Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OC2CCNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 30.4 %

Procedure:
To 1.3 gm of 3-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-pyridine was added 10 mL of solution containing 5 mL of TFA and 5 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1: 0.05, CHCl3: MeOH:conc. NH4OH) to obtain 120 mg (30.4% yield in two steps) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=4.7 Hz), 7.38 (2H, m), 5.00 (1H, m), 3.13-2.88 (4H, m), 220-1.95 (2H, m); Mass spectrum (ESI) m/z 165.6 (M+H+).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN1C(=O)CCC1>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN1CCCC1=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.2 g, 41 mmol) in NMP (60 mL) was added K2 CO3 (12 g, 82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at r.t. under N2 for 16 h. Then, the reaction mixture was diluted and filtered, and then the filtrate was diluted with EtOAc (300 mL). The resulting solution was washed with sat. NaHCO3 (aq) (3×200 mL), H2O (4×200 mL), brine (1×200 mL), dried over Na2SO4, filtered, concentrated and dried in vacuo to yield intermediate Int-15a (11.4 g, 86%) as a clear yellowish oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 0.010 mol) and DMF (30.0 mL, 0.387 mol) was cooled to 0° C. Sodium hydride (320 mg, 0.013 mol) (60% in oil) was added and the mixture was stirred for 10 min. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) was added and the resulting mixture was stirred for 20 min at 0° C. and 2 h at room temperature. The reaction was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrazole as a crude material. LC/MS (M+H)+: 325, 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 5.45 (s, 2H), 3.55 (t, 2H), 1.35 (s, 12H), 0.95 (t, 2H), 0.0 (s, 9H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:11])[C@@H:8]([CH3:10])[OH:9]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:9][C@H:8]([CH3:10])[C:7]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C1=COCCC1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)COC(=O)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
21.8 g (0.26 mole) of 3,4-dihydro-2H-pyran was dropwise added at room temperature to a mixture of 29.2 g (0.2 mole) of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 4 hours. After the reaction, 100 ml of ethyl acetate was added, followed by washing with 70 ml of a saturated aqueous sodium hydrogen carbonate solution, 70 ml of water and 70 ml of a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 49.0 g (yield: 92.1%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxyphenol (18.34 g) in tetrahydrofuran (150 ml) was added 60% sodium hydride (4.76 g) with ice-cooling, and the mixture was stirred at the same temperature for 15 min. Ethyl bromoacetate (14.2 ml) was added dropwise, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, 5% hydrochloric acid was added and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained solid was filtrated with hexane and dried under reduced pressure to give the title compound (21.78 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:57][NH:58][O:59][CH3:60]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:58]([O:59][CH3:60])[CH3:57])=[O:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a cold (0° C.) solution of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid (7.000 g, 30.531 mmol) in dichloromethane (200 mL) including triethylamine (4.681 mL, 33.584 mmol) were added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (15.885 g, 30.531 mmol), N,O-dimethylhydroxyamine (3.276 g, 33.584 mmol) and triethylamine (4.255 mL, 30.531 mmol) successively. The mixture was allowed to warm to room temperature, and the stirring was continued for 12 hrs. The reaction mixture was diluted with dichloromethane and washed with an aqueous 1N HCl solution, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10/1-9/1) to give 3-{[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester as a white solid. (8.050 g, yield; 96%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[S:11]([Cl:15])(=O)(=[O:13])[OH:12]>[OH-].[Na+]>[Cl:15][S:11]([C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 200 °C

Procedure:
5-(Chlorosulfonyl)-2-fluorobenzoic acid was prepared from 2-fluorobenzoic acid using a Biotage Initiator 8 microwave set to high absorbance as follows. Using conditions described, the reaction typically reached a pressure of 12 barr. The pressure was reduced to 3 barr after cooling and was vented prior to decapping the reaction vessel. To a 5 ml Biotage microwave reaction tube was added 2-fluorobenzoic acid (0.5 g, 3.57 mmol) and a Teflon covered magnetic stir-bar. To this was added 2 ml of chlorosulfuric acid. The vessel was capped and heated to 200° C. for 3.25 min. After cooling to room temperature, the remaining pressure was vented into a 50 ml syringe and discharged into 30 ml 1M NaOH. Reaction was quenched by adding dropwise to 30 ml of crushed ice. The solid product was collected by vacuum filtration, washed with water (5 ml, 3×) and air-dried under vacuum for 2 h, yielding 5-(chlorosulfonyl)-2-fluorobenzoic acid as a light yellow solid.
Reaction SMILES: C1([OH:7])C=CC=CC=1.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.C[C@:33]1([OH:63])[C@@H:47]2[C:42](=[C:43](O)[C@:44]3([OH:60])[C:51](=[O:52])C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2>>[CH:42](/[CH:47]=[CH:33]/[OH:63])=[CH:43]\[C:44]([C:51]([OH:7])=[O:52])=[O:60]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Reactant: Oc1ccccc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: O=C(O)C(=O)/C=C/C=C/O

Procedure:
Transformants were spread on LB plates containing 1 mM phenol, 50 μg of ampicillin per ml, and 12.5 μg of tetracycline per ml and incubated overnight at 37° C. Colonies that became yellow (as a result of 2-hydroxymuconic semialdehyde) following spraying of a 0.1% of catechol solution were patched on LB plates containing 1 mM phenol. Colonies in which the yellow compound formed during growth without catechol addition were retained as putative carriers of both pheA and pheB.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].C(O[Si](CCC[N+:59]1[CH2:63][CH2:62][N:61](C)[CH:60]=1)(OCC)OCC)C.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].[NH+:59]1[CH:63]=[CH:62][NH:61][CH:60]=1
Reactant: CCO[Si](CCC[N+]1=CN(C)CC1)(OCC)OCC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CO
Solvent: CCO
Solvent: O
Product: c1c[nH+]c[nH]1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.34 g of tetraethoxysilane, 22.02 g of methyltriethoxysilane, 0.73 g of the 30% ethanol solution of triethoxysilylpropyl-3-methyl-4,5-dihydroimidazolium trifluoromethanesulfonate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.10 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-14):
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[C:21]1([NH:20][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a stirred solution of N-BOC-L-phenylalanine (20 g, 75.4 mmol) in methylene chloride (200 mL) is added aniline (7.0 mL, 75.4 mmol), dicyclohexylcarbodiimide (15.5 g, 75.4 mmol), and 1-hydroxy-7-azabenzotriazole (10.3 g, 75.4 mmol). The mixture is stirred at room temperature overnight. The solid is filtered away and the filtrate is washed with 5% citric acid (50 mL), a saturated solution of sodium bicarbonate (50 mL), and brine (50 mL). The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a light brown solid. The solid is recrystallized from ethyl acetate to afford N-BOC-L-phenylalanine-N-phenylamide as a white solid (11 g).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:10][O:9][C:7]1([O:11][CH3:12])[CH2:8][CH:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1(OC)CC(CO)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83.8 %

Procedure:
A solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (1.48 g, 8.49 mmol) in tetrahydrofuran (5 ml) was added dropwise to a cooled 0° C. suspension of lithium aluminum hydride (0.39 g, 10.19 mmol) in tetrahydrofuran (15 ml). The reaction was allowed to warm to 25° C. and stirred for 17 h. After such time, ethyl acetate (1 ml) and a few crystals of sodium sulphate decahydrate were added with caution and stirred until gas evolution stopped. The resulting residue was filtered through a short celite pad and washed with ethyl acetate and then concentrated in vacuo to afford (3,3-dimethoxy-cyclobutyl)-methanol (1.04 g, 84%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.57 (brs, 1H, OH), 1.82-1.97 (m, 2H, CH2), 2.23-2.36 (m, 3H, CH2 and CH), 3.14 (s, 3H, OCH3), 3.16 (s, 3H, OCH3), 3.64-3.68 (m, 2H, OCH2).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH:26]=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C=CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)CCC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.4 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]but-2-enoate are dissolved in 35 ml of methanol, and 200 mg of PD (10% on activated carbon) are added. At room temperature, the mixture is stirred under an atmosphere of hydrogen for 7 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. This gives 2.3 g of tert-butyl 4-[cis-3-(tert-butyldiphenylsilanyloxy)cyclohexyl]-butanoate as an oil. C30H44O3Si (480.75), MS(ESI): 481 (M+H+).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.CCCCCC.[C:19]1([CH2:25][CH2:26][C:27](OCC)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O1CCCC1>[O:28]=[C:27]([CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A solution of dimethyl methylphosphonate (12.4 g., 0.1 mole) in dry tetrahydrofuran (75 ml.) is stirred, maintained under a nitrogen atmosphere, cooled to -50° C., and treated with a 2 N solution of n-butyl lithium in hexane (50 ml., 0.1 mole) added dropwise. Upon completing the addition, the reaction mixture is kept at -50° C. for 1/2 hour to ensure anion formation and then is treated with ethyl 3phenylpropionate (8.9 g., 0.05 mole) added dropwise at -50° C. After stirring for an additional 11/2 hours at -50° to -40° C., the reaction mixture is poured into ice water (250 ml.) providing a turbid solution which is acidified with 2 N hydrochloric acid and extracted with ethyl acetate (4 × 75 ml.). The combined organic extract is dried over sodium sulfate and filtered. Evaporation of the filtrate in vacuo at 40° to 50° C. leaves an oily residue which is distilled to provide the title compound as an oil (11.0 g., 86%), b.p. 148°-150° C./0.1 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:15])([CH3:14])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]([CH3:14])([CH3:15])[CH2:4][CH2:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH:8]([OH:13])[CH2:7]1
Reactant: COC(C)(C)CCC1CC(=O)CC(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(C)CC(O)C1
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of 3-(3-methoxy-3-methylbut-1-yl)-5-methylcyclohexan-1-one (0.50 g, 0.0024 mol) in tetrahydrofuran (1 mL) was added to a suspension of lithium aluminum hydride (0.10 g, 0.0027 mol) in tetrahydrofuran (1 mL) cooled to 0~C. The mixture was stirred at 20~C. for 16 h. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5-methylcyclohexanol (0.40 g) as a mixture of four diastereoisomers (ratio 2.8:15.3:79.2:2.8).
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[Cl:23][CH2:24][C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)=[O:26].CC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:23][CH2:24][C@H:25]([C@H:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:37])[CH:33]=2)[O:28]1)[OH:26]
Reactant: O=C(CCl)C1CCc2cc(F)ccc2O1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O[C@H](CCl)[C@H]1CCc2cc(F)ccc2O1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of (+)-B-chlorodiisopinocampheylborane [(+)-DIP-Chloride™] (2.10 g, 6.55 mmoles) in toluene (7 ml) is cooled to 0° C. under nitrogen atmosphere. On the magnetically stirred solution is added in 3 hours a solution of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanone (1.0 g, 4.373 mmoles) in toluene (3 ml). At the end of the addition, the mixture is stirred at 0° C. for further 20 hours. On the reaction mixture is added acetone (0.5 g), followed by a 10% w/w (5 ml) aqueous solution of sodium carbonate, and then demi water (5 ml). The reactive mixture is heated to 20° C. at the end of the additions and transferred in a separator funnel. The mixture is diluted with demi water (5 ml) and toluene (5 ml) and phases are separated. The organic layer is then washed with additional demi water (15 ml) and concentrated and anhydrified under vacuum to obtain crude (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol (99% de via GC). The product is purified by chromatography on silica using a toluene:ethyl acetate 9:1 eluting mixture. After separation, the product (S*)-2-chloro-1-((R*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)-ethanol is isolated as a colorless oil (0.64 g, 63%).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:1])([F:11])[O:3][C:4]=2[CH:10]=1
Reactant: BrBr
Reactant: FC1(F)Oc2ccccc2O1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: FC1(F)Oc2ccc(Br)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Iron powder (2.8 g, 50 mmol) was added to a solution of 2,2-difluoro-1,3-benzodioxole (15.8 g, 100 mmol) in carbon tetrachloride (200 mL) at 0° C. under a nitrogen atmosphere. Bromine (5.2 mL, 100 mmol) was then added to the mixture dropwise over 15 min. The reaction was heated to reflux for 1 h and then stirred at room temperature overnight. The mixture was filtered through Celite and the filtrate was washed with 0.1N sodium thiosulfate solution. The organic layer was then dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A as an oil (15.2 g, 64%). 1H NMR (CDCl3): δ6.96 (m, 1H), 7.22 (m,2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-:18])(=[S:17])[CH3:16].[K+].[Na+].[I-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:17][C:15](=[O:18])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 173821.91 %

Procedure:
To a solution of 6.9 g (0.02 mol) of 4-bromo-piperidine-1-carboxylic acid tert-butyl ester in DMF (18 mL) are added 5.25 g (0.012 mmol) potassium thioacetate, followed by a catalytic amount of NaI (0.35 g, 10 mol %) at room temperature. After complete addition, the reaction is heated to 50° C. for 20 h. The reaction mixture is partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer is dried over Na2SO4, filtered and the solvent is removed under reduced pressure to afford 5.41 g of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 81%; ES-MS: m/z 245 [M+H—CH3], 160 [M+H—O5H9O2]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.37-1.64 (11 H, m), 1.78-1.99 (2 H, m), 2.25-2.35 (3 H, m), 3.06 (2 H, ddd, J=13.63, 10.43, 3.05 Hz), 3.61 (1 H, tt, J=10.28, 4.04 Hz), 3.76-3.96 (2 H, m)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[N-:10]=[N+:11]=[N-:12].[Na+]>>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:11]=[N-:12]
Reactant: O=C(O)CCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCCCCCC(=O)O

Procedure:
Reaction of 6-bromohexanoic acid and NaN3, as described for the synthesis of 6, gave 6-Azidohexanoic acid 9. Saponification was not necessary. Used without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:16]>C1COCC1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the solution of 2,3,4,5-tetrafluorobenzoic acid (compound f, 29.5 g, 150 mmol) in 200 ml THF, was added SOCl2 20 ml dropwise at 0° C., then the mixture was stirred at room temperature for 6 hours. After removal of the solvent and excessive SOCl2, the residue was used for the next step directly.