Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C@@H:13]([CH:15]([O:18][CH3:19])[O:16][CH3:17])[O:12][CH:11]([OH:20])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:17][O:16][CH:15]([O:18][CH3:19])[C@H:13]1[O:12][CH:11]([OH:20])[CH2:10][C@H:9]([OH:8])[CH2:14]1
Reactant: COC(OC)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(OC)[C@@H]1C[C@@H](O)CC(O)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.47 g of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(dimethoxymethyl)-tetrahydro-2H-pyran-2-ol (I′) in 14 mL of tetrahydrofurane, tetra-n-butylammonium fluoride in 14 mL of THF is added. After 15 minutes of stirring at 25° C., the THF is distilled off. The residue is flash chromatographed (methanol). After methanol is distilled off, the title compound is obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 75.8 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (160 mg, 76%). MS (ISP) 423.2 [(M+H)+]; mp 182° C.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1.[Zn].O>[OH:36][C@H:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CBr
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@H](O)c1ccccc1
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under protective nitrogen gas was initially charged with 5 g of zinc dust (77 mmol) in 30 ml of tetrahydrofuran. After 1.2 ml of trimethylchlorosilane had been added, the mixture was heated to 55 C for 15 min, and 10.9 g of methyl bromoacetate (71 mmol) were subsequently added dropwise undiluted while refluxing at 45° C. within 7 min. The mixture was then stirred for 10 min. After cooling to 10 C, 30 ml of tetrahydrofuran were added and 17 g of (−)-sparteine (72 mmol) were subsequently added undiluted at 0 C, and the temperature rose to 5 C. The mixture was cooled to 15 C and 6.4 g of benzaldehyde (60 mmol) were added undiluted. The reaction mixture was subsequently stirred at 15 C for 20 h, then acidified at this temperature with 35 ml of 20% hydrochloric acid to a pH of 3 and stirred for 10 min, and the temperature of the mixture rose to 0 C. 150 ml of water were then added. Precipitated sparteine salt was filtered off with suction and washed twice with 40 ml of ethyl acetate each time. After removing the organic phase, the aqueous phase was extracted with 50 ml of ethyl acetate and the organic phase was subsequently removed. The organic phase was then stirred with 20 ml of concentrated ammonia solution at −10° C. for 5 min. After phase separation, drying and removal of solvent under reduced pressure, methyl (S)-(−)-3-hydroxy-3-phenylpropionate was obtained in a yield of 10.5 g (97% of theory) and a purity of >95% and 89% ee (HPLC).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1ccc(C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCO)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a suspension of ethyl 3-(6-methyl-3-pyridinyl)propanoate (500 mg, 2.59 mmol) in tetrahydrofuran (15 ml) at 0° C., LiAlH4 (1.42 ml, 2.85 mmol) was added dropwise. When the addition was complete, the ice bath was removed and the reaction stirred at room temperature for 1 hour. Wet THF was added dropwise until a white solid precipitated and the evolution of gas ceased. The solid was filtered off, washed twice with Et2O and the filtrate evaporated under vacuum to afford the title compound (403 mg).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Br[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1>O.COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[C:12]1[S:13][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: Brc1ncccn1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: O=Cc1ccc(-c2ncccn2)s1
Yield: 25.9 %

Procedure:
A mixture of Na2CO3 (3.16 g) and 5-formyl-2-thiopheneboronic acid (2.4 g, 15.1 mmol) in water (15 mL) were added to a solution of 2-bromopyrimidine (2 g, 12.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (480 mg, 0.46 mmol) in DME (30 mL) and the mixture was heated to reflux for 24 hr. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 620 mg (26%) of the title compound. MS 191 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C(OCC)(=O)C.O>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][NH:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Reactant: CCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCNCCc1ccccc1Br
Reaction time: 0.08 h

Procedure:
7 g of 2-(2-bromophenyl)ethyl methanesulfonate, 14.5 cm3 of 1-pentanamine, 17.33 g of potassium carbonate and 200 cm3 of tetrahydrofuran are stirred at a temperature between 65° C. and 70° C. under an inert atmosphere for 72 h. The reaction mixture is brought to 30° C. in order to be poured over a mixture of water, ice and ethyl acetate. The phases are stirred for 5 min, then are separated. The aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 6.6 g of oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 95% dichloromethane/5% methanol to 90% dichloromethane/10% methanol gradient). After concentrating the fractions under reduced pressure, 4.56 g of N-[2-(2-bromophenyl)ethyl]pentan-1-amine are obtained in the form of a white oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:12]([C:18]([C:20]([F:23])([F:22])[F:21])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[C:1]1([NH:7][C:8]2[O:9][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([C:20]([F:21])([F:23])[F:22])[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=O)Nc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1oc(Nc2ccccc2)nc1C(F)(F)F
Yield: 41.3 %

Procedure:
By the procedure of Example 4, 8.2 g (60 mmol) of phenyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 24 hours. The product mixture was treated with methylene chloride, washed with water, dried and concentrated. The residue was recrystallized from methylcyclohexane to yield 6.2 g of crystal product (m.p.=114°-116° C.) identified in Table I.
Reaction SMILES: C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH2:13]([C:16]([P:22]([OH:25])([OH:24])=[O:23])([P:18]([OH:21])([OH:20])=[O:19])[OH:17])[CH2:14][NH2:15].[OH-].[Na+:27].P(=O)(O)(O)O>O>[CH2:13]([C:16]([P:22]([O-:25])([OH:24])=[O:23])([P:18]([O-:20])([OH:21])=[O:19])[OH:17])[CH2:14][NH2:15].[Na+:27].[Na+:27]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: O=P(O)(O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Product: NCCC(O)(P(=O)([O-])O)P(=O)([O-])O
Reaction time: 0.25 h

Procedure:
For a batch size of 5 L, 587.5 g (3.2 moles) of mannitol is dissolved in 3.5 L of water. Pamidronic acid (31.6 g, 0.133 moles) is mixed with a 1.0 L aliquot of the mannitol solution to form a slurry. The slurry is transferred into the remainder of the mannitol solution, and stirred for about 15 min. Aqueous 1 N sodium hydroxide (270 ml) is added and the mixture is stirred until a clear, colorless solution results. The pH is adjusted to 6.5±0.1 using either 1 M aqueous phosphoric acid or 1 N aqueous sodium hydroxide, as needed. The solution is filtered through a 0.22 micron filter, and filled at 20° C. into glass vials at 4.0 ml (4.172 g)/vial, and the vials are sealed in the lyophilizer in an inert atmosphere under sterile conditions.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([OH:21])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]([O:21][CH3:30])[CH:12]2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CN(C1c2cc(OCc3ccccc3)ccc2OC(C)(C)C1O)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
0.5 g (1.3 mmol) of N-(6-benzyloxy-3-hydroxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 1g) dissolved in 4 ml of DMF was added dropwise to a suspension of 0.05 g (1.7 mmol) of sodium hydride in 3 ml of DMF. The mixture was stirred at RT for 30 min, 0.25 g (1.8 mmol) of methyl iodide was added, and the mixture was stirred at RT for another 3 h. The reaction mixture was concentrated under reduced pressure, the residue was taken up in water and EA and the organic phase was washed with dilute hydrochloric acid and saturated sodium bicarbonate solution. Drying over magnesium sulfate and concentration under reduced pressure gave 0.52 g of N-(6-benzyloxy-3-methoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide, m.p. 119-121° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=[C:17]([NH2:29])[CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN1C(=O)CCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10]([NH:29][C:17]1[CH:16]=[C:15]([Cl:14])[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Temperature: 40 °C
Reaction time: 60 h

Procedure:
A mixture of 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.17 g, 6.19 mmol), 4-chloro-6-(2-phenylethynyl)pyridin-2-amine B3a (1.09 g, 4.76 mmol), triethylamine (3.63 ml, 25.7 mmol) HATU (2.89 g, 7.61 mmol) and NMP (3.75 ml) is stirred at 40° C. for 60 h. 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (0.72 g, 3.81 mmol) and HATU (1.45 g, 3.81 mmol) is added to the mixture and stirring continued for 48 h at 60° C. At RT water is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 712 mg (37%). HPLC-MS: M+H=400; tR=2.27 min (*Method—2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>C1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[C:6]2[C:7](=[CH:16][CH:15]=1)[C:8]([O:12][C:3](=[O:2])[CH3:9])=[C:9]([O:10][CH3:11])[C:3]([O:2][CH3:1])=[C:4]2[O:5][C:4](=[O:5])[CH3:6]
Reactant: COC1=C(OC)C(=O)C=CC1=O
Reactant: C=C(Cl)C=COC
Solvent: c1ccccc1
Product: COc1c(OC)c(OC(C)=O)c2cc(Cl)ccc2c1OC(C)=O
Reaction time: 12 h
Yield: 203.1 %

Procedure:
A benzene (8 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 30 hours under an inert atmosphere. After this time, the reaction mixture is concentrated and then dissolved in pyridine (8 ml). Acetic anhydride (3.0 g) is added, and the solution is stirred for 12 hours under an inert atmosphere. The contents are diluted ten-fold with water and extracted with ethyl acetate. The organics are then washed with water, brine, and then dried over sodium sulfate. Concentration, followed by flash chromatography (hexane/ethyl acetate 3:1) affords 2.03 g (93%) of a compound of the formula ##STR5##
Reaction SMILES: Cl.[NH2:2]O.C([O-])(=O)C.[Na+].[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:14][C:15]=1[Cl:16].O>C(O)C>[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:17]([C:18]1[CH:24]=[N:2][O:20][C:19]=1[CH:21]1[CH2:23][CH2:22]1)=[O:28]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(Cl)c1N(CC)C(=O)OC)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(C(=O)OC)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Yield: 40.9 %

Procedure:
Hydroxylamine hydrochloride (0.53 g) and sodium acetate (0.63 g) were added to a stirred solution of 1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.88 g) in ethanol. After 05 hours water was added, and the mixture extracted (dichloromethane), dried (magnesium sulphate) and evaporated to dryness. Purification by chromatography gave 4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole (compound number 2, 1.09 g), m.p. 76-78° C. as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11]>O1CCOCC1.C([O-])(O)=O.[Na+]>[C:10]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11]
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a stirred and cooled suspension of trans-3-hydroxy-(L)-proline (2.00 g, 15.3 mmol, 1.00 eq.) in 1,4-dioxane (110 mL) and aq. NaHCO3 (5% w/v, 55 mL) was added slowly a solution of Fmoc-Cl (4.02 g, 15.56 mmol, 1.02 eq.) in dioxane (50 mL). The reaction mixture was kept at 4° C. for 4 h, allowed to warm to room temperature, and stirred for another 6 h to afford a clear, colorless solution. Most of the dioxane was evaporated in vacuo (45° C. bath temperature), and the resultant solution was extracted with diethyl ether (2×100 mL) to remove excess Fmoc-Cl. The aqueous layer was acidified to pH 2-3 with 1 M HCl to afford a cloudy solution, which was extracted with EtOAc (4×100 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and co-evaporated twice with CH2Cl2. Drying under vacuum afforded the product as an off-white, microcrystalline solid (3.10 g, expected 5.39 g, yield 58%). Spectroscopic data were in agreement with the literature (Taylor, Hardre et al. 2005).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13]O)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:13][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12][CH:11]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)s1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
To a suspension of [2-(4-chlorophenyl)thiazol-5-yl]methanol (3.24 g, 14.3 mmol) in dichloromethane (40 ml) is added dropwise the thionyl chloride (1.3 ml, 18 mmol) at room temperature under nitrogen. The reaction mixture is stirred at room temperature for 4 hours. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-chloromethyl-2-(4-chlorophenyl)thiazole (3.24 g)
Reaction SMILES: [CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][N:20](CC2C=CC=CC=2)[CH2:19][CH2:18]1)([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.C(O)=O>CO.[Pd]>[CH:1]([NH:14][C:15](=[O:30])[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(c1ccccc1)c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: O=C(NC(c1ccccc1)c1ccccc1)OC1CCNCC1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
1-benzyl-4-piperidyl benzhydrylcarbamate (1.1 g, 4.5 mmol) was dissolved in anhydrous methanol (15 mL) and formic acid (5 mL, 132 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (0.3 g) was added and the reaction mixture was stirred under nitrogen atmosphere . After 18 h, the reaction mixture was filtered through Celite® and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 mL) and diethyl ether (300 mL). The aqueous layer was washed with diethyl ether and then basified with 1 N sodium hydroxide solution to pH 12. A white solid precipitated out which was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness to give 4-piperidyl benzhydrylcarbamate as a colorless solid (0.65 g, 78%). MS=311.3 MH+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][O:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.Cl[CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>>[C:8]1([CH:5]2[O:4][CH2:3][CH:2]([O:1][CH2:15][C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:7][O:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CO[C@@H](c2ccccc2)OC1
Reactant: ClCc1cccs1
Product: c1ccc(C2OCC(OCc3cccs3)CO2)cc1

Procedure:
Using the procedure of Example 56, cis-5-hydroxy-2-phenyl-1,3-dioxane was reacted with 2-chloromethylthiophene to give, after repeated recrystallization from petroleum ether, cis-2-phenyl-5-(2-thienyl)methoxy-1,3-dioxane m.p. 68.5°-69°. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[C:2]#[CH:3].O=[C:13]([C:19]([O:21]CC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[O:21]=[C:19]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:4]1[CH2:1][C:2]#[CH:3]
Reactant: C#CCNc1ccccc1N
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)c(C(=O)OCC)nc2ccccc21
Yield: 93.1 %

Procedure:
9.2 g (62.9 mmol) of N-(2-propynyl) 1,2-phenylenediamine and 12.1 g (69.2 mmol) of diethyl ketomalonate were dissolved in toluene (100 mL), and the solution was refluxed for 3 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the solid matter thus obtained was washed with diisopropyl ether, to obtain 15.0 g (yield: 93%) of ethyl 2-oxo-1-(2-propynyl)-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:7]=1[CH3:15].CS(C)=[O:27].C([O-])([O-])=O.[K+].[K+].OO>O>[C:20]([O:19][C:17]([NH:16][C@@H:4]([CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13](=[O:27])[NH2:14])=[CH:8][C:7]=1[CH3:15])[C:3]([OH:2])=[O:24])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@H](Cc1c(C)cc(C#N)cc1C)NC(=O)OC(C)(C)C
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: Cc1cc(C(N)=O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 mL three-necked round bottom flask equipped with magnetic stirrer, and thermocouple was charged under nitrogen with (S)-2-tert-butoxycarbonylamino-3-(4-cyano-2,6-dimethyl-phenyl)-propionic acid methyl ester (166.2 mg, 0.5 mmol), DMSO (5.0 mL), and K2CO3 (75 mg, 0.5 mmol) and the resulting mixture cooled in an ice bath. To the resulting mixture was then added 30% H2O2 (110 μl), dropwise via a syringe. The resulting mixture was then allowed to warm up to ambient temperature, with the solids observed to dissolve to yield a clear solution. After stirring for about 2 hours at 45-50° C., water (10 mL) was added, cooling was applied, and a precipitated product isolated by filtration. The isolated white solid was washed with water (2×25 mL), then dried for 24 hours on high vacuum pump to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH3:27])[CH2:19][C:20]#[CH:21]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]3[O:16][C:20]([CH2:19][CH2:18][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])=[CH:21][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: O=C(c1cccc(F)c1)c1ccc(O)c(I)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3cccc(F)c3)ccc2o1

Procedure:
The product from Example 69B and a 0.1 M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.26 (d, 3H, J=6.1 Hz), 1.57 (m, 1H), 1.91 (m, 2H), 2.10-2.63 (m, 2H), 2.87 (m, 2H) 3.18 (m, 2H), 3.42 (m, 2H), 6.76 (s, 1H), 7.37-7.59 (m, 5H), 7.76 (d, 1H, J=8.9 Hz), 7.98 (s, 1H); MS (ESI) m/z 352.1 (M++1).