C:27](=[O:29])[CH:28]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)Cc1ccc(OCc2cc(=O)c(O)co2)cc1
Reactant: NCC(O)c1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CC(Cc1ccc(OCc2cc(=O)c(O)co2)cc1)NCC(O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the sodium salt of octopamine (0.65 g), and 2-(4-acetonylphenoxymethyl)-5-hydroxy-4H-pyran-4-one (1.0 g) in methanol was treated with sodium cyanoborohydride (0.3 g) and stirred at ambient temperature for 18 hours. The solvent was evaporated in vacuo. The residue was suspended in acetone and filtered, washed with acetone and then purified by column chromatography on silica using 5% methanol:chloroform as eluent-increasing to 15% methanol:chloroform after elution of fast-running impurities. This gave 2-[4-[2-[(β,4-dihydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-4H-pyran-4-one(0.4 g) as a (50:50) mixture of diastereoisomers.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O>CN(C)C=O.O>[OH:9]/[N:8]=[C:1](\[Cl:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O/N=C/c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a colorless, homogeneous solution of (E)-benzaldehyde oxime (24.4 g, 201 mmol) in N,N-dimethylformamide (60 mL) at room temperature was added N-chlorosuccinimide (26.9 g, 201 mmol) portion-wise over 30 min. During each addition, the reaction mixture became yellow and then gradually returned to near colorlessness. Additionally, an exotherm was noted with each portion added. (It is extremely important to make sure the reaction initiates after the addition of the first ˜1/5 of the NCS; an ice-bath was readily available.). After the addition was complete, the homogeneous reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 250 mL of water and extracted with ether (3×100 mL). The organic layers were combined, washed with water (2×100 mL), washed with a 10% aqueous solution of lithium chloride (2×100 mL), and washed with brine (100 mL). The aqueous layers were back extracted with ether (100 mL), and the combined organic layers (400 mL) were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)—N-hydroxybenzimidoyl chloride (30.84 g, 198 mmol, 98% yield) as a fluffy, pale yellow solid. The product had an HPLC ret. time=1.57 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=155.8. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.30-7.64 (m, 3H), 7.73-7.87 (m, 2H), and 12.42 (s, 1H).
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[C:9]([C:10](OC)=[O:11])[C:8]=1[OH:17])([O-:6])=[O:5].[OH-].[Na+]>O1CCCC1>[OH:17][C:8]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:2][NH2:3])=[O:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NNC(=O)c1cccc([N+](=O)[O-])c1O
Yield: 90 %

Procedure:
40 ml of hydrazine hydrate were added to a solution of 30 g (0.15 mol) of methyl 3-nitrosalicylate in 200 ml of anhydrous tetrahydrofuran (THF). After dilution with THF, the resulting suspension was stirrable; it was refluxed for approximately 18 hours. After cooling, the batch was poured onto ice. The aqueous solution was rendered neutral by adding NaOH solution. The crystals which precipitated were filtered off and washed with water. After drying, 27 g (90%) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180° C. under nitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhat and 200 ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature, 40.1 g of solid was filtered off and recrystallized twice from methanolisopropyl ether giving 4.3 g, presumably the hydrochloride salt; m.p. 187°-90° C. This solid was dissolved in a mixture of water-methanol, basified with 3N sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product; m.p. 91°-3° C. Drying prior to analysis was overnight at room temperature/0.02 mm Hg.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-pyrimidinyl)amino)ethoxy]benzaldehyde (1.7 g) and 2,4-thiazolidinedione (0.7 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 189-90° C.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]=[C:7]2[CH2:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])(=[O:24])=[O:23])=[O:20])=[CH:17][C:16]=1[O:34][CH3:35])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:49][C@H:50]([CH2:53][C:54]([F:57])([F:56])[F:55])[CH2:51][NH2:52]>CN(C)C1C=CN=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:35][O:34][C:16]1[CH:17]=[C:18]([CH:32]=[CH:33][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:2])[NH:52][CH2:51][C@H:50]([CH3:49])[CH2:53][C:54]([F:57])([F:56])[F:55])[CH:5]=2)[N:9]([CH3:13])[CH:8]=1)[C:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])(=[O:24])=[O:23])=[O:20]
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](CN)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (103.5 g), 4-dimethylaminopyridine (112.4 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (51.8 g) in tetrahydrofuran (distilled from sodium benzophenone ketyl) (2.0 L), which had been stirred for 2 hours, was added (R)-2-methyl-4,4,4-trifluorobutylamine hydrochloride (42.6 g); and the reaction mixture was stirred overnight (about 18 hours, incomplete reaction) then heated to reflux for two hours (complete reaction). The cooled reaction mixture was diluted with ethyl acetate (2 L) washed with 1N hydrochloric acid (twice) and brine, dried (MgSO4) and evaporated. The residue (138.6 g) was combined with impure product from similar procedures (28.0 g) and purified by flash chromatography, eluting with methylene chloride:ethyl acetate (sequentially, 1:0, 9:1 and 3:1) to afford a solid which was triturated twice with ether to give the crude title compound (135.2 g) which was recrystallized from ethanol (1.2 L) and acetone (0.3 L) (concentrated by boiling to about 0.9 L and refrigerated) and dried under vacuum to provide the title compound (117.1 g, 65% recovery) as a white crystalline solid; mp 141.5°-143.5° C.; NMR (300 MHz, DMSO-d 6): 1.01 (d, 3H, CH3), 2.0-2.2 (m, 2H, CF3CH2), 2.3-2.5 (m, 1H, CHCH3), 2.61 (s, 3H, ARCH3), 3.23 (br t, 2H, CH2N), 3.76 (s, 3H, NCH3), 3.92 (s, 3H, OCH3), 4.07 (s, ArCH2Ar'), 7.13 (s, 1H), 7.17 (d, 2H), 7.38-7.69 (m, 6H), 7.72 (d, 1H), 8.05 (d, 1H), 8.11 (s, 1H), 8.46 (br t, 1H, NHCO).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32])[CH:21]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:11]([CH3:19])[N:10]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NCCOCCCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.1 mL, 44 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (7.50 g, 36.2 mmol), prepared as described in Part A of Example 1, in anhydrous DMF (160 mL). Neat 2-[3-(pyridin-3-yl)propoxy]ethylamine (6.60 g, 36.6 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with 2% aqueous potassium bicarbonate (1×), water (1×), and brine (1×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (600 g, eluting with methanol:ethyl acetate in various ratios) to afford an oil which was dried under reduced pressure to yield 4.9 g of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([C@H:18]([NH2:22])[C:19](O)=[O:20])[CH2:14][CH2:13]1.C1C([C@@H](N)C(O)=O)=CC=C(O)C=1.N[C@@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:22][C@@H:18]([CH:15]2[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]2)[CH2:19][OH:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: N[C@H](C(=O)O)C1CCCCC1
Agent: CSCC[C@@H](N)C(=O)O
Agent: N[C@@H](C(=O)O)c1ccc(O)cc1
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: O=S(=O)(N[C@H](CO)C1CCCCC1)c1ccc(Br)cc1

Procedure:
The following compounds (Examples 16–19, Table 3) were prepared using 4-bromobenzensulfonyl chloride with L-cyclohexylglycine, D-4-hydroxyphenylglycine, D-methionine, and L-tryptophan and following the procedure outlined in Example 16.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8](C(=O)C(OC)=O)[C:7](=[O:15])[C@H:6]1[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:3])[CH3:2].O>CO>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:15])[C@H:6]1[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 48 h
Yield: 74.3 %

Procedure:
A mixture containing 2.34 g (6.43 mmol) methyl ((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidin-2-on-1-yl)-2-oxoacetate and 5 ml of water in 250 ml of methanol is left at room temperature for 2 days. The mixture is evaporated in vacuo and the residue dried in high vacuo and recrystallized from methylene chloride-n-hexane. In this way, 1.33 g (74%) of title compound of melting point 110° to 113° C. is obtained. Chromatography of the mother liquors on 70 g of silica gel using a 3:1 mixture of toluene and ethyl acetate (20 fractions, 70 ml each) affords 300 mg (17%) pure crystalline product, additionally. IR spectrum in methylene chloride: 3500, 1800, 1745, 1730, 1510 and 1210 cm-1.
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:36]=[CH:35][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[C:29]1([CH:26]([N:23]2[CH2:22][CH2:21][CH:20]([C:18](=[O:19])[C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:36][CH:35]=3)[CH2:25][CH2:24]2)[CH2:27][N:5]2[C:4](=[O:8])[N:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]3=[N:1][C:6]2=[O:7])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(CO)c2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(C(Cn2c(=O)nc3n(c2=O)CCCC3)c2ccccc2)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione obtained in Example 1-1) and 4-(4-fluorobenzoyl)-1-(1-phenyl-2-hydroxyethyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)=[O:16])=[CH:22][CH:21]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 320 mg of ethyl 4-hydroxy-6-methoxy-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1204 (1946)) and 1.0 mL of 4-chlorobenzylamine is stirred for 1 h at 210° C. The mixture is cooled to 25° C. and it is diluted with 2.0 mL of toluene. The mixture is filtered and the filtrant is dissolved in a minimum volume of refluxing glacial acetic acid. The hot solution is treated with distilled water dropwise until it becomes cloudy, and it is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with a small amount of dilute aqueous acetic acid. It is dried in a stream of air and then it is dissolved in 7 mL of refluxing acetonitrile. The solution is allowed to cool to 25° C. and after an additional 2 h the precipitate is collected by filtration. The solid is dried for 48 h at torr and 85° C. This procedure gives the title compound as 64 mg of a light tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C@H:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].[C:40]1(=[O:47])[O:46][C:44](=[O:45])[CH2:43][CH2:42][CH2:41]1>>[C:40]([O:21][C@@H:13]([CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH:22][C:23](=[O:39])[CH2:24][CH:25]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[O:32][C:33]3[C:38]2=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:7]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]
Reactant: CC(C)(C)c1ccc(CC[C@H](O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C1CCCC(=O)O1
Product: CC(C)(C)c1ccc(CC[C@@H](CC2CCCCC2)OC(=O)CCCC(=O)O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21

Procedure:
Following a procedure similar to that described in Example 56, but using (S)-N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 102) and glutaric anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a foam-like material.