Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CN(C=O)C.O>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][CH2:22][P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=P(CCCOC1CCCCO1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dibenzyl phosphite (1.70 mL, 7.63 mmol) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.381 g, 9.53 mmol) in dry DMF (11.4 mL) at 25° C. under N2. After 15 min 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.29 mL, 7.63 mmol) was added and the mixture was stirred at 25° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to afford dibenzyl [3-(tetrahydro-2H-pyran-2-yloxy)propyl]phosphonate. Rf=0.06 (20% EtOAc/hexanes). LCMS calc.=427.17; found=427.15 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:16][O:17][CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40]S(C3C=CC(OC4CCOCC4)=CC=3)(=O)=O)[C:31]([N:33]3[CH2:38][CH2:37][CH:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1>>[NH2:19][C:20]1[C:25]2[CH:26]=[C:27]([CH2:29][CH:30]([NH:40][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH:4]([CH2:16][O:17][CH3:18])[CH2:3][O:2][CH3:1])=[CH:7][CH:8]=3)(=[O:14])=[O:13])[C:31]([N:33]3[CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH2:38]3)=[O:32])[S:28][C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: CC1CCN(C(=O)C(Cc2cc3c(N)nccc3s2)NS(=O)(=O)c2ccc(OC3CCOCC3)cc2)CC1
Reactant: COCC(COC)Oc1ccc(S(=O)(=O)Cl)cc1
Product: COCC(COC)Oc1ccc(S(=O)(=O)NC(Cc2cc3c(N)nccc3s2)C(=O)N2CCC(C)CC2)cc1

Procedure:
This compound was prepared from 0.75 mmol of 4-(2-methoxy-1-methoxymethyl-ethoxy)-benzenesulfonyl chloride and 210 mg (0.5 mmol) of 30a using the procedure described for 58c. Yield: 120 mg (oil), EI-MS: 576 (M+).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C1COCC1>[CH3:24][N:25]([CH3:39])[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH:29]([CH:2]=[O:3])[CH2:28][CH2:27]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
Tert-BuOK (8.41 g, 75 mmol) dissolved in abs. THF (100 mL) was added in drops to a solution of (methoxymethyl)triphenyl phosphonium chloride (25.7 g, 75.0 mmol) in abs. THF (100 mL) at 0° C. in argon. The resulting red solution was mixed after 30 min at 0° C. with a solution of 4-dimethylamino-4-phenyl cyclohexanone (10.9 g, 50.0 mmol) in abs. THF (100 mL) and stirred overnight at RT. The solvent was removed in a vacuum, the residue mixed with 1N sulphuric acid (150 mL) and stirred for 2 h. The precipitate precipitated out during this was separated and the filtrate (pH 1) washed with ether (6×100 mL). The aqueous solution was adjusted to pH 11 with 5N NaOH and extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [CH2:1]([C@@:4]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:36]CC1>C1COCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C@:4]2([CH2:1][CH2:2][CH2:3][OH:36])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:26][CH:27]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OCC(F)(F)F)cc2)C(=O)O1
Agent: B
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (500 mg, 1.6 mmol) in THF (20 mL) was added BH3/THF (1 M, 3.2 mL) at 0° C. The mixture was stirred at rt for 2 h. The mixture was quenched with H2O (2.5 mL) at 0° C., then NaOH (3 M, 1.1 mL) and 30% H2O2 (2.5 mL) were added. After stirring at rt for another 2 h, 1N HCl was added to the mixture. The mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (320 mg, 62%).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].COCCOC.C1(C)C=CC(S(O[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[C:26]#[N:27])(=O)=O)=CC=1>CO.O>[CH2:1]([S:5][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)[C:26]#[N:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: CCCCSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Butylmercaptan (105 mg) was dissolved in 1 ml of methanol, and 0.4 ml of a 2.7 M methanol solution of sodium methoxide was added at room temperature. The solution was added dropwise to 2 ml of a 1,2-dimethoxyethane solution of 391 mg of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile in an argon atmosphere under ice cooling. The mixture was stirred for 1 hour under ice cooling, and 20 ml of water was added. The mixture was extracted with 20 ml of methylene chloride three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; benzene) to afford 95 mg (yield 31%) of alpha-(butylthio)(m-benzoylphenyl)acetonitrile as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:21])=[O:20])[C:9](=[O:11])[CH:10]=1)=[O:5])C.[CH2:23]([CH2:25][NH2:26])[OH:24]>C(O)C>[OH:24][CH2:23][CH2:25][NH:26][C:4]([C:6]1[NH:7][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([OH:22])(=[O:20])=[O:21])[C:9](=[O:11])[CH:10]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Solvent: CCO
Product: O=C(NCCO)c1cc(=O)n(Cc2ccccc2S(=O)(=O)O)[nH]1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
14.5 g of Intermediate A and 15.3 g of ethanolamine were mixed and made to react with each other over a period of 2 hours under a pressure reduced to 30 mm Hg inside the reaction container and a temperature kept at 120° C. outside the reaction container. After cooling to room temperature, the reaction product was dissolved in 30 ml of ethanol, and separated out in a crystallized condition upon addition of 300 ml of isopropanol. After filtration, the crystals were washed with isopropanol, and dried. Thus, 13 g (yield: 86.5%) of Intermediate C was obtained. Melting Point: 215°-219° C. (decomposed).
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[CH3:16][O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][N:12]3[C:5]4[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=4[C:3]([CH3:13])=[C:2]3[CH3:1])=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Cn3c(C)c(C)c4c(=O)n(C)ncc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (1.06 g) in DMF (90 ml) was dripped into a suspension of 60% sodium hydride-oil (288 mg) in DMF (24 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-methoxybenzoyl)benzyl bromide (2.40 g) in DMF (30 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1-1:2) to provide the title compound as light-yellow powder (1.70 g, yield 71%).
Reaction SMILES: C([N:5]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:10]1)[C:6](=[O:8])[CH3:7])CCC.C1(N(C2CCN(CCC(C3C=CC(Cl)=C(Cl)C=3)CN(C)C(=O)C3C=CC=CC=3)CC2)C(=O)C)CCCCC1.ClC1C=C(C(CCN2CCC(N(CCCCCC)C(=O)C)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(C)C(=O)C)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.C(N(C1CCN(CCC(C2C=CC(Cl)=C(Cl)C=2)CN(C)C(=O)C2C=CC=CC=2)CC1)C(=O)C)C=C.ClC1C=C(C(CCN2CCC(N(CCC)C(=O)C)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(C(C)C)C(=O)C)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(=O)CC)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(=O)CCC)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(=O)C(C)C)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(=O)C(F)(F)F)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(NC)=O)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C(N(C)C)=O)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl.ClC1C=C(C(CCN2CCC(N(CC)C=O)CC2)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl>>[C:6]([NH:5][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:18][N:19]([CH3:28])[C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: CCCCN(C(C)=O)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: C=CCN(C(C)=O)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)N(C(C)C)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)N(C)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Product: CC(=O)NC1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-[4-(H-ethylacetamido)-piperidino]butyl]-H-methylbenzamide; N-[4-[4-(N-Butylacetamido)-piperidino]-2-(3,4-dichloro-phenyl)butyl]-N-methylbenzamide; N-[4-[4-(N-Cyclohexylacetamido)piperidino]-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-hexylacetamido)-piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-methylacetamido)-piperidino]butyl]-N-methylbenzamide; N-[4-[4-(N-Allylacetamido)-piperidino]-2-(3,4-dichloro-phenyl)butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-propylacetamido)-piperidino]-butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-isopropylacetamido)piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethylpropionamido)piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethylbutyramido)-piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethylisobutyramido)-piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethyltrifluoroacetamido)piperidino]-butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethyl-N'-methylureido)-piperidino]butyl]-N-methylbenzamide; N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethyl-N',N'-dimethyl-ureido)piperidino]butyl]-N-methylbenzamide; or N-[2-(3,4-Dichlorophenyl)-4-[4-(N-ethylformamido)-piperidino]butyl]-N-methylbenzamide; in either the racemic form or as the (S)-enantiomeror;
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH:12](P(OCC)(OCC)=O)[CH3:13])=[O:11].[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)=O>C1(C)C=CC=CC=1>[Br:31][C:27]1[CH:26]=[C:25]([C:23]([CH3:22])=[C:12]([CH3:13])[C:10]([O:9][CH2:8][CH3:7])=[O:11])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=C(C)c1cccc(Br)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a suspension of potassium tert-butoxide (183.1 g, 1.63 mol) in toluene (1400 ml) under an atmosphere of nitrogen was slowly added triethyl 2-phosponopropionate (361.1 g, 1.52 mol) with ice cooling at such a rate that the internal temperature was maintained at approximately 20° C. The resultant yellow solution was stirred at room temperature for 3 h after which time it was cooled in an ice bath. To this cooled solution was added a solution of 3-bromoacetophenone (274.2 g, 1.38 mol) in toluene (400 ml) at such a rate that the internal temperature did not rise above 20 ° C. The resultant red-brown solution was then stirred at room temperature for 18 h. After this time, more potassium tert-butoxide (38.7 g, 0.34 mol) was added, and the resultant mixture was stirred at room temperature for an additional 20 h. The reaction was quenched by the cautious addition of water (2000 ml), and the layers were separated. The organic layer was washed with water (4×2000 ml), and was then concentrated in vacuo to give the crude product as a brown oil (344 g) which was distilled under reduced pressure to give the impure title compound (2:3 mixture of geometric isomers) as a colourless liquid (212 g) which was contaminated with small amounts of triethyl 2-phosphonopropionate and 3-bromoacetophenone. In the present synthetic route the impure title compound was taken forward into the next step without any further purification. However, purification, for example using flash chromatography eluting with 5% ethyl acetate in hexane, affords the analytically pure title compound as a clear colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][CH3:31])=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1C(=O)C(CC(=O)OC(C)(C)C)SC12CCC(=CCC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 7 ml of N,N-dimethylformamide was added 0.70 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.14 ml of ethyl iodide and 0.25 g of anhydrous potassium carbonate at 0-5° C., the resulting mixture was stirred at ambient temperature for 3 hours. The resulting mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.70 g of ethyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate was obtained as a light yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13](O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCO
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
90.05 g of 3,4-dichlorophenylacetic acid was dissolved in 150 ml of ethanol, and the solution was treated according to the procedure of Example 5 to obtain 101.30 g (90.0% yield) of the title substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
In the drybox, 20.0 mg (0.0876 mmol) of (Me2CH)PH(O)(2,4-(MeO)2C6H3) from Experiment 3, 20 mg (0.0218 mm) of Pd2 (dba)3 and 5.0 mL of 1,4-dioxane were loaded into a reactor (20 ml) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 143.0 mg (1.0 mm) of 4-chloroanisole, 228 mg (1.5 mm) of 4-MeOC6H4B(OH)2 and 456 mg (3.0 mmol) of CsF were added into the reactor. The resulting mixture was refluxed for 60 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 213 mg (99% yield) of p-(4-methoxyphenyl)anisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ8 7.38 (d, J=8.68 Hz, 4H), 6.86 (d, J=8.68 Hz, 4H), 3.74 (s, 6H) ppm. 13C NMR (125 MHz, CDCl3): δ 158.7, 133.5, 127.7, 114.2, 55.3 ppm. Anal Calcd for C14H14O2 :C, 78.48; H, 6.59. Found: C, 78.44; H, 6.53.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1N)#[N:2].[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].C1CCN2C(=NCCC2)CC1>O>[NH:13]1[C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:1]([NH2:2])=[N:14][S:10]1(=[O:12])=[O:11]
Reactant: N#Cc1ccccc1N
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=NS(=O)(=O)Nc2ccccc21
Temperature: 160 °C

Procedure:
A stirred mixture of 2-cyanoaniline (236 mg, 2.0 mmol), sulfamide (192 mg, 2.0 mmol) and DBU (304 mg, 2.0 mmol) was heated at 160° C. under nitrogen for 3 days. After cooling to room temperature, the reaction mixture was diluted with water and extracted three times with EtOAc. The aqueous layer was removed under vacuum and the residue was purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.03 (dd, J=0.8, 8.0 Hz, 1H), 7.12 (dt, J=0.8, 8.0 Hz, 1H), 7.56 (dt, J=0.8, 8.0 Hz, 1H), 7.85 (dd, J=0.8, 8.0 Hz, 1H). MS 198 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[N:4](CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[N:7]=1)[CH3:2].[CH2:48]([C:50]1[N:51]=[C:52]2[CH:57]=[CH:56][N:55]([CH2:58][C:59]3[CH:64]=[CH:63][C:62]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=4[C:71]4[N:75]([C:76]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)([C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[C:77]5[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=5)[N:74]=[N:73][N:72]=4)=[CH:61][CH:60]=3)[N:53]2[N:54]=1)[CH3:49]>>[CH2:48]([C:50]1[N:51]=[C:52]2[CH:57]=[CH:56][N:55]([CH2:58][C:59]3[CH:60]=[CH:61][C:62]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=4[C:71]4[N:75]([C:76]([C:77]5[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=5)([C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)[N:74]=[N:73][N:72]=4)=[CH:63][CH:64]=3)[N:53]2[N:54]=1)[CH3:49].[CH2:1]([C:3]1[NH:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nn2nccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCc1nc2ccn(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Product: CCc1nn2nccc2[nH]1

Procedure:
In the same manner as described in Example 38, 612 mg of 2-ethyl-1-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 51a) and 449 mg of 2-ethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 51b) were obtained from 378 mg of 2-ethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([CH2:10][C@@H:11]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6][C:5]=1[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:20]([OH:22])=[O:21])[CH:7]=[CH:6][C:5]=1[O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC

Procedure:
5-((2S)-2-Benzyloxycarbonyl-2-tert-butoxycarbonylamino-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step D (135 mg, 0.27 mmol) is stirred in 95% EtOH (3 mL) with Pearlman's catalyst (palladium hydroxide on carbon) (70 mg) and put through a vacuum/purge cycle 3 times with H2 gas. The reaction is then held under 1 atm of H2 overnight. The catalyst is then filtered off on GF/F filter paper and the filtrate concentrated to provide 5-((2S)-2-tert-butoxycarbonylamino-2-carboxy-ethyl)-2-methoxycarbonylmethoxy-benzoic acid methyl ester which is used without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:25][CH2:26][C:27]([CH3:29])=[CH2:28])[CH:6]([CH3:24])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:23])[CH:16]2[O:17][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH2:14][CH2:15]2)[CH2:12][O:11]1)(=[O:3])[CH3:2].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][CH:5]([CH2:25][CH:26]=[C:27]([CH3:28])[CH3:29])[CH:6]([CH3:24])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:23])[CH:16]2[O:17][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])([CH2:14][CH2:15]2)[CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: C=C(C)CCC(OC(C)=O)C(C)CCCC1(C)OCC2(CC(=O)OC)CCC1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CC12CCC(O1)C(C)(CCCC(C)C(CC=C(C)C)OC(C)=O)OC2
Temperature: 80 °C
Yield: 77.4 %

Procedure:
A mixture of methyl (1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-8-nonenyl)-4-methyl-3,8-dioxabicyclo [3.2.1] octane-1-acetate (93 mg, 0.24 mM), benzene (6 ml) and p-toluenesulfonic acid monohydrate (1 crystal) is heated to 80° C. for sixteen hours under nitrogen. The resulting mixture is cooled to room temperature and treated with ether (100 ml). The organic phase is washed with 5% sodium bicarbonate solution (5 ml) and dried (sodium sulfate). The solvent is removed in vacuo to give methyl (1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-7-nonenyl)-4-methyl-3,8-dioxabicyclo [3.2.1] octane-1-acetate (72 mg, 90%) as a colorless oil. This material is homogeneous by thin layer chromatography and is used directely in the next step.