Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-:22]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].C1(=O)O[CH2:40][CH2:39][O:38]1>CO>[F:36][C:33]([F:34])([F:35])[S:30]([N-:22][S:23]([C:26]([F:27])([F:28])[F:29])(=[O:24])=[O:25])(=[O:31])=[O:32].[OH:38][CH2:39][CH2:40][P+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Product: OCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and heated to 60° C. 321.8 g (1.1 mol) of trifluoromethanesulfonimide was then added dropwise under strong stirring, and 176.0 g (2.0 mol) of ethylene carbonate was also added after a half hour of reaction. The reaction mixture was transferred to an autoclave, wherein air was removed prior to heating. After 4 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 616.3 g of 2-hydroxyethyl triphenyl phosphonium bis(trifluoromethyl sulfonyl) amide was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]2[C:7]([OH:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:19]([SH:21])[CH3:20]>ClCCl>[OH:18][C:7]1[C:8]2[C:9](=[O:17])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH:2]([S:21][CH2:19][CH3:20])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CCS
Reactant: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Solvent: ClCCl
Product: CCSC1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
10-Bromo-1,8-dihydroxy-9-anthrone (3.05 g) was dissolved in dichloromethane (100 ml) and ethanethiol (1 ml) was added. The solution was left stirring at room temperature for 6 hours, during which time the red-brown solution became yellow-green Removal of the solvent gave a yellow solid which, recrystallised from hexane, gave 1,8-dihydroxy-10-ethylthio-9-anthrone (2.63 g, 91%) as bright yellow needles, melting point 117°-118° C.
Reaction SMILES: C(O[C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C1C=CC=CC=1.[O-]CC.[Na+].[CH3:27][C:28]([CH3:32])=[CH:29]C=O.C(O)(=O)C>C(O)C.[Pd]>[C:18]([C:12]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:28]([CH3:32])([CH3:29])[CH2:27][CH2:9][NH:11]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CC(C)=CC=O
Agent: [Pd]
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)NCCC1(C)C
Reaction time: 24 h
Yield: 37 %

Procedure:
Diethyl benzyloxycarbonylaminomalonate (3.09 g, 10 mM) was dissolved in dry ethanol (15 ml) and added to a solution of sodium ethoxide (from 100 mg sodium) in ethanol (3 ml). 3-Methylbut-2-enal (840 mg, 10 mM) in ethanol (6 ml) was added and the solution stirred at 25° for 24 hrs. Acetic acid (0.28 ml) was then added and the solution hydrogenated for 24 hrs using palladium on carbon (10% 500 mg) as catalyst. The solution was filtered, evaporated and the residue chromatographed on silica column using ether/petroleum ether (40°-60°) (1 : 1) as eluant to give 2,2-dicarboethoxy-3,3-dimethylpyrrolidine (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.CN([CH:21]=[O:22])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[S:36](S([O-])=O)([O-:39])(=[O:38])=[O:37].[Na+:43].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:21]([OH:22])[S:36]([O-:39])(=[O:38])=[O:37])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1.[Na+:43]
Reactant: CN(C)C=O
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)([O-])C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-Chloro-4-fluoro-benzotrifluoride (20.0 g, 100.7 mmol) in THF (200 ml) was added at −78° C. n-BuLi (1.6 M in hexanes, 66.1 ml, 105.7 mmol, 1.05 equiv.) over a period of ca. 20 min. The clear yellow solution was stirred for 30 min at −78° C. and a solution of DMF (8.54 ml, 110.8 mmol, 1.1 equiv.) in THF (100 ml) was added dropwise, such as that the internal temperature stayed below −70° C. The light yellow reaction mixture was stirred for 3 h at −78° C. and was then warmed to 0° C. At this temperature the reaction mixture was quenched upon addition of a solution of citric acid (58.13 g, 302.1 mmol, 3.0 equiv.) in water (400 ml) keeping the temperature below 5° C. The organic phase was separated and washed with water (300 ml), whereas the aqueous phase was washed with TBME (300 ml). The combined organic phases were dried over sodium sulfate, the solvents were removed under vacuum and the residue was treated with toluene (200 ml), whereupon a white precipitate was formed. The suspension was stirred for 15 min, the precipitate was filtered off and the mother liquor was treated by dropwise addition of a solution of sodium pyrosulfite (21.68 g, 111.8 mmol, 1.11 equiv.) in water (60 ml), whereupon a white suspension was formed. The suspension was stirred overnight (ca. 15 h), the precipitate was filtered off, washed with toluene (100 ml) and dried under vacuum to yield the title compound as a off-white crystalline compound (32.54 g, 97.7% yield). MS (EI): m/z 306.9 ([M−H]−, 100%). 1H-NMR (DMSO, 300 MHz): δ 8.00-7.85 (m, 2H), 6.58 (d, 1H), 5.31 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([NH2:8])[NH:5][N:4]=1)[CH3:2].[C:9]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:18][CH:19]=2)[CH:14]=[N:13]1)(=[O:11])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:9]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[NH:8][C:6]4[N:5]([N:4]=[C:3]([CH2:1][CH3:2])[N:7]=4)[C:23](=[O:24])[CH:22]=3)=[CH:18][CH:19]=2)[CH:14]=[N:13]1)(=[O:11])[CH3:10]
Reactant: CCc1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1nc2[nH]c(-c3ccc4c(cnn4C(C)=O)c3)cc(=O)n2n1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
To a solution of 3-ethyl-1H-1,2,4-triazol-5-amine (150 mg, 1.34 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (550 mg, 2.00 mmol) and TsOH (8 mg, 0.04 mmol), and the reaction mixture was stirred for 1 h at 170° C. The solids were collected by filtration and washed with hexane (10 ml) and ethanol (3 ml) to afford 5-(1-acetyl-1H-indazol-5-yl)-2-ethyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a yellow solid (130 mg, crude).
Reaction SMILES: CC[O-].[Na+].[CH2:5]([C:12](=[CH2:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:19][C:20](S)([CH3:30])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[S:32]([O:36]OS([O-])(=O)=O)([O-])(=O)=[O:33].[K+].[K+]>O1CCOCC1.O>[CH2:16]([O:15][C:13]([CH:12]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:18][S:32]([C:20]([CH3:30])([CH3:19])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])(=[O:36])=[O:33])=[O:14])[CH3:17]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC(C)(S)CNC(=O)OC(C)(C)C
Reactant: C=C(Cc1ccccc1)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
10.2 ml (11 mmol) of 1.08N sodium ethylate solution are added dropwise at 0° to a mixture of 1.99 g (10.47 mmol) of ethyl α-benzylacrylate and 2.26 g (11 mmol) of tert-butyl [2-methyl-2-mercaptopropyl]carbamate in 5 ml of dioxan. Thereafter, the mixture is stirred at 0° for 0.5 hours and at room temperature for 2.5 hours. The reaction mixture is treated while cooling with ice with 8.96 g (14.6 mmol) of potassium monopersulphate triple salt, suspended in 15 ml of water, and stirred at room temperature for 1 hour. Thereafter, the mixture is cooled to 0° and a suspension of 8.96 g (14.6 mmol) of potassium monopersulphate triple salt in 15 ml of water is again added. Subsequently, the mixture is stirred at room temperature for 15 hours. The reaction mixture is diluted with 50 ml of water and the aqueous solution is extracted three times with 50 ml of ether each time. The combined organic solutions are dried over sodium sulphate and evaporated. There are obtained 3.25 g of tert-butyl [2-[[(RS)-2-(ethoxycarbonyl)-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate as a colourless oil; MS: 445 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17](O)=[O:18])=[C:12]([CH2:15][OH:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>CC(C)=O.O>[CH3:1][O:2][N:3]=[C:4]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[C:5]([NH:7][CH:8]1[CH:9]2[S:14][CH2:13][C:12]3[CH2:15][O:16][C:17](=[O:18])[C:11]=3[N:10]2[C:20]1=[O:21])=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C3=C(COC3=O)CSC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.3 g) in a mixture of acetone (3 ml) and water (1.5 ml) was adjusted to pH 2 with 6N hydrochloric acid and stirred for 4 hours at ambient temperature. After the acetone was distilled off, to the residue was added water (1 ml). The mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate and ice-cooled for 1 hour. Precipitating crystals were collected by filtration, washed with water and dried to give 6-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione (syn isomer) (0.23 g), mp 210° to 215° C.(dec.).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH2:26]([CH:28]([CH2:39][CH3:40])[CH2:29][C:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:27].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.C(OCC)(=O)C>[CH2:39]([CH:28]([CH2:26][CH3:27])[CH2:29][C:30]1([C:36]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:40]
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Reactant: CCC(CC)CC1(C(=O)O)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)CC1(C(=O)NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(O)c2ccc(F)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
While stirring (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (0.335 g, 0.927 mmol), 1-(2-ethylbutyl)cyclohexanecarboxylic acid (0.22 g, 1.02 mmol), 4-N,N-dimethylaminopyridine (0.11 g, 0.93 mmol) and 1-hydroxybenzotriazole hydrate (0.14 g, 0.93 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g, 0.93 mmol) was added, and the mixture was stirred at 80° C. for 1 day. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-2/1) to give the objective substance.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[Cl:16].[CH3:18][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[O:17])[CH3:18])=[C:10]([Cl:16])[CH:11]=1
Reactant: O=C(Sc1ccccn1)c1ccc(Br)cc1Cl
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 80 %

Procedure:
4-Bromo-2-chloro-thiobenzoic acid S-pyridin-2-yl ester (1.86 g, 5.66 mmol) from Step 1 above was dissolved in dry THF (30 mL) and cooled to −78° C. A solution of methyl magnesium bromide in 75:25 toluene/THF (1.4 M, 4.45 mL, 6.23 mmol) was added dropwise. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated 1N HCl and extracted with EtOAc (30 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (1.05 g, 80%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([O:11][CH3:12])=[N:4][CH:3]=1.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[N:14]([CH3:13])[C:8](=[O:10])[C:7]5[CH:6]=[C:5]([O:11][CH3:12])[N:4]=[CH:3][C:2]=5[N:1]=4)=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: CN
Reactant: COc1cc(C(=O)O)c(N)cn1
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1
Product: COc1cc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)cc3)nc2cn1

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 5-amino-2-methoxyisonicotinic acid, methylamine and 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzaldehyde. The resulting compound was recrystallized from ethyl acetate-heptane to give a colorless tabular crystal (m.p. 146.5-148.0° C.).
Reaction SMILES: C[C:2]1[C:3]([CH:16]([C:19]2[CH:26]=[CH:25]C(C#N)=[CH:21][CH:20]=2)[CH:17]=[CH2:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[OH-:27].[K+].C[C:30]([CH3:32])=[O:31]>CCCCCC>[CH3:13][C:9]1([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]2[CH:4]=[C:3]([CH:16]([C:19]3[CH:20]=[CH:21][C:32]([C:30]([OH:27])=[O:31])=[CH:25][CH:26]=3)[CH:17]=[CH2:18])[CH:2]=[CH:11][C:10]1=2
Reactant: C=CC(c1ccc(C#N)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: [OH-]
Reactant: CC(C)=O
Agent: [K+]
Solvent: CCCCCC
Product: C=CC(c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 4 h
Yield: 96 %

Procedure:
A suspension of the derivative (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzonitrile (0.44 g, 1.20 mmol) in solution in alcoholic potassium hydroxide (0.94 g, 16.8 mmol KOH in 0.55 ml H2O and 3.3 ml EtOH) is heated to reflux under magnetic stirring for 4 hours. The progress of the reaction is followed by CCM (eluent acetone:hexane=10:90). The ethanol is evaporated in a rotary evaporator, the product taken up in water (50 ml), acidified with 1N HCl and extracted 3 times with ether. The ether phase is dried with MgSO4, filtered and evaporated to obtain, after washing with pentane and drying, 0.40 g of a white powder the acid (E) 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-propenyl]benzoic acid (yield=96%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.[OH-].[K+].O>C(O)C>[F:13][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:3]2[CH2:2][O:22]2)[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Reaction time: 1 h

Procedure:
To a 250 mL 3-neck round bottom flask equipped with magnetic stir bar, nitrogen inlet and thermocouple, is added tert-butyl (1S,2S)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate IV, EXAMPLE 3, 3.5 g, 0.010 moles, 1 equivalent) followed by absolute ethanol (60 mL) and cooled to 0°. To this mixture is added potassium hydroxide (0.73 g, 0.013 moles, 1.25 equivalents) dissolved in absolute ethanol (10 mL) over 1 hr and the resulting suspension is warmed to 15-20° and stirred for 1 hr. At this time, water (100 mL) is added and the reaction contents are cooled to −5° and stirred for 30 min. The solids are collected by filtration and washed with cold water (2×25 mL) then dried under reduced pressure at 450 to give the title compound, mp=133°; NMR (DMSO-d6) δ 7.03, 3.61, 2.68-2.98 and 1.33; CMR (DMSO-d6) δ 163.72, 161.29, 155.55, 143.35, 112.65, 101.80, 78.17, 53.42, 52.71, 44.90, 36.98 and 28.36.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:3])[CH3:2]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Product: CCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 97.2 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (4.99 g) and nonanoyl chloride (7.16 g), the desired compound (10.12 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH2:21]([NH:29][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCc1ccccc1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3ccccc3)cc2s1
Yield: 7.3 %

Procedure:
the title compound (9 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), phenethylamine (76 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 414.5 (M+1, 100%). Yield=7%.
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[CH3:21][CH2:22][O-:23].[Na+].[CH3:25][C:26](C)=[O:27]>>[CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:13])=[CH:21][C:22]([O:27][CH2:26][CH3:25])=[O:23])=[CH:8][CH:7]=1
Reactant: CC(C)=O
Reactant: CC[O-]
Reactant: CC(=O)c1ccc(C=CC=C(C)CCC=C(C)C)cc1
Agent: [Na+]
Product: CCOC(=O)C=C(C)c1ccc(C=CC=C(C)CCC=C(C)C)cc1
Temperature: 25 °C

Procedure:
8 g of p-(4,8-dimethyl-1,3,7-nonatrienyl)acetophenone was added to a solution of 15 g of triethyl phosphonoacetate and 4.2 g of sodium ethylate in 50 ml of dimethylformaldehyde under stirring at room temperature. After stirring at 70° C. for 3 h, the reaction liquid was poured into ice/water, extracted with n-hexane, washed with water and dried over magnesium sulfate. After concentration followed by silica gel column chromatography, 6.1 g of intended ethyl 3-[4-(4,8-dimethyl-1,3,7-nonatrienyl)-phenyl]-2-butenoate was obtained as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5].B.[Na].O.CCCCCC>CO>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5].[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[OH:18])=[C:8]([Cl:19])[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(CC2CCCC2=O)c(Cl)c1
Agent: B
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(C[C@@H]2CCC[C@@H]2O)c(Cl)c1
Product: COC(=O)C(C)c1ccc(C[C@@H]2CCC[C@H]2O)c(Cl)c1
Yield: 28 %
Yield: 48 %

Procedure:
7 g of methyl-2-[3-chloro-4-(2-oxocyclopentane-1-yl methyl)phenyl]propionate were dissolved in 40 ml of methanol and then incorporated with 0.9 g of sodium boron hydride under agitation at room temperature, agitated at room temperature for 30 minutes, incorporated with 100 ml of water and then extracted with 100 ml of ethyl acetate. The extract obtained was washed with water, dried and then freed of the solvent at a reduced pressure to obtain a mixture of trans-form and cis-form bodies. The thus obtained mixture was adsorbed onto a silica gel-packed column and then separated with ethyl acetate.hexane (1:3) to obtain 2.0 g (yield 28%) of methyl-2-[3-chloro-4-(cis-2-hydroxycyclopentane-1-yl methyl) phenyl]propionate and 3.4 g (yield 48%) of methyl-2-[3-chloro-4-(trans-2-hydroxycyclopentane-1-yl methyl) phenyl]propionate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]([O:21]C)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][Al](C)C.CNCCNC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](=[O:21])[CH3:23])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C[Al](C)C
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: CC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, methyl 5,6-diphenyl-pyrazine-2-carboxylate (Compound 93, 83 mg, 0.29 mmol), Me3Al (0.4 ml, 2M in toluene), DMEDA (28 mg, 0.32 mmol) in toluene was reacted to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21](O)=[O:22])[O:12]1.[CH3:24][C:25]([CH3:31])([CH3:30])[C:26]([NH:28][NH2:29])=[O:27].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:24][C:25]([CH3:31])([CH3:30])[C:26]([NH:28][NH:29][C:21]([C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)=[O:22])=[O:27]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CC(C)(C)C(=O)NN
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)NNC(=O)C(C)(C)C)O[C@H]2n1cnc2c(Cl)ncnc21
Yield: 59.6 %

Procedure:
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (2.5 g) suspended in 1,2-dimethoxymethane (100 ml) was treated with 2,2-dimethyl-propionic acid hydrazide (1.1 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the mixture heated under reflux for 16 h. The mixture was poured into aqueous citric acid (250 ml) and extracted with ethyl acetate; the organic layers were washed with citric acid and brine, dried (MgSO4) and evaporated in vacuo to give the crude product. Purification by flash chromatography on silica gel (Biotage cartridge), eluting with ethyl acetate:cyclohexane 65:35, gave the title compound as a white solid (1.92 g).