Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[N-:50]=[N+:51]=[N-:52].[Na+].Cl.C([NH+](CC)CC)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]4[NH:52][N:51]=[N:50][N:38]=4)[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:25][CH2:26]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCCC#N)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCCc4nnn[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (0.7 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1 M aqueous hydrochloric acid solution. The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:31]=[CH:32][C:33]=1[CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]([CH3:30])=[CH:22][CH:23]=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Rh]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:31]=[CH:32][C:33]=1[CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:41])[CH3:42])([CH3:37])[CH3:38])[O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]([CH3:30])[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CC=C(C)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(C)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
350 mg of 5% rhodium/alumina are added to 750 mg (1.22 mmol) of ethyl 5-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]phenyl}-hexa-2,4-dienoate in 50 ml of ethyl acetate. Hydrogen is bubbled through the medium for 1 hour 30 minutes. The mixture is then filtered on celite and concentrated.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCC)c2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCC
Yield: 98 %

Procedure:
Benzyl bromide (1.32 ml, 11.1 mmol) was added to a stirred solution of diethyl 1-(ethyloxy)-4-hydroxy-2,3-naphthalenedicarboxylate (2.45 g, 7.38 mmol) and potassium carbonate (1.53 g, 11.1 mmol) in acetone (50 ml). The reaction mixture was refluxed for 1 hour under an atmosphere of argon. The resulting mixture was evaporated and the residue was partitioned between 2× ethylacetate and brine. The combined organics were washed with water and dried over magnesium sulphate. The clear oil was purified by chromatography on silica gel, eluting with ethyl acetate (0-40%) in hexane to give the title compound as clear oil (3.05 g, 7.23 mmol). LC/MS: Rt=3.77, [MH]+ 423.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[C:15]3[N:31]=[CH:30][S:29][C:16]=3[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[N:19]=2)[CH:10]=[CH:11][CH:12]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:24](=[O:26])[C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH:8]=3)[C:15]3[N:31]=[CH:30][S:29][C:16]=3[N:17]=2)=[CH:28][CH:27]=1
Reactant: CN(C)CCN
Reactant: C[C@H]1CCCN1c1cccc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3ccc(C(=O)NCCN(C)C)cc3)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
To a solution of (S)-4-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (80 mg, 0.19 mmol) and N1,N1-dimethylethane-1,2-diamine (18 mg, 0.2 mmol) in DCM (20 mL) was added 1-methyl-1H-indozole (92 mg, 1.12 mmol) and EDCI (217 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography (DCM:MeOH=50:1) and product treated with conc. HCl to give (S)—N-(2-(dimethylamino)ethyl)-4-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (22 mg, 24%) as HCl salt. 1H NMR (300 MHz, CD3OD): δ 9.15 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 7.97-7.91 (m, 3H), 7.63-7.57 (m, 1H), 7.41 (d, 1H, J=8.1 Hz), 4.06-3.93 (m, 2H), 3.77-3.68 (m, 3H), 3.37-3.33 (m, 2H), 2.91 (s, 6H), 2.53-2.42 (m, 1H), 2.35-2.18 (m, 2H), 2.06-1.87 (m, 1H), 1.36 (d, 3H, J=6.6 Hz). LC-MS: 502 [M+H]+, tR=1.344 min. HPLC: 97.57% at 214 nm, 97.17% at 254 nm, tR=4.793 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].NC(N)=[O:15].OP([O-])(O)=O.[K+].C([O-])([O-])=O.[Ca+2]>>[CH2:2]([OH:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C:9]([C:11]([OH:15])=[O:12])=[O:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: O=P([O-])(O)O
Agent: [Ca+2]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Five ml of the resulting individual seed cultures as prepared above was inoculated into a 500 ml of Erlenmeyer flask containing 50 ml of production medium (PM): D-sorbitol 8%, corn steep liquor 1%, urea 1.5% (sterilized separately), KH2PO4 0.1%, MgSO4.7H2O 0.01%, CaCO3 0.6% and antifoam 0.1% (pH 7.0 before sterilization) and incubated at 30° C. for 4 days with shaking (180 rpm). Table 1 summarizes the results of the quantitative determination of 2-keto-L-gulonic acid of the cultured broths as assayed by high performance liquid chromatography.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](=[O:41])[NH:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([O:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([NH:16][C:17]2[S:18][C:19]3[CH:25]=[C:24]([O:26][S:27]([C:30]4[CH:31]=[CH:32][C:33]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:41])[CH2:10][CH2:9]1
Reactant: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CC4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CC4CCNCC4)sc3c2)cc1
Yield: 64 %

Procedure:
2nd step: A solution of 4-{[6-(4-isobutylaminobenzenesulfonyloxy)benzo-thiazol-2-ylcarbamoyl]methyl}piperidine-1-carboxylic acid tert-butyl ester (110 mg, 182 μmol), dioxane (2 ml) and 4N hydrochloric acid in dioxane is stirred for 2 hours at room temperature. The reaction medium is concentrated to dryness and the residue obtained is washed with ethyl ether to give 183 mg of 4-isobutylaminobenzenesulfonic acid 2-(2-piperid-4-ylacetylamino)benzo-thiazol-6-yl ester hydrochloride (white powder) in a yield of 64%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: COc1ccnc(Br)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round bottomed flask 2-bromo-4-methoxypyridine (315 mg, 1.68 mmol) was dissolved in THF (6 mL). The solution was cooled to 0° C. and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.35 mL, 1.76 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min then at room temperature for 1.5 h. An additional portion of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 0.15 mL, 0.20 mmol) was added and stirring was continued at room temperature for 30 min. Tributyltin chloride (0.50 mL, 1.84 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 4-methoxy-2-tributylstannanyl-pyridine as a white paste which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15]C(=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:26]([O:25][C:21]1([O:22][CH2:23][CH3:24])[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15]1)[CH3:27]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCOC1(OCC)CCC(CCOCc2ccccc2)CC1

Procedure:
4-(2-benzyloxyethyl)cyclohexanone (133.0 g, 0.57 mol) is dissolved in ethanol (1200 mL), and then triethylorthoformate (296 mL) and p-toluenesulfonic acid monohydrate (10.9 g, 0.057 mol) are added. The resulting mixture is stirred and refluxed for 2 hours. After addition of triethylamine (8.8 mL, 0.063 mol) at room temperature, the mixture is concentrated. After addition of sat. NaHCO3 aq. (500 mL), the resulting mixture is extracted with EtOAc (1000 mL). The water layer is extracted with EtOAc (1000 mL×2) and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by short pad silica gel column chromatography to afford [2-(4,4-diethoxycyclohexyl)ethoxymethyl]benzene as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([N:42]2[C:46]3([CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[C:45](=[O:52])[NH:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:49]3[CH2:48][CH2:47][C:46]4([N:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:43][NH:44][C:45]4=[O:52])[CH2:51][CH2:50]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC4(CC3)C(=O)NCN4c3ccccc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [AlH4-].[Li+].[C:3]1([C@@H:9]2[CH2:13][NH:12][C@H:11]([C:14](OC)=[O:15])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][OH:15])[CH2:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H]1C[C@H](c2ccccc2)CN1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@H](c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium tetrahydroaluminate in tetrahydrofuran (1.00 M, 1.00 mL) was added to methyl (2S,4R)-4-phenylpyrrolidine-2-carboxylate (103.0 mg, 0.0005018 mol) in tetrahydrofuran (3.00 mL, 0.0370 mol) at 0° C. Then the ice-water bath was removed and the reaction mixture was stirred at rt for 1 h and was quenched with brine (1 mL). The resulting mixture was extracted with ethyl acetate (2×2 mL). The combined organic layer was washed with brine, dried over Na2SOa, filtered, and concentrated under reduced pressure to give the desired product which was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:20].[K+]>C1C=CC=CC=1.O.[I-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[C:2]1([C:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)=[O:20])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: c1ccc(Cc2nc(-c3ccncc3)cs2)cc1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1nc(-c2ccncc2)cs1
Yield: 18.8 %

Procedure:
To a mixture of 2-benzyl-4-(4-pyridyl)thiazole (3.00 g, 0.01 mol) and potassium permanganate (3.16 g, 0.02 mol) in benzene (30 mL) and water (60 mL) was added tetrahexyl ammonium iodide (0.96 g, 0.02 mol). The biphasic mixture was heated at reflux for 15 hours. After cooling the organic layer was separated and concentrated. The residue was taken up in ethyl acetate, filtered through silica gel, concentrated and chromatographed (ethyl acetate/hexane as eluant). Recrystallization from ethyl acetate/hexane afforded 1-phenyl-1-[4-(4-pyridyl)-2-thiazolyl]methanone (0.50 g, 11%). mp. 135°-136° C.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH2:7]=[C:8]([CH3:10])[CH3:9].[Sn](Cl)(Cl)(Cl)Cl>C(OCC)C>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: C=C(C)C
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOCC
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 59.0 psrts of chloral [trichloroacetaldehyde], 29.2 parts of isobutene and 80 parts of petroleum ether was cooled to a temperature in the range of from -20° C. to -5° C. 4.2 Parts of anhydrous tin tetrachloride were added thereto dropwise and the mass was stirred for 5 hours while the temperature was kept at that point. Thereafter, the reaction mixture was diluted with diethyl ether and washed with about 50 parts of water. Low boiling point matter was distilled out from the organic layer. After reduced pressure distillation, 69.2 parts (yield: 85%) of 1,1,1-trichloro-4-methyl-4-penten-2-ol of b.p. 104°-107° C./22 mmHg were obtained. Properties of the product were as shown below:
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1

Procedure:
12.1 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 18.16 g of yellow liquid. MS: 346(M+′), 345(M+−1), 301 (M+—OCH2CH3), 273(M+—CO2CH2CH3), 262, 241 (M+−C6H5CO), 225(M+—C6H5CO2), 195, 185, 151, 140, 105 (base), 77.
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][Si](C=[N+]=[N-])(C)C>CO.C1COCC1>[C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@H]1CCC=C[C@H]1c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1CCC=C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 900 mg (4.45 mmol) of 1(R)-phenyl-2(S)-carboxy cyclohex-5-ene (See U.S. Pat. No. 5,750,549, Example 158, Step B) in a 4:1 solution of MeOH/THF was added trimethylsilyldiazomethane until a yellow color persisted. After stirring at room temperature for 3 hour the reaction was concentrated in vacuo and the residue was purified by flash chromatography eluting with 0-15% EtOAc in hexanes to afford the ester (300 mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.19-7.30 (m, 5H), 5.98-6.01 (m, 1H), 5.76-5.79 (m, 1H),3.89 (s, 1H),3.50 (s, 3H), 2.95-2.98 (m, 1H), 2.16-2.32 (m, 2H),1.80-1.87 (m, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>[O-]CC.[Na+]>[C:14]([CH:13]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOc1ccc(CC#N)cc1OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(OCC)c(OCC)c1

Procedure:
By following the procedures outlined in Examples 1 and 3, 3,4-diethoxyphenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide solution to give ethyl 3-cyano-3-(3',4'-diethoxyphenyl)pyruvate. This compound is similarly reacted with 3,4-diethoxyphenylacetonitrile which results in the formation of 2,5-di-(3',4'-diethoxyphenyl)-3,4-dioxoadiponitrile. The latter is refluxed with water, acetic acid and sulfuric acid to give 3,4,3',4'-tetraethoxypulvinic acid which is treated with acetic anhydride to give the corresponding acid lactone.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)[C:12]#N)=[CH:7][CH:6]=1)[CH2:2][CH3:3].O=[CH:26][C:27](=C)[CH3:28]>>[CH3:28][C:27]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=2)[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][CH:16]=2)[CH:26]=1
Reactant: C=C(C)C=O
Reactant: CCCOc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1
Product: CCCOc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-propoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 5%), melting at 142-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@:7]([C:25](=O)[CH3:26])([CH3:24])[CH2:6]1)=[O:4].C(O)(=O)C.[CH3:32][NH:33][NH2:34]>CO>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@@:7]([CH3:24])([C:25](=[N:34][NH:33][CH3:32])[CH3:26])[CH2:6]1)=[O:4]
Reactant: CNN
Reactant: COC(=O)N1CC(c2ccc(OC)c(OC3CCCC3)c2)[C@@](C)(C(C)=O)C1
Solvent: CC(=O)O
Solvent: CO
Product: CNN=C(C)[C@@]1(C)CN(C(=O)OC)CC1c1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a stirred solution of (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (see Example 12 of Feldman et al. U.S. Pat. No. 5,665,654, incorporated herein by reference) (or (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester) (0.133 mmol, 50 mg) in methanol (2 mL) with catalytic amount of acetic acid (20 μL) was added methyl hydrazine (0.147 mmol, 7.8 μL). The reaction was heated gently for 36 hours, and three more portions of methl hydrazine were added. The resulting hydrazone was purified by HPLC. The named product was confirmed by HNMR.
Reaction SMILES: Cl.[F:2][C:3]1([F:29])[CH2:7][CH2:6][C@@H:5]([C@@:8]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([O:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH:20]=[NH:21])[CH2:16][CH2:15]2)=[O:10])[CH2:4]1.[Br-:30].[Na+]>O>[BrH:30].[F:29][C:3]1([F:2])[CH2:7][CH2:6][C@@H:5]([C@@:8]([OH:28])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]([O:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH:20]=[NH:21])[CH2:18][CH2:19]2)=[O:10])[CH2:4]1
Reactant: [Br-]
Agent: Cl
Agent: N=CN1CCC(CCOC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Agent: [Na+]
Solvent: O
Product: Br

Procedure:
A solution of 50 mg of 2-(1-(iminomethyl)piperidin-4-yl)ethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate monohydrochloride in 2 ml of ultrapure water was developed on reversed phase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC Co.)], and 60 ml of 0.2 M aqueous sodium bromide solution was flowed. After washing with 100 ml of ultrapure water, the title compound was eluted from tetrahydrofuran/water=1/5, and 35 mg thereof was obtained as a colorless solid upon condensation to dry solid.