Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[FH:7].[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12](N)=[C:11]([I:17])[CH:10]=1.N([O-])=O.[Na+]>>[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([F:7])=[C:11]([I:17])[CH:10]=1
Reactant: Cc1cc(Br)cc(I)c1N
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(I)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
A PFA plastic round bottom flask was charged with a solution of hydrogen fluoride pyridine (70 wt % HF, 100 ml, 1150 mmol). The solution was cooled to 0° C. and 4-bromo-2-iodo-6-methylaniline (9.2 g, 29.5 mmol, Organic Letters 2009, 11, 249-251) was added portion wise. After 15 minutes, sodium nitrite (1.032 ml, 32.4 mmol) was added and the reaction mixture was stirred at 0° C. for additional 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 15 minutes, followed by heating at 90° C. for 3 hour. The reaction mixture was then cooled to room temperature and quenched with water and diethyl ether. The organic layer was separated, washed with brine and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure. The crude material was purified via silica gel chromatography eluting with hexanes to afford the title compound (8.45 g, 26.8 mmol, 91% yield) as a brown solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.29 (s, 3H) 7.27-7.34 (m, 1H) 7.64-7.75 (m, 1H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:22][CH2:23][OH:24]>CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][OH:24])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCO)CC1

Procedure:
To a solution of piperidin-4-yl-carbamic acid tert-butyl ester 3 (10 g, 50 mmol) in 100 ml of methanol are added sodium carbonate (21.2 g, 200 mmol) and 2-bromoethanol (7.1 ml, 100 mmol). The mixture is stirred over night. The solvents are then evaporated and the residue is triturated with DCM, filtered and evaporated again. The crude product is purified by chromatography using EtOAc/MeOH (saturated with ammonia): 9/1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[OH:10][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: CCC(=O)Cl
Product: CCC(=O)c1ccc(O)c(C(C)C)c1
Yield: 32.1 %

Procedure:
In a manner similar to that of Example 1(a), by reacting 10 g (73 mmol) of 2-isopropylphenol with 6.3 ml (73 mmol) of propionyl chloride, 4.5 g (32%) of the expected product are obtained in the form of white crystals with a melting point of 105° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11]I.O>CS(C)=O.CCOCC>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[N:9][CH:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(C)nc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 60% NaH (in mineral oil) (18.27 g, 0.458 mol, Aldrich, India) in DMSO (66 mL, Spectrochem., India) at 0° C., was added 6-methylpyridin-3-ol (25.0 g, 0.229 mol) dissolved in DMSO (100 mL) drop wise over a period of 15 min. After complete addition, the reaction mixture was stirred at 0° C. for 40 min. Methyl iodide (29.5 mL, 0.458 mol, Spectrochem, India) was added and the reaction mixture was stirred at rt for 2 h. The reaction with water and Et2O (1:1, 200 mL). The organic layer was separated and aqueous layer was back extracted with Et2O (75 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the title compound as a dark brown gummy oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (d, J=2.8 Hz, 1H), 7.12-7.05 (m, 2H), 3.83 (s, 3H), 2.49 (s, 3H). MS (ESI, positive ion) m/z: 124.0 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[N:5]=1)[CH3:3].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:23][C:18]1[CH:17]=[C:16]([CH2:15][N:5]2[C:6]3[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CC(C)c1nc2c([nH]1)CCCC2=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To Intermediate 56 (1st Alternative preparation) (88.83 g, product of multiple previous experiments) was added toluene (2000 mL) followed by 4-(bromomethyl)-1,2-dichlorobenzene (132 g) and tetrabutylammonium bromide (80 g) then sodium hydroxide (1096 mL). The mixture was then stirred at room temperature, stirring vigorously to mix the phases. The temp rose by 5° C. over 5 mins. After 1.5 hr the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted well with ethyl acetate—aq phase got up to 50° C. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated. The crude product was purified by column chromatography, loaded in DCM, eluting with 0-100% ethyl acetate in cyclohexane. The appropriate fractions were evaporated and this gave the title compound, a cream solid, two batches 114.8 gm and 16.22 gm. LC/MS MH+337, 339, Rt 0.96 min (2 min run).
Reaction SMILES: FC(F)(F)C([O-])=O.FC(F)(F)C(O)=O.[NH2:15][C@@H:16]1[C:37](=[O:38])[N:18]2[C:19]([C:34]([OH:36])=[O:35])=[C:20]([CH2:23][N+:24]3[N:28]4[CH2:29][CH2:30][C:31](=[O:33])[NH:32][C:27]4=[CH:26][CH:25]=3)[CH2:21][S:22][C@H:17]12.CN(C)C=O.[NH2:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=[N:63][O:64][CH3:65])[C:51](N2C3C=CC=CC=3[N+]([O-])=N2)=[O:52])[N:49]=1.Cl>O1CCCC1.O>[NH2:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=[N:63][O:64][CH3:65])[C:51]([NH:15][C@@H:16]2[C:37](=[O:38])[N:18]3[C:19]([C:34]([O-:36])=[O:35])=[C:20]([CH2:23][N+:24]4[N:28]5[CH2:29][CH2:30][C:31](=[O:33])[NH:32][C:27]5=[CH:26][CH:25]=4)[CH2:21][S:22][C@H:17]23)=[O:52])[N:49]=1
Reactant: CON=C(C(=O)n1n[n+]([O-])c2ccccc21)c1csc(N)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(C[n+]3ccc4n3CCC(=O)N4)CS[C@H]12
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc4n3CCC(=O)N4)CS[C@H]12)c1csc(N)n1
Reaction time: 4 h

Procedure:
To a solution of 7β-amino-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate bis(trifluoroacetate) (1.5 g) in a mixture of tetrahydrofuran (40 ml) and water (20 ml) was added N,N-dimethylformamide solvate (1.02 g) of 1-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetyl]-1H-benzotriazol-3-oxide at ambient temperature. The mixture was stirred for 4 hours at pH 7. The solution was adjusted to pH 2 with 1N hydrochloric acid, washed with ethyl acetate five times and evaporated in vacuo to remove ethyl acetate. The solution was subjected to column chromatography on HP-20 and the elution was carried out with 5% aqueous isopropyl alcohol. The objective fraction was collected and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(5-oxo-4,5,6,7-tetrahydro-1-pyrazolo[1,5-a]pyrimidinio)methyl-3-cephem-4-carboxylate (syn isomer) (261 mg).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CC1C=CC(S([O:17][CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25]O)[CH2:21][CH2:20]2)(=O)=O)=CC=1>C1COCC1>[CH3:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([CH2:18][OH:17])[CH2:20][CH2:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](CO)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiAlH4 (153 g, 4 mol) was added to a solution of trans-4-(hydroxymethyl)cyclohexylmethyl 4-methylbenzenesulfonate (400 g, 1.34 mol) in THF (3000 mL) at −20° C. The mixture was stirred at room temperature for 3 h. It was quenched with water (10 L) and filtered. The filtrate was concentrated in vacuo to give trans-(4-methylcyclohexyl)methanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCCN1CCO
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a Stirred solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (2.6 g, 20 mmol) in pyridine (15 ml) was added methanesulfonyl chloride (2.28 g, 20 mmol) and the reaction mixture was stirred at RT overnight. Solution was concentrated and diluted with ethyl acetate (50 ml) and washed with water (50 ml). Ethyl acetate layer was separated, dried over anhydrous sodium sulfate and evaporated to yield 3.0 g of 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate, as an oil (yield: 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9](P(OCC)(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].C=O.[C:25](=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[CH2:25])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)P(=O)(OCC)OCC
Agent: C=O
Agent: [K+]
Solvent: O
Product: C=C(Cc1ccccc1Cl)C(=O)OCC
Temperature: 90 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
To a stirred mixture of ethyl 3-(2-chlorophenyl)-2-(diethoxyphosphoryl)propanoate (step 1, 14.6 g, 41.9 mmol) and 37% formaldehyde in water (20 mL) was added a solution of potassium carbonate (17.4 g) in water (80 mL) at the room temperature and the mixture was stirred for 6 h at 90° C. After cooling to room temperature, the mixture was extracted with diethyl ether (300 mL), and then the organic layer washed with brine (100 mL), dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (300 g) eluting with hexane/ethyl acetate (30/1) to afford 6.57 g (70%) of the title compound as a colorless oil:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[Li]CCCC.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:3]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Reaction time: 0.25 h
Yield: 84 %

Procedure:
3 g (0.015 mol) of 2 in 20 mL of anhydrous THF was cooled to −78° C. and n-BuLi 2.5 M in hexanes (6.7 mL, 0.167 mol) was added dropwise. After 15 minutes of stirring, tosyl chloride in 5 mL of THF was added dropwise. The cooling bath was removed and the reaction mixture stirred at rt for 1 h. Extracted with ether and the organic phase washed with brine, dried with magnesium sulfate and concentrated in vacuo to give a white solid that was passed through a pad of silica (70% EtOAc; 30% Hexanes) to give 4.65 g (84%) of 3. 1H NMR CDCl3 8.4 (s, 1H), 8.1 (d, 2H), 7.8 (s, 2H), 7.2 (m, 3H), 2.3 (s, 3H).
Reaction SMILES: Br[CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[C:11]([O:15][C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16](=[O:27])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])([CH3:12])[CH3:14]
Reactant: COC(=O)C(Br)C(=O)OC
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)C(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dimethyl bromomalonate (6.6 ml.) was added to a stirred solution of L-alanyl-L-proline t-butyl ester (22.9 g.) in dichloromethane (40 ml.) which was cooled to 0° C., and the mixture was allowed to warm up to laboratory temperature and stirred at that temperature for 16 hours, then diluted with dichloromethane (150 ml.). The solution was washed successively twice with aqueous 0.5N-citric acid solution (150 ml. each time), water (200 ml.) and saturated aqueous sodium chloride solution (200 ml.), dried over magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on a silica gel column using a 4:1 v/v mixture of dichloromethane and ethyl acetate as eluant, and there was thus obtained as an oil N-(dimethoxycarbonylmethyl)-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:19][CH2:20][CH2:21][NH:22][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCCF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FCCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 2-fluoroethylamine hydrochloride (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added to the reaction mixture, and the mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (12 mg) and a syn-form compound (12 mg).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C>ClCCl>[CH2:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Cl:5])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methanesulfonyl chloride (3.069 g, 26.791 mmol) was added to a solution of 4-butylbenzyl alcohol (4.000 g, 24.355 mmol) in dichloromethane (120 mL) at 0° C. under argon atmosphere. Then triethylamine (2.711 g, 26.791 mmol) was added dropwise at a slow speed to this mixture at 0° C., and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane) to give the title compound (3.64 g, 82%) as a colorless oil.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][OH:44])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]1)=[O:17])=[O:9].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([C:39]#[C:40][C:41]([CH3:45])([CH3:46])[CH2:42][CH2:43][O:44][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:13][C:14]=1[N:15]([CH:25]1[CH2:30][CH2:29][CH:28]([O:31][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33])[CH2:27][CH2:26]1)[C:16]([CH:18]1[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23]1)=[O:17])=[O:9]
Reactant: COC(=O)c1sc(C#CC(C)(C)CCO)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)CCO[Si](C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
TMSCl (0.08 mL, 0.596 mmol) was added dropwise to a solution of 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(5-hydroxy-3,3-dimethyl-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (300 mg, 0.497 mmol) and triethylamine (0.11 mL, 0.745 mmol) in dichloromethane at 0° C. After stirring for 1 h, the reaction was warmed to room temperature and stirred for an additional 1.5 h. The solution was washed with water, brine, dried and concentrated to give crude 3-[[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-5-trimethylsilanyloxy-pent-1-ynyl)-thiophene-2-carboxylic acid methyl ester (330 mg) which was carried to next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+].Cl>C1COCC1.O>[OH:8][CH2:7][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:13]=[C:12]([I:14])[CH:11]=1
Reactant: COC(=O)c1cc(I)cc(C(=O)OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(I)cc(CO)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of dimethyl-5-iodisophthalate in 800 ml of THF was treated with with 22.2 g of CaCl2. Then, 15.2 g of NaBH4 were added portionwise. The mixture was stirred for one day at room temperature. Then, the mixture was acidified with 250 ml of 3N HCl and diluted with 2 l of H2O. The crude product was isolated by extraction and purified by crystallization from THF/hexane. There were obtained 11.2 g of (3-hydroxymethyl-5-iodo-phenyl)-methanol as white crystals.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:11](O)(=[O:14])[CH:12]=[CH2:13].C(OOC(C)(C)C)(C)(C)C>>[CH:1]([CH:4]1[CH2:9][CH2:8][C:7]2([O:10][C:11](=[O:14])[CH2:12][CH2:13]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C=CC(=O)O
Reactant: CC(C)C1CCC(O)CC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(C)C1CCC2(CCC(=O)O2)CC1

Procedure:
To 1247 g of 4-isopropylcyclohexanol at 143°-150° C. was added in 6 hrs a mixture of 71.1 g (1.0 m) acrylic acid, 142 g (1.0 m) 4-isopropylcyclohexanol and 14.6 g (0.1 m) di-tert-butylperoxide. After an additional hour at 143°-150° the mixture was distilled at reduced pressure yielding 142.1 g. Bp:125°-141° C. (1.0 mm Hg). Odor:woody, milky-lactone, dry. Analysis:99% pure by VPC: 44% cis (odor:nonalactone, celery-lactone) 56% trans (odor:strong woody, cinnamic, urine)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H+].[B-](F)(F)(F)F.CCOCC.[I:22]N1C(=O)CCC1=O>C(#N)C>[I:22][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1I
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: O=C(O)c1ccc(O)c(I)c1
Reaction time: 16 h
Yield: 57.1 %

Procedure:
To a stirring solution of 4-hydroxy-benzoic acid (6.91 g, 50.03 mmol) in dry acetonitrile (250 mL) at −20° C. under an atmosphere of N2 was added HBF4-Et2O (10.50 g, 9.50 mL, 55.00 mmol) dropwise via syringe. The solution was stirred at 0° for 0.5 hours at which time solid N-iodosuccinimide (13.5 g, 60 mmol) was added at one time. The solution was left to stir for 16 hours and then filtered to remove precipitated succinimide. The solution was diluted with water (500 mL) and extracted with ethyl acetate (2×250 mL). The organic portions were combined and washed with 10% sodium bisulfite (250 mL), water (2×250 mL) and saturated aqueous NaCl (250 mL). The solvent was removed in vacuo to yield 8.76 g of crude solid. The crude solid was purified by column chromatography (6:4:0.1 hexane:ethyl acetate:formic acid) to yield 7.54 g (57%)of the desired product as white crystals. 1H NMR (DMSO-d6) δ 12.74 (br s, 1H), 11.18 (s, 1H), 8.20 (s, 8.20, 1H), 7.79 (d, 1H), 6.94 (d, 1H).
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[I-].[Na+].[OH:14][CH:15]([CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:16][C:17]([O:19][CH3:20])=[O:18]>C(#N)C>[CH3:25][C:24]1([CH3:26])[O:14][CH:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)CC(O)CCC=C(C)C
Agent: [Ce+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: COC(=O)CC1CCCC(C)(C)O1

Procedure:
Cerium chloride heptahydrate (812 mg) and sodium iodide (327 mg) were added to a solution of methyl 3-hydroxy-7-methyl-6-octenoate obtained by the method described in Heterocycles, 34, 1107-1117 (1992) (4.06 g) in acetonitrile (10 ml), and the reaction solution was heated under reflux for 10 hours. The reaction solution was left to cool and then concentrated under reduced pressure. Diethyl ether and 12 ml of 1 N hydrochloric acid were added to the resulting residue, and the organic layer was separated. Diethyl ether was added to the aqueous layer, and the organic layer was separated. The combined organic layers were sequentially washed with water, a saturated sodium bicarbonate solution (pH=9), a 5% sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.65 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCCCC1.C([C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1)=O>N1C=CC=CC=1>[C:3](/[CH:2]=[CH:1]/[C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1)([OH:5])=[O:4]
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ncc(/C=C/C(=O)O)c(OC)n1

Procedure:
Malonic acid (13.03 g; 126.2 mmol) and redistilled piperidine (2 ml) were added to a solution of 5-formyl-2,4,dimethoxypyrimidine (10.52 g; 6.2.6 mmol) in dry pyridine (60 ml). The mixture was heated on a steam bath for 10 h then the solvent was removed by distillation under reduced pressure. The residual oil was re-evaporated from water (3×25 ml) and the solid thus obtained recrystallised firstly from water and then from dry methanol to give the product as white needles, yield 6.45 g; a second crop was obtained from the filtrate (1.08 g). Total yield 7.53 g (57%). Mass spectrum: (El) m/z 210 (M+). Analysis, found: C,52.1;H,4.8;N, 13.1%: C9H10N2O4 requires: C, 52.43; H, 4.79; N, 13.33%.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1ccc(OCC(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)F
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (520 mg, clear colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethanone (750 mg, 3.5 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.