Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([OH:21])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:3]1.O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[C:33](O)(=O)[CH3:34]>C(O)C>[OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([O:21][CH2:33][CH3:34])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC(=O)C[C@@H]2C[C@H]1C(=O)O
Reactant: CC(=O)O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](O)CC[C@H]2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a −78° C. solution of (3S, 4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (6.88 g, 21.14 mmol)(see Preparation 2, Steps A and B, below and Scheme III, Step A generally) and cerium trichloride heptahydrate (7.9 g, 21.2 mmol) in absolute ethyl alcohol (90 mL), under nitrogen sodium borohydride (1.24 g, 32.73 mmol) was added in portions. The resulting mixture was slowly warmed up to room temperature over 5 hours. The reaction mixture was cooled down to 0° C. and acetic acid (50% in water, 25 mL) was carefully added. The resulting mixture was stirred for 1 hour at room temperature and the solvent was removed in vacuo. To the resulting material water and ethyl acetate were added and the phases separated. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated in vacuo. Flash chromatography (silicagel, 70% ethyl acetate/hexane) gave ethyl (3S, 4aS, 6S, 8aR) 6-hydroxy-2-tert -butoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (2.4 g, 35%) and the title compound (4.15 g, 60%)
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][C:12]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([CH:32]([C:36](Cl)=[O:37])[C:33](Cl)=[O:34])C.[OH-:39].[Na+]>ClCCl>[CH2:1]([O:8][N:9]([CH2:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][C:12]=1[O:21][CH3:22])[C:36](=[O:37])[CH2:32][C:33]([OH:34])=[O:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c(CNOCc2ccccc2)c(OC)c1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CC(=O)O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To a solution of O-benzyl-N-(2,4,6-trimethoxy-benzyl)hydroxylamine (2.0 g, 6.59 mmol) in dichloromethane (15 mL) was added triethylamine (1.0 mL, 7.25 mmol). The solution was cooled at 0° C. and ethyl malonyl chloride (0.85 mL, 6.59 mmol) was added. Precipitation was gradually formed. The resulting yellow slushy mixture was stirred at 0° C. for 15 min then brought up to rt and stirred for overnight. The solvent was removed under reduced pressure and the crude product was dissolved in EtOAc. The organic solution was consecutively washed with aq. 10% KHSO4 and aq. saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The crude material was stirred in H2O-THF (1:1 by volume, 30 mL) containing NaOH (1.32 g, 33 mmol) for 1 h. The reaction mixture was washed with EtOAc and the aqueous layer was acidified with aq. 10% KHSO4 solution. The product was extracted with EtOAc, dried over Na2SO4, and concentrated to give 1.62 g of 3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropanoic acid as a white solid (63% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([N:26]=[N+:27]=[N-:28])=[O:10])=[CH:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccoc1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)C=Cc1ccoc1
Temperature: 1 °C
Reaction time: 0.5 h

Procedure:
In an oven-dried three-necked flask were placed a mixture of 3-(furan-3-yl)prop-2-enoic acid (20.0 g, 145 mmol) and dry triethylamine (17.2 g, 171 mmol) in acetone (200 mL, dried over anhydrous MgSO4). The mixture was cooled to 0 to 2° C. To the cold mixture, isobutyl chloroformate (25.2 mL, 193 mmol) was added at 0° C. The mixture was stirred at 0 to 2° C. for 30 min, then a solution of sodium azide (14.0 g, 215 mmol) in water (60 mL) was added slowly at 0° C. The reaction mixture was stirred for 1 h at the same temperature. It was quenched with an ice-water (500 mL) and the title azide was extracted with toluene (4×100 mL), dried over an anhydrous sodium sulfate and filtered. The filtrate containing the crude title compound was used as such for the next reaction.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])N)=[N:6][CH:5]=1.[H-].[Na+].CI.C[N:20]([CH:22]=O)[CH3:21]>>[CH3:22][N:20]([CH3:21])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:14])=[O:2])=[CH:5][N:6]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1ccc(S(N)(=O)=O)nc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)cn1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
1st step: To a stirred solution of 6-sulfamoyl-nicotinic acid methyl ester (250 mg, 1.15 mmol) in DMF (10 mL) at 0° C. was added NaH (53 mg, 55%, 1.20 mmol). After 10 minutes, MeI (0.079 mL, 1.26 mL) was added. Stirring was continued for one hour before the reaction was quenched upon addition of H2O. The product was extracted with EtOAc, the combined organic layers were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/H, 1/2) afforded 51 mg of the title compound (19%) as a white solid.
Reaction SMILES: [CH2:1]([OH:5])[C@H:2]([OH:4])[CH3:3].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH3:33][S:34]([O:4][C@H:2]([CH3:3])[CH2:1][O:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:36])=[O:35]
Reactant: C[C@@H](O)CO
Reactant: CS(=O)(=O)Cl
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of (R)-propane-1,2-diol (2.82 g, 37.1 mmol) and trityl chloride (10.5 g, 37.7 mmol) in DCM (100 mL) at 0° C., dimethylaminopyridine (53 mg, 0.43 mmol) was added followed by dropwise addition of triethylamine (13.0 mL, 93.3 mmol). The solution was allowed to warm to room temperature, stirred overnight, and re-cooled to 0° C. Methanesulfonyl chloride (3.2 mL, 41.2 mmol) was added to the reaction, and the mixture was stirred for 4 h at 0° C. The reaction was quenched (50 mL 1N HCl), and the layers were separated. The organic phase was washed (50 mL 1N HCl and 50 mL brine), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified on a silica gel column to give (R)-1-(trityloxy)propan-2-yl methanesulfonate (13.1 g) as a thick oil which solidified over time. 1H NMR (DMSO-d6): δ 7.50-7.20 (m, 15H), 4.85 (m, 1H), 3.34 (s, 3H), 3.12 (m, 2H), 1.28 (d, 3H).
Reaction SMILES: [N:1]([C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@H:4]([CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18](=[O:19])[C:17]2[N:16]([CH3:20])[CH:15]=[N:14][C:13]=2[N:12]([CH3:21])[C:10]1=[O:11]
Reactant: C[C@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O

Procedure:
A solution of the (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (620 mg) in ethanol (25 ml) was hydrogenated at 70 psi of hydrogen gas in presence of 10% palladium on carbon (150 mg) for 12 hours. After filtration to remove the catalyst, the filtrate was concentrated under reduced pressure to provide (R)-1-(5-aminohexyl)-3,7-dimethylxanthine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH2:16][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (500 mg, 1.3 mmol) in methylene chloride at room temperature, triethylamine (0.44 mL, 3.2 mmol) and 2-chloroethylsulfonyl chloride (0.168 mL, 1.6 mmol) were added. The reaction mixture was stirred for 30 min. Removed the solvent, the residue was purified by combiflash to give the title compound (150 mg, 75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Combine 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) and water (100 mL). Add sodium carbonate (6.84 g, 64 mmol) and N-carbethoxyphthalimide (14.0 g, 64 mmol). After 1.5 hours, extract the reaction mixture with ethyl acetate (100 mL). Cool the aqueous layer in an ice bath and acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give 6-phthalimidohexanoic acid (12.7 g, 80% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CS(O[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH:27]=[CH2:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH:27]=[CH2:28]
Reactant: C=CCC1CCCCC1OS(C)(=O)=O
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCC1CCCCC1Nc1ccc(CCC(=O)OCC)cc1

Procedure:
A mixture of 5.0 g. of ethyl 4-aminohydrocinnamate, 10.0 g. of 1-methanesulfonyloxy-2-allylcyclohexane (prepared by the method of Example 189), 4.2 g. of anhydrous powdered potassium carbonate and 40 ml. hexamethylphosphoramide is heated to 80 for 17 hours. The mixture is then cooled, diluted with water and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from ethanol yielding the title compound as white crystals.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@H:14]2[C:18]([OH:20])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@H:14]2[C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CCc2ccccc21)C1SCN[C@H]1C(=O)O
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(CC1CCc2ccccc21)C1SCN[C@H]1C(=O)N1CCCC1
Yield: 44 %

Procedure:
Colorless crystals of 1-[3-(2-indanylacetyl)-D-thioprolyl]pyrrolidine were prepared in the same manner as in Example 1, except that 3-(2-indanylacetyl)-D-thioproline prepared in Reference Example 26 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 44%).
Reaction SMILES: COC(=O)CC[CH2:6][CH2:7][CH2:8][CH:9]=[C:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15].Cl.[C:18](=O)(O)[O-].[Na+].[C:23]([O:26][CH2:27]C)(=[O:25])[CH3:24]>CO>[CH3:27][O:26][C:23](=[O:25])[CH2:24][CH2:6][CH2:7][CH2:8][CH:9]([C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)[CH3:18]
Reactant: COC(=O)CCCCCC=C1CCCC1=O
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCC(C)C1=CCCC1=O

Procedure:
To a solution of 6-(2-oxo-cyclopentylidene)-heptanoic acid methyl ester obtained in Step B in methanol (1000 mL) was added concentrated hydrochloric acid (100 mL) and the reaction was heated at reflux for 20 h. The reaction mixture was cooled and was diluted with ethyl acetate. The organic solution was neutralized with aqueous sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated. Purification by distillation (145-155° C. at about 0.2 mmHg) provided 40 g of the title compound of Step C. 1H NMR (CDCl3, 250 MHz) d 7.28 (m, 1H), 3.65 (s, 3H), 2.54 (t, 2H), 2.38 (m, 2H), 2.28 (t, 2H), 2.14 (m, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.31 (m, 4H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O1CCCC1.C([Li])CCC.O[CH:38]1[CH2:42][C:41]2[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=2[O:39]1>CCCCCC>[CH2:42]([C:41]1[C:43]([Cl:48])=[C:44]([Cl:47])[CH:45]=[CH:46][C:40]=1[OH:39])[CH:38]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1Cc2c(ccc(Cl)c2Cl)O1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC=CCc1c(O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Twenty-five grams of n-hexyltriphenylphosphonium bromide were dissolved in 350 ml. of dry tetrahydrofuran and cooled to -10° C. To the solution were added 37 ml. of a 1.6M solution of n-butyllithium in hexane. The solution was slowly warmed to room temperature and stirred for one hour. The solution was then cooled to 0° C. and a solution of 2.38 g. of 2,3- dihydro-2-hydroxy-4,5-dichlorobenzofuran in 20 ml. of tetrahydrofuran was added. The reaction was allowed to reflux for approximately 18 hours. The solution was then cooled and evaporated to dryness. Ethyl acetate and water were added and the pH was adjusted to 2.5. The layers were separated. The organic layer was washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness. The residue was purified by high pressure liquid chromatography giving 2.51 g. of the desired intermediate as a mixture of cis and trans isomers.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and p-anisaldehyde (0.27 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.51 g, in 93% yield, mp: 209.0° C. 1H NMR (CD3OD) δ 8.23 (s, 1H), 7.82 (d, 2H), 7.76 (d, 2H), 6.97 (d, 2H), 6.87 (d, 2H), 3.82 (s, 3H). 13C NMR (CD3OD) δ 166.8, 163.2, 162.7, 149.8, 130.8, 130.4, 128.2, 124.8, 116.3, 115.2, 55.9.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][Br:10])(=[O:3])[CH3:2].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[Br-:10].[C:1]([NH:4][C:5]([CH2:6][CH2:7][CH2:8][CH2:9][P+:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)NC(=O)CCCCBr
Solvent: Cc1ccccc1C
Product: CC(=O)NC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of 50.5 g. (0.227 mole) of N-acetyl-5-bromovaleramide and 64.6 g. (0.274 mole) of triphenylphosphine in 250 ml. of xylene was heated at reflux under nitrogen for 4 hours then was let cool to room temperature. The xylene was decanted from the resulting oil which was recyrstallized from methylene chloride:ethyl acetate to afford colorless needles of [4-(acetylaminocarbonyl)butyl]triphenylphosphonium bromide weighing 50.2 g. (45.7% yield) melting at 164°-165°.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[C:14]1([N:20]2[CH2:24][C:23]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[O:22][C:21]2=[O:30])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:27]3[CH2:26][CH2:25][C:23]4([O:22][C:21](=[O:30])[N:20]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:24]4)[CH2:29][CH2:28]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: O=C1OC2(CCNCC2)CN1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)CN(c3ccccc3)C(=O)O4)nn2)n1

Procedure:
The object product (72 mg, 29%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (130 mg), 3-phenyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one (142 mg) and potassium carbonate (127 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16]C(OC(C)(C)C)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of 3.21 g 3-tert-butoxycarbonylamino-pyrrolidine-1-carboxylic acid benzyl ester in 40 ml dichloromethane were added 13 ml TFA. After 16 h the solution was evaporated to give the crude hydrotrifluoroacetate. Yield: 3.20 g.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:24]([C:23](=[O:32])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:1]
Reactant: CCCCCCCCC(=O)Cl
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)CCCCCCCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (133.7 mL of a 2.0 M solution, 0.267 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (24.73 g, 0.126 mol) is dissolved in THF (40 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of nonanoyl chloride (21.88 g, 0.119 mol) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (60 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [I:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[H-].[Na+].[CH3:14]I.O>C1COCC1>[I:1][C:2]1[C:3](=[O:11])[N:4]([CH3:14])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])cc(I)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-iodo-5-nitropyridin-2-ol (2.66 g, 10.0 mmol) in THF (30 mL) was cooled to −20° C. NaH (60% dispersion in mineral oil, 0.600 g, 15.0 mmol) was added cautiously in three portions. After being stirred for 30 min at this temperature, methyl iodide (6.23 mL, 100.0 mmol) was added dropwise through a syringe. The resulting mixture was allowed to warm to rt during a 30 min period. Stirring was continued for 18 h at rt. Water (15 mL) was added with caution to quench the reaction. THF was removed under reduced pressure and methylene chloride (80 mL) was added to the aqueous phase. Layers were separated and the aqueous phase was extracted with methylene chloride (2×50 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford the desired product as a yellow crystalline solid. 1H-NMR (CDCl3, 400 MHz): δ=3.73 (s, 3H), 8.65 (d, J=2.8 Hz, 1H), 8.74 (d, J=2.8 Hz, 1H). MS (ES+): m/z 280.96 [MH+]. HPLC: tR=2.55 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7](Br)[CH:6]=1)[CH3:2].C(O[C:21](=[O:34])[C:22]1[CH:27]=[C:26](Br)[C:25](OCOC)=[C:24](Br)[CH:23]=1)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([CH:35]=[O:42])[CH:37]=2)[C:8]([O:12][CH2:13][O:14][CH3:15])=[C:7]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:21]=[O:34])[CH:27]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(Br)c1
Reactant: CCOC(=O)c1cc(Br)c(OCOC)c(I)c1
Reactant: O=Cc1ccccc1
Product: CCOC(=O)c1cc(-c2cccc(C=O)c2)c(OCOC)c(-c2cccc(C=O)c2)c1

Procedure:
3,5-Bis-(3-formylphenyl)4-methoxymethoxybenzoic acid ethyl ester was prepared as a white solid (980 mg, 13.7%) in a similar manner to Step 1 of Example 143 from a 2:1 mixture of 3-bromo-4-methoxymethoxy-5-iodobenzoic acid ethyl ester and 3,5-dibromo-4-methoxymethoxybenzoic acid ethyl ester. There also yielded 1.6 g of a mixture of benzaldehyde and the starting halogenated compound, and 1.4 g, 20.7% of the monoarylated material as a white solid. Bis-arylated compound: 1H NMR (CDCl3) 8 1.38 (t, J=7.36 Hz, 3H); 2.59 (s, 3H); 4.33-4.42 (m, 4H); 7.62 (t, J=7.36 Hz, 2H);