Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[Cl:12].C(=O)([O-])[O-:15].[K+].[K+].OO>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH2:11])=[O:15])=[CH:6][C:5]=1[Cl:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C#N)cc1Cl
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 498 %

Procedure:
A mixture of 2-chloro-4-cyano benzoic acid methyl ester (12.4 g, 63.4 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in dimethylsulfoxide (40 mL) was treated dropwise under cooling with 30% hydrogen peroxide (7.6 mL). The mixture was allowed to warm to room temperature and stirred overnight. The solution was quenched with water and the resulting precipitate collected by filtration. The crude material was dissolved in dichloromethane and absorbed on a silica gel Merck-60 flash column. Elution with a dichloromethane-methanol gradient (from 98:2 to 90:10) provided the title compound (10 g) as a white solid, m.p. 154-156° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[CH2:2][CH3:3].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14]>>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]([C:7]2[S:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:8]=2)[OH:14])[CH:15]=[CH:16][CH:17]=1
Reactant: CCCc1ccsc1
Reactant: O=Cc1cccc(Br)c1
Product: CCCc1csc(C(O)c2cccc(Br)c2)c1

Procedure:
3-n-Propylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 7-(1) to give 3-bromophenyl-4-n-propyl-2-thienyl methanol. APCI-Mass m/Z 293/295 (M+H−H2O).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:51])([F:50])[CH2:47][CH2:48][NH2:49]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:49][CH2:48][CH2:47][C:46]([F:51])([F:50])[F:45])[CH3:14])=[O:43])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:18][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)F
Product: C[C@H](OC(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester and 3,3,3-trifluoropropylamine, the title compound was prepared in the same manner as described for example 5c. Colorless, waxy solid (94%). MS: m/e=570(M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]2[O:18][C:9]3[CH:10]=[CH:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:8]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ccccc2c1-c1cccc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cccc2c1oc1ccc3ccccc3c12
Yield: 104.3 %

Procedure:
In a 300-mL recovery flask were put 3.1 g (11 mmol) of 1-(3-chloro-2-fluorophenyl)-2-naphthol, 70 mL of N-methyl-2-pyrrolidone, and 4.2 g (31 mmol) of potassium carbonate, and this mixture was stirred at 150° C. in air for 7 hours. After stirring, about 50 mL of water and about 50 mL of hydrochloric acid (1.0 mol/L) were added to the resulting mixture. To the resulting solution was added about 100 mL of ethyl acetate; then, the aqueous layer was subjected to extraction with ethyl acetate three times. The solution of the extract combined with the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and magnesium sulfate was then added. The mixture was gravity-filtered, and the resulting filtrate was concentrated to give 2.9 g of a pale brown solid of a target substance in a yield of over 99%.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH3:5].Cl[C:7]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:8].[Cl-].[NH4+]>C1COCC1>[O:8]=[C:7]([CH2:3][CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(=O)CCCC(=O)OC
Reaction time: 0.17 h

Procedure:
2.82 g of magnesium is introduced into a 250 ml reaction vessel under a nitrogen atmosphere. It is covered with THF and 1 ml of 1-bromopropane is poured in. When the reaction starts, a solution of 9.9 ml of 1-bromopropane in 150 ml of THF is added dropwise over 1.5 hours. Once addition is complete, agitation is carried out for 10 minutes, then the reaction medium is taken to reflux for 3 hours followed by bringing to a temperature of -80° C. A solution of 17 ml of methyl 4-(chloroformyl)butyrate is added very slowly over 45 minutes. Agitation is then carried out for 1 hour at -70° C., then the reaction medium is allowed to return very slowly to 18° C. (over 17 hours). The reaction medium is treated by adding 160 ml of a saturated aqueous solution of ammonium chloride. Agitation is carried out for 30 minutes followed by decanting and re-extraction of the aqueous phase with 100 ml of ether. The organic phases are concentrated. The residue is taken up in 200 ml of ether, then washed twice with 100 ml of water followed by drying over magnesium sulphate and concentration with a rotary evaporator. In this way, 20.2 g of an oil corresponding to the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[NH:40]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:28]2[C:35]3[C:34](=[C:33]([F:32])[CH:38]=[C:37]([CH3:39])[CH:36]=3)[NH:40][CH:29]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)c(F)c1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CC=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OC)cc1)[C@H](c1ccc(Cl)cc1)c1c[nH]c2c(F)cc(C)cc12

Procedure:
An acetic acid solution (10 ml) of methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-β-alaninate, INTERMEDIATE 4, (757 mg, 1.76 mmol), ZnCl2 (3.1 M in AcOH, 1.7 ml, 5.27 mol) and 2-fluoro-4-methylphenylhydrazine hydrochloride (374 mg, 2.1 mmol) was heated at 80° C. for 45 minutes. The solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water (2×), brine (2×) and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. Data for the major diastereomer: 1H NMR (500 MHz, CD3CN): δ 9.11 (s, 1H); 7.54 (d, J=8.2 Hz, 2H); 7.48 (d, J=8.5 Hz, 2H); 7.38 (d, J=8.2 Hz, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.15 (d, J=2.5 Hz, 1H); 7.11 (s, 1H); 7.02-6.97 (m, 1H); 6.59 (d, J=12.3 Hz, 1H); 4.49 (d, 11.6 Hz, 1H); 3.60 (s, 3H); 3.56-3.48 (m, 3H); 2.52 (t, J=6.8 Hz, 2H); 2.32 (s, 3H); 1.49-1.35 (m, 2H); 1.04-0.90 (m, 2H); 0.69 (t, J=7.4 Hz, 3H). LC1=3.94 min. (M+H)=535. Chiral LC1 (1% to 15% EtOH/heptane over 25 min, 15% EtOH/heptane isocratic >25 min) retention time 28.38 minutes. The material also contains ca 2% by area of the enantiomer. Chiral LC1 (1% to 15% EtOH/beptane over 25 min, 15% EtOH/heptane isocratic >25 min) retention time 26.88 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([N:17]1[CH2:21][CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:21]1)=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C1
Yield: 23.7 %

Procedure:
2-Hydroxybenzaldehyde (25; 1.2 g, 9.8 mmol), N-Boc-3-(methylsulfonyloxy)pyrrolidine (29; 2.6 g, 9.8 mmol), K2CO3 (2.0 g, 14.7 mmol) and tetrabutyl ammonium iodide (300 mg, cat) in CH2Cl2 (20 mL) was stirred at 70-80° C. for 18 h. DMF was removed by concentration under reduced pressure. The resulting residue was diluted with EtOAc (100 mL), washed with water (50 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane:EtOAc=1:10) to afford 676 mg of tert-butyl 3-(2-formylphenoxy)pyrrolidine-1-carboxylate 30 as an oil (yield: 23%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:13]([OH:17])[CH2:14]NC)[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10].C[O:19]C1C=CC=C(OC)C=1O.O=CC(Cl)(Cl)Cl.COC1C=C(C(O)C(Cl)(Cl)Cl)C=C(OC)C=1O>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:13]([CH:14]=[O:19])=[O:17])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10]
Reactant: CNCC(O)c1cc(OC)c(O)c(OC)c1
Reactant: COc1cccc(OC)c1O
Agent: COc1cc(C(O)C(Cl)(Cl)Cl)cc(OC)c1O
Agent: Cl
Agent: O=CC(Cl)(Cl)Cl
Product: COc1cc(C(=O)C=O)cc(OC)c1O

Procedure:
A process for preparing 1-(3,5-dimethoxy-4-hydroxy phenyl)-2-(N-methylamino) ethanol hydrochloride is described by reacting 2,6-dimethoxyphenol with anhydrous chloral in the presence of a catalyst, hydrolyzing 1-(3,5-dimethoxy-4-hydroxyphenyl)2,2,2-trichloro ethanol and subsequently isolating the 3,5-dimethoxy-4-hydroxyphenyl glyoxal thus obtained; finally, this compound, in the form of the bisulfite, is directly converted to the desired product by amination with methylamine in the presence of hydrogen with a hydrogenation catalyst and the final product is converted into the hydrochloride.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])=[O:7])C[CH2:2]1.[Cl-].C(O)(=O)CCC=C.CN1CCOCC1.C([Li])CCC.CCCCCC.CC([C@H]1COC(=O)N1)C.[NH4+].[Cl-]>C1COCC1.O>[CH3:15][CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6](=[O:7])[CH2:5][CH2:4][CH:1]=[CH2:2])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CCC1CC1
Agent: C=CCCC(=O)O
Agent: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(3-Cyclopropyl-1-oxopropyl)-4(S)-(1-methylethyl)-2-oxazolidinone: A solution of mixed anhydride was prepared by adding, under N2, pivoloyl chloride (14.8 mL, 120 mmol) over a period of 5 min to a cooled solution (0°) of 4-pentenoic acid (12.3 mL, 120 mmol) and N-methylmorpholine (15.4 mL, 140 mmol). The mixture was stirred at 0° for 30 min. Meanwhile, a second solution was prepared by adding dropwise under N2 a 1.4M solution of butyllithium in hexane (71 mL, 100 mmol) to a stirred cooled solution (-78°) of (S)-4-(1-methylethyl)-2-oxazolidinone (12.9 g, 100 mmol) in dry THF (300 mL) over a period of 45 min. (Note: The agitation was done by an overhead stirrer.) After stirring for 15 min at -78°, the latter solution was added by cannulation to the stirred solution of the mixed anhydride at -78° over a period of 20 min. The mixture was stirred for an additional 30 min at the same temperature. A saturated aqueous solution of NH4Cl (50 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with H2O (300 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and evaporated to dryness under reduced pressure to give an oily residue [i.e. 4(S)-(1-methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone].
Reaction SMILES: [OH-].[NH4+].Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[C:16]([O-:47])(=[O:46])[CH2:17][CH2:18][C@H:19]([NH:23][C:24]([C:26]1[CH:45]=[CH:44][C:29]([NH:30][CH2:31][C:32]2[CH2:33][NH:34][C:35]3[N:36]=[C:37]([NH:39][C:40]([C:42]=3[N:43]=2)=[O:41])[NH2:38])=[CH:28][CH:27]=1)=[O:25])[C:20]([OH:22])=[O:21].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>O>[C:16]([OH:47])(=[O:46])[CH2:17][CH2:18][C@H:19]([NH:23][C:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][CH2:31][CH:32]2[NH:43][C:42]3[C:40](=[O:41])[NH:39][C:37]([NH2:38])=[N:36][C:35]=3[NH:34][CH2:33]2)=[CH:44][CH:45]=1)=[O:25])[C:20]([OH:22])=[O:21]
Reactant: Nc1nc2c(c(=O)[nH]1)N=C(CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1)CN2
Agent: Cl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Reaction time: 1 h

Procedure:
In the second step, the recovered solid is suspended in water (100 mL) and concentrated ammonium hydroxide (7.2 mL) is added to dissolve the solid and attain a pH of 8.6. The pH of this solution is adjusted to 7.5 by the addition of 6N hydrochloric acid (9 mL). To this solution is added glucose dehydrogenase (20 mg), dihydrofolate reductase (7 mg), NADP (280 mg), glucose (6 g) and water (40 mL). This solution is allowed to stir under N2 for 1 hour. After this time glucose dehydrogenase (16 mg), dihydrofolate reductase (8 mg) and water (20 mL) is added. This solution is allowed to stir for 3.5 hours. The pH of this solution is maintained at 7.5 by the intermittent addition of concentrated ammonium hydroxide. Concentrated hydrochloric acid (9.5 mL) is added to the solution in order to attain a pH of 2.9. The precipitate formed is isolated by centrifugation or other suitable means. The solid is suspended in water (100 mL) and isolated by vacuum filtration. The solid is dried in vacuo at 40° C. overnight to give 5.037 grams of crude tetrahydrofolic acid.
Reaction SMILES: C([NH:8][C:9]1[C:10](=[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]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(OC(C)(C)C)=O.Cl.C(OCC)(=O)C.CO.C([Cl:45])(=O)C>C(OCC)(=O)C>[ClH:45].[CH2:26]([O:25][C:22]1[CH:21]=[C:10]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C:9]([NH2:8])=[CH:24][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 86 %

Procedure:
N-Boc-5-benzyloxyanthranilic acid, benzyl ester (70 g, 161 mmol) was added to a 1.4 M HCl/ethyl acetate solution (prepared by the addition of methanol to acetyl chloride and subsequent dilution with ethyl acetate). The reaction mixture was stirred at room temperature for 21 hours. After cooling to 0° C., the reaction was gently stirred for an additional 2 hours. The crystalline product was filtered off and washed with 50 ml of cold ethyl acetate. Trace solvents were removed under high vacuum to yield 5-benzyloxyanthranilic acid, benzyl ester, hydrochloride (53.4 g, 86% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1.CCN(CC)CC.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([NH:1][CH2:2][C:3]1[NH:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(CN)NC2=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
tert-Butyl 2-(aminomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (1E) in CH2Cl2 (150 mg, 0.05 M), prepared by the procedure of Example 1, was added Et3N and acetyl chloride at −45° C. The reaction was complete after 20 minutes at −30° C. as determined by LCMS analysis, and then partitioned between ethyl acetate and water. The organics were subsequently washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was passed thorough a pad of silica to afford the tert-butyl 2-(acetamidomethyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (2A, 87%).
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[CH2:6]1)[CH2:3][CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C1COCC1>[CH2:3]([CH:2]1[NH:1][C:31](=[O:32])[C:30]([OH:36])=[C:6]2[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]2=[O:19])[CH3:4]
Reactant: CCC(N)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1NC(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of 4-(1-aminopropyl)-1-(4-fluorobenzyl)piperidin-2-one (2.0 g, 8 mmol) in anhydrous THF (20 mL) was added LiHMDS (1M in THF, 18.9 mL, 18.9 mmol) under an atmosphere of nitrogen. After stirring at −78° C. for 5 min, diethyl oxalate (3.32 g, 22.7 mmol) was added to the reaction mixture. After stirring for 2 hours at −78° C., then for 0.5 hour at −20° C., LiHMDS (1M in THF, 22 mL, 22 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was quenched with 1N HCl. The mixture was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, concentrated under vacuum, then filtered through a plug of silica gel and eluting with 1% methanol in CH2Cl2. The diastereomers were separated using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compounds. Diastereomer 1, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.67 (br, 1H), 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.68 (d, J=14.7 Hz, 1H), 4.52 (d, J=14.7 Hz, 1H), 3.35 (m, 4H), 1.79 (m, 3H), 1.48 (m, 1H), 0.97 (t, J=7.3 Hz, 3H) ppm. ES MS M+1=319. Diastereomer 2, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.54 (br, 1H), 4.72 (d, J=14.7 Hz, 1H), 4.49 (d, J=14.7 Hz, 1H), 3.34 (m, 3H), 2.73 (dt, J=4, 13 Hz, 1H), 1.99 (m, 1H), 1.78 (m, 1H), 1.57 (m, 2H), 1.01 (t, J=7.5 Hz, 3H) ppm. ES MS M+1=319.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[N:6][C:7]=1[NH2:8].Cl.Br[C:12]([CH3:35])([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]23[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=O>O.C(O)C>[NH2:8][C:7]1[C:2]2[N:1]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]45[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]4)[CH2:23][CH2:22]5)=[CH:19][CH:20]=3)[C:12]([CH3:35])([CH3:34])[O:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: Nc1ncnc(O)c1N
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of 5,6-diaminopyrimidin-4-ol (280 mg, 2.2 mmol) in water (8 mL), absolute ethanol (25 mL) and 1M HCl (2.2 mL, 2.2 mmol) was added a solution of methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (Intermediate 9; 877 mg, 2.15 mmol) in absolute EtOH (80 mL). The solution was heated to 100° C. overnight then allowed to cool to ambient temperature, evaporated to dryness, and the residue treated with 2M NaOH to adjust the pH to 10. The resulting suspension was filtered to provide a yellow solid which was purified on a 12 g presearch silica cartridge dry loading on silica (2 g) and eluting with 0-2.5-5% MeOH-DCM to provide the title compound as a white solid (601 mg, 1.38 mmol, 64%) 1H NMR δ 1.59-1.63 (12H, m), 1.79-1.83 (6H, m), 2.16 (2H, s), 3.59 (3H, s), 6.91 (2H, s), 7.39 (2H, d), 7.64 (2H, d), 7.95 (1H, s); MS m/e MH+ 435.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:31])/[CH:12]=[CH:13]/[CH:14]=[C:15](/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)\[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH:33]=1>O1CCCC1>[F:30][C:26]1[CH:25]=[C:24](/[C:15](/[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(F)c2)c1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccc(F)c2)c1
Yield: 86.6 %

Procedure:
As in Example 134, a solution of (2E,4E)-5-(3-fluorophenyl)-5-(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.8 g) and 3-pyridinebutanamine (0.650 g) in tetrahydrofuran (20 mL) was stirred for 17 hours at room temperature. The crude amide, isolated in the usual fashion, was purified by HPLC (ethyl acetate) and then crystallized from ether-hexane to furnish 1.6 g of (2E,4E)-5-(3-fluorophenyl)-5-(3-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 55°-60° C. A sample was recrystallized from ethyl acetate-hexane to yield the analytical specimen, mp 58°-60° C. Anal. Calculated for C27H27FN2O2 : C, 75.33; H, 6.32; F, 4.41; N, 6.51 Found: C, 75.31; H, 6.34; F, 4.38; N, 6.47.
Reaction SMILES: [CH3:1]N(C)C=O.[NH2:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(OCC)(=O)C>[NH2:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:1])=[O:10]
Reactant: Nc1cc(Oc2ccccc2)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(Oc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide 5.0 mL solution of 2-amino-4-phenoxybenzoic acid 0.40 g were added potassium carbonate 0.29 g and dimethyl sulfate 0.20 mL, and it was stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, it was dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to give methyl 2-amino-4-phenoxybenzoate 0.33 g of colorless oil.