Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:16][C@@H:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([C:20]1[S:21][CH2:22][CH2:23][N:24]=1)[OH:19])=O)C1C=CC=CC=1>C(#N)C>[NH2:16][C@@H:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([C:20]1[S:21][CH2:22][CH2:23][N:24]=1)[OH:19]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(O)C1=NCCS1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N[C@@H](Cc1ccccc1)C(O)C1=NCCS1

Procedure:
Iodotrimethylsilane (10 ml) is added to a solution of (1RS,2S)-2(benzyloxycarbonyl)amino-1-(4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol (650 mg, Reference compound No. 11-1) in acetonitrile (10 ml), and the mixture is stirred for 30 minutes. The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the resulting residue, and the whole is extracted with 1 N hydrochloric acid. Sodium hydrogencarbonate is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (323 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Reactant: OB(O)c1cccnc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2cccnc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 3-pyridylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 198). HPLC Ret time=1.98 min. LCMS [M+H]+ 392.29.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[CH:7][C:8]=1[CH3:9])#[N:2].S(=O)(=O)(O)[OH:13]>>[Cl:11][C:4]1[C:3]([C:1]([NH2:2])=[O:13])=[C:8]([CH3:9])[CH:7]=[C:6]([Cl:10])[N:5]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Product: Cc1cc(Cl)nc(Cl)c1C(N)=O
Reaction time: 0.5 h

Procedure:
3-Cyano-2,6-dichloro-4-methylpyridine (80g, 0.42 mole) was dissolved in concentrated sulfuric acid (440ml). The mixture was heated at 150° C.-170° C. with stirring for 30 minutes, cooled and poured on ice. The precipitate was filtered and washed with water. The wet filter cake was dissolved in methylene chloride, washed, neutralized with Na2Co3, dried over Na2SO4 (anhydrous), and concentrated until a white precipitate separated. Petroleum ether was added, the crystals were filtered and dried at room temperature overnight to give 83g (94%) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([N:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[CH2:15]([N:22]1[C:26]([C:27]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=3)[NH:8][CH:7]=2)=[O:28])=[CH:25][C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)n(Cc2ccccc2)n1
Yield: 59 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0445 g, 0.189 mmol), 1-benzyl-3-(tert-butyl)-1H-pyrazole-5-carbonyl chloride (0.055 g; 0.189 mmol), and triethylamine (0.0663 mL; 0.472 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0485 g (59%) of 1-benzyl-3-tert-butyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C(O[CH:19](N(CCC)CCC)[N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])(C)(C)C>O1CCCC1>[CH2:21]([N:20]([CH2:24][CH2:25][CH3:26])[CH:19]=[CH:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2)[CH2:22][CH3:23]
Reactant: Cc1ccc([N+](=O)[O-])c2[nH]ncc12
Reactant: CCCN(CCC)C(OC(C)(C)C)N(CCC)CCC
Solvent: C1CCOC1
Product: CCCN(C=Cc1ccc([N+](=O)[O-])c2[nH]ncc12)CCC
Yield: 90.7 %

Procedure:
2.1 g of 4-methyl-7-nitro-1H-indazole and 5.0 g of tert-butoxybis(dipropylamino)methane are heated to 80° C. in 10 ml of tetrahydrofuran for 2.5 hours. The mixture is concentrated, distilled with tetrahydrofuran, and recrystallized from dichloromethane/hexane, yielding 3.1 g of N,N-dipropyl-N-[2-(7-nitro-1H-indazol-4-yl)ethenyl]amine, mp 166°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)cc1N1CCCCC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (3.0 g), piperidine (2.93 ml) and potassium carbonate (5.11 g) in N,N-dimethylformamide (30 ml) was stirred at 100° C. for 12 hours. The mixture was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give 4-bromo-2-(1-piperidinyl)benzaldehyde (3.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16]CC)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2
Reactant: CCOC(=O)c1nc2cc(C)c(C)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc2nc(Cl)c(C(=O)O)nc2cc1C

Procedure:
3Chloro-6,7-dimethyl-2-quinoxalinecarboxylic acid, ethyl ester (14.5 g) and sodium carbonate (3.2 g) in methanol (300 ml) and water (75 ml) were heated under reflux for 2 hours. The methanol was distilled off and the aqueous solution was acidified with dilute hydrochloric acid. The solid was collected, dried and crystallised from a mixture of ethyl acetate and light petroleum (b.p. 60°-80°). It had m.p. 146.5°-148.5° (d) (75%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][Si:24]([CH3:52])([CH3:51])[C:25]1[CH:26]=[C:27]([CH:44]=[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=1)=O>C1(C)C=CC=CC=1>[CH3:23][Si:24]([CH3:52])([CH3:51])[C:25]1[CH:26]=[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[S:10])[CH:44]=[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=1
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cc(C(=S)Nc2ccc(CCC(=O)O)cc2)cc([Si](C)(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 131.8 %

Procedure:
Lawesson's reagent (90 mg) was added to a toluene (5 ml) solution of Compound 20a (140 mg). The obtained mixture was stirred at 100° C. in a nitrogen atmosphere for 1 hour. After the reaction was over, the reaction mixture was allowed to cool, and concentrated. The obtained residue was purified by column chromatography (5% ethyl acetate/n-hexane). Fractions containing the ester body of Compound 4 were collected, and concentrated to dryness. As a result, 126 mg of yellow solid was obtained. The obtained yellow solid (90 mg) was, without further purification, dissolved in ethanol (1 ml). A 1N sodium hydroxide aqueous solution (1 ml) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred under heating at 45° C. for 1 hour. After the reaction was over, the mixture was allowed to cool, and a 1N hydrochloric acid aqueous solution was added thereto. The mixture was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 20 (54 mg, 64%) was obtained as an opalescent solid.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1>FC(F)(F)C(O)=O.ClCCl>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:6]2[CH:23]=[CH:24][C:3]([N:2]([CH3:25])[CH3:1])=[CH:4][CH:5]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)c2ccc(N)cc2)cc1
Yield: 94.3 %

Procedure:
The compound 4 (51 mg, 0.15 mmol) was stirred in 10% trifluoroacetic acid (TFA) in dichloromethane (10 mL) at room temperature for 1 hour and extracted with ethyl acetate with aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated to give intermediate B (34 mg, 95%). 1H-NMR (CDCl3) 7.76 (d, J=8.7, 2H), 7.66 (d, J=8.4, 2H), 6.68 (d, J=8.7, 2H), 6.67 (d, J=8.4, 2H), 4.04 (br. s, 1H), 3.06 (s, 6H) ppm; ESI-MS m/z calcd for C15H16N2O: 240. 3004. found 241.2071 [M+1].
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Nc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Nc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A mixture of 4-phenylamino-benzaldehyde (3 g, 15.2 mmol) described in Manufacturing Example 69-1-1, nitromethane (1.63 mL, 30.4 mmol), ammonium acetate (1.76 g, 22.8 mmol) and acetic acid (30 mL) was stirred for 6 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.2 g). This compound was used in the following reaction without being purified.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20]O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:11]1([O:16][C:17](=[O:30])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOc1cccc([N+](=O)[O-])c1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a slurry of 3-nitrophenol (1.2 g, 8.4 mmol) in anhydrous DCM (60 ml) at 0° C. was added (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid cyclopentyl ester (2 g, 7 mmol) (see Scheme 9) in DCM (10 ml), triphenyl phosphine (7.5 g, 28.7 mmol) followed by slow addition of DIAD (5.8 g, 28.7 mmol). The reaction was allowed to warm to room temperature and stirred for 16 h. The solvent was removed and the crude material purified by column chromatography. (EtOAc:heptane, 1:9), (1.6 g, 56%). LCMS purity 95%, m/z 309 [M++H-boc]+.
Reaction SMILES: ClC(OCC)=O.N[C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1.COC(=O)CC1C=CC([NH2:28])=CC=1>>[C:12]([NH2:28])(=[O:13])[C:11]1[CH:16]=[CH:17][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: CCOC(=O)Cl
Product: NC(=O)c1ccccc1

Procedure:
Converting 3,4-dialkoxy benzoic acid to anhydride by adding ethyl chloroformate thereto, and reacting the anhydride with methyl 4-aminobenzoate or 4-aminophenyl acetic acid methylester, to produce a benzamide compound;
Reaction SMILES: [Br:1]Br.[O:3]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[Br:1][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:9][CH:8]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: BrBr
Product: O=Cc1cccc(Oc2ccc(Br)cc2)c1
Reaction time: 1 h

Procedure:
9.60 Grams (0.060 mole) of bromine were added dropwise to 9.90 g (0.050 mole) of m-phenoxybenzaldehyde at 0° C. taking a period of 1 hour with vigorous stirring. After the addition was finished, the reaction was continued for a further 3 hours at the same temperature. The unreacted bromine was distilled off under reduced pressure from the reaction system to obtain m-(p-bromophenoxy)benzaldehyde (No. 9 in Table 2).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[C:21](O)=[O:22]>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3,4-bis(trifluoromethyl)benzoic acid (CAS RN 133804-66-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow solid (43%). MS (ESI): m/z=439.12 [M+H]+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([N:18]1[C@H:21]([CH2:22][C:23](OC)=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[Si:11]([N:18]1[C@H:21]([CH2:22][CH:23]=[O:24])[C@@H:20]([C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH3:28])[C:19]1=[O:37])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Diisobutylaluminum hydride (3.72 ml of 0.91 M in hexane, 3.38 mmol) is added slowly by syringe to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethyl azetidin-2-one (936 mg, 2.26 mmol) in 25 ml of freshly distilled toluene at -78° C. The resulting solution is stirred at -78° C. for 3 hrs., then quenched by addition of 2.5 N hydrochloric acid (5 ml). The resulting mixture is stirred for 2 min., then poured into a separatory funnel containing 100 ml of ether and 50 ml of 1.25 N hydrochloric acid saturated with tartaric acid. The organic phase is separated and the aqueous phase is extracted with ether (2×50 ml). The combined organic phases are washed with brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is recrystallized from ether-petroleum ether to give (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)- 1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)-azetidin-2-one. m.p. 115°-116° C.; n.m.r. (CDCl3) δ4.1(m,1), δ4.03(m,1), δ2.7-3.2(m,3), δ1.23(d,3,J=6.4), δ1.08(s,9), δ0.9(s,9), δ0.25(s,6), δ0.1(s,6), δ9.83(t,1,J=1.4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](I)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: ICc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.2 %

Procedure:
To 1 ml of a DMF solution containing 55.5 mg (0.1438 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 21.82 μl (0.1798 mmol) of benzyl iodide, there was added 27.43 μl (0.1798 mmol) of DBU and the resulting mixture was agitated for 4.5 hours at room temperature. After the solvent in the reaction mixture was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 5 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 52.8 mg (0.111 mmol, 77%) of 2-benzyloxy-2'-hydroxy-5,5'-bis (2-ethyoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.23 (6H, t, 2CH3), 2.5-2.8 (4H, m, 2CH2), 2.8-3.1 (4H, m, 2CH 2), 4.13 (4H, q, 2CH2), 5.06 (2H, s, CH2), 6.27 (1H, s, OH), 6.8-7.4 (11H, m, arom-H) MS (FAB): 475 (M-H)-
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:18][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:20][CH2:21][CH:22]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].O1CCCC1.[OH-].[Na+].Cl>CO>[CH2:18]1[C:19]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:20][CH2:21][CH:22]=[C:17]1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:11]=1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=CCCC3(CCCCC3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCC2=CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.5 %

Procedure:
To a solution of (S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (0.82 g) obtained in Step 8 in a mixed solvent of tetrahydrofuran (4 mL)-methanol (4 mL) was added 2N aqueous sodium hydroxide solution (2 mL), followed by stirring the reaction mixture at room temperature for 14 hours. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give (S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (0.77 g) as the desired compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1>O1CCOCC1>[NH2:2][CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(CN)CCNCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
Hydrogen chloride 4M in dioxane (33.2 ml, 132.7 mmol) was added to 1-tert-butyl 4-ethyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (Intermediate 8) (7.6 g, 26.5 mmol) in dioxane (35 ml). The resulting solution was stirred at 20° C. for 3 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and pure fractions were evaporated to dryness to afford ethyl 4-(aminomethyl)piperidine-4-carboxylate (3.34 g, 67.6%) as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]3[CH2:14][CH2:15][CH2:16]3)=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnn(-c2ccc(Cl)cc2)c1C1CCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnn(-c2ccc(Cl)cc2)c1C1CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of methyl 1-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 28.5 mmol) and lithium hydroxide monohydrate (3.6 g, 85.6 mmol) in MeOH (25 mL), THF (25 mL) and H2O (12 mL) was stirred at 80° C. for 1 h. After cooling to room temperature the mixture was acidified with 1 M aqueous HCl and extracted with EtOAc (400 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield 1-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (6.92 g, 87% yield).
Reaction SMILES: [C:1]([P:5](C(C)(C)C)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C([Mg][Cl:19])(C)(C)C.[Mg].C(Cl)(C)(C)C.P(Cl)(Cl)Cl>>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[Cl:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Mg]
Solvent: ClP(Cl)Cl
Solvent: CC(C)(C)Cl
Product: CC(C)(C)P(Cl)C(C)(C)C

Procedure:
By way of example, the preparation of tri-tert-butylphosphine is described in Chem. Ber., 100(2), 692-3 (1967). Tertiary butyl magnesium chloride is first prepared from magnesium metal and t-butyl chloride, then this is allowed to react with PCl3 to form di-tert-butylchlorophosphine. This product is then treated with tert-butyl lithium to yield tri-tert-butyl phosphine.