Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 90 °C

Procedure:
23.3 gm (0.13 mol) of hippuric acid, 93.05 gm of acetic anhydride, and 50 ml of toluene were charged into a 500 ml eggplant-type flask, and heated on an oil bath at a temperature of 90° C. for 10 minutes to dissolution, followed by immediate quenching the resultant solution. The produced liquid was kept at -20° C. on a dry ice-methanol bath.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH2:13]>C(#N)C>[OH:13][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4]
Reactant: O
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CC#N
Product: N#Cc1cccc(C(=O)CO)c1

Procedure:
A solution of 776 mg of 3-(2-bromoacetyl)benzonitrile in acetonitrile (5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is realized a second time with 976 mg. All the vials are collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].[CH2:10](I)[CH2:11][CH2:12][CH3:13]>CN(C=O)C>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCCCC1=O

Procedure:
2-Piperidinone is deprotonated with NaH in DMF solution and butylated with n-butyl iodide to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1([CH3:19])[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)([OH:11])[CH2:9][CH2:8][N:7]([CH2:27][CH2:28][CH:29]=[C:30]2[C:36]3[CH:37]=[CH:38][CH:39]=[N:40][C:35]=3[CH2:34][O:33][C:32]3[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]2=3)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(C)CNCCC1(O)c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1(C)CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.9 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-hydroxy-3-methyl-piperidine-3-carboxylic acid methyl ester (0.71 g, 2.5 mmol) in acetonitrile/water (8:2) (25 mL) was added K2CO3 (1.40 g, 10.0 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.937 g, 2.5 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound (0.835 g, 58%). 1H-NMR (CDCl3): 1.30 (s, 3H), 1.57 (s, 6H), 1.76 (d, 1H), 2.24–2.53 (m, 7H), 2.65 (d, 1H), 2.86 (d, 2H), 3.44 (s, 3H), 5.30 (bs, 2H), 6.16 (d, 1H), 6.82 (d, 1H), 7.26 (m, 4H), 7.45 (s, 1H), 7.53 (d, 1H), 7.58 (d, 1H), 8.49 (d, 1H). ESI-MS m/z: 577 (M+1), retention time 1.50.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>[Pd].CCO.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN1CCN(c2ccc(N)cc2)CC1
Reaction time: 8 h

Procedure:
4-Methyl-1-(4-nitrophenyl)piperazine (2.0 g, 9 mmol, Step A) and 10% Pd/C (200 mg) were added to EtOH/MeOH (1:1) (50 ml) at RT. The reaction stirred under a H2 atmosphere (via balloon) overnight. The mixture was filtered through a plug of Celiteo and the filtrate was concentrated under reduced pressure to leave the desired material as a light yellow oil. The material was used in subsequent reaction without purification. MS: (ES+) 192 (M+1)+; (ES−): 190 (M−1)−. Calc'd for C11H17N3: 191.14.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=[O:5].[CH3:14][Mg]Br.CCOCC.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH:4]([OH:5])[CH3:14]
Reactant: O=Cc1c(Cl)cccc1C(F)(F)F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)benzaldehyde (266.9 mg, 1.280 mmol, 1 eq) in anhydrous THF (5 mL) at 0° C. under nitrogen, a 3.0 M solution of methylmagnesium bromide in Et2O (0.50 mL, 1.5 mmol, 1.2 eq) was added and the reaction was allowed to stir and warm to ambient temperature overnight. The reaction mixture was again cooled to 0° C. and saturated NH4Cl was added. Diethyl ether was also added and the layers were separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The colorless oil crude was purified by chromatography on silica gel [0.5″×10″ glass column, eluting with 1:1 CH2Cl2:Heptane]. Fractions containing product were combined and concentrated in vacuo, affording the title material as a clear and colorless oil. 1H NMR (400 MHz, CDCl3) δ=1.73 (d, J=6.8 Hz, 3H), 3.04 (br s, 1H), 5.43 (q, J=6.8 Hz, 1H), 7.33 (ddq, J=8.0, 8.0, 0.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H). MS (ES+): m/z 248.01/250.03 (100/37) [MNa+]. HPLC: tR=3.26 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cccc(C(O)c2cccc(F)c2)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: COc1cccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)c1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(3-methoxy-phenyl)-methanol.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5](=S)[C:4]=2[CH:3]=1.[CH3:17][C:18]([OH:27])([CH3:26])[CH2:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:26][C:18]([OH:27])([CH3:17])[CH2:19][C@H:20]1[CH2:25][N:24]([C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:23][CH2:22][NH:21]1
Reactant: Cc1cc2c(s1)Nc1ccccc1NC2=S
Reactant: CC(C)(O)C[C@H]1CNCCN1
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CC(C)(C)O)C1

Procedure:
In a manner similar to that described in Example 359, combine 2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (0.574 g, 2.33 mmol) and (S)-2-methyl-1-piperazin-2-yl-propan-2-ol (0.369 g, 2.33 mmol) to obtain the title compound: mass spectrum (APCI): m/z=371.2 (M+1).
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](N(CC)CC)[CH3:15].ClC(OCC)=O>O>[CH:1](=[CH:8][C:9](=[O:13])[C:10]([O:12][CH2:14][CH3:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(=O)C=Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: O
Product: CCOC(=O)C(=O)C=Cc1ccccc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To the benzalpyruvic acid of step A in water-saturated ethyl acetate there was added triethylamine (56.2 g, 0.55 mol) at a rate less than 0.5 ml/min with good agitation. Water was then azeotropically removed by vacuum distillation and the benzalpyruvic acid concentration readjusted to 120 g/l with dry ethyl acetate. Ethyl chloroformate (59.7 g, 0.55 mol) was then added over a one hour period at 20°-25° C. followed by a one hour age. The mixture was cooled to 0°-5° C. and quenched with 350 ml of cold water. The aqueous layer was discarded and the organic layer was washed with cold (0°-5° C.) 5% sodium bicarbonate solution (350 ml) followed by cold (0°-5° C.) 5% sodium chloride (350 ml). The ethyl acetate was removed by vacuum concentration affording crude ethyl benzalpyruvate in a yield of 95-97%. The ester was subsequently purified by distillation using a short-path wiped film evaporator (WFE) apparatus (150° C., 0.1 mm Hg).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[O:7][C:8]=1[CH:9]([OH:11])[CH3:10])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=1[CH3:35].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:11][CH:9]([C:8]2[O:7][C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:14][CH:13]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:10])=[CH:30][C:29]=1[CH3:35]
Reactant: CC(C)c1nc(-c2ccc(OC(F)(F)F)cc2)oc1C(C)O
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
A solution of 1-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethanol (140 mg, 0.446 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (122 mg, 0.624 mmol) in toluene (15 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (144 mg, 0.713 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (169 mg, 0.669 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The mixture is loaded directly on silica gel column chromatography with 10–25% EtOAc/Hexanes to afford the title compound (25 mg, 11%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]#[CH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[CH:18]([NH:20][NH2:21])=O.CN(C)C=O>O>[C:11]1([C:6]2[N:5]=[C:4]([NH2:17])[N:3]3[CH:18]=[N:20][N:21]=[C:2]3[C:7]=2[CH2:8][C:9]#[CH:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNC=O
Reactant: C#CCc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(-c2ccccc2)nc(N)n2cnnc12

Procedure:
1.7 Parts of 4-chloro-6-phenyl-5-(2-propynyl)pyrimidin-2-amine and 0.84 part of formylhydrazine are added to 20 parts by volume dimethylformamide containing 2.0 parts of molecular sieve 3A and refluxed under nitrogen for two hours. The solution is allowed to cool and is poured into cold water. The crystalline product is filtered out, washed with water and dried. The product is chromatographed to give 7-phenyl-8-(2-propynyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-amine having the formula: ##STR6##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>O1CCCC1>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: BrCCCCCCCCCCCBr
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 2.50 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 50 mL of tetrahydrofuran, under an argon atmosphere with stirring, is added 0.367 g of 60% sodium hydride in oil. After 1.5 hours, 10.0 g of 1,11-dibromoundecane is added and stirring is continued for 43 hours. The reaction mixture is evaporated and the residue partitioned between diethyl ether and water. The organic phase is separated, washed with water, dried with magnesium sulfate, filtered and evaporated leaving an oil. The oil is purified via column chromatography, using hexane/ether (1:1) to afford 3.25 g of the desired product as a colorless oil. MS(CI): m/z 532(MH+). Calcd for C32H39NO6S: C=63.15, H=7.19, N=2.63, Br=15.00, S=6.02 Found C=63.12, H=7.17, N=2.52, Br=14.77, S=6.02
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]2.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5]3)=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(C(=O)Nc2ccc3[nH]c(C(=O)OC(C)(C)C)cc3c2)cc1
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
A solution of tert-butyl 5-amino-1H-indole-2-carboxylate (220 mg, 0.94 mmol), 4-acetylbenzoic acid (155 mg, 0.94 mmol) and TBTU (303 mg, 0.94 mmol) in DMF (6 mL) at 4° C. was treated with diisopropylethylamine (329 uL, 1.89 mmol) and stirred 40 min at 0˜5° C. The solvent was removed under vacuo. The crude product was chromatographed on silica gel eluted with 1% MeOH in CH2Cl2 to give 2 (350 mg, 98%). 1HNMR DMSO-d6) δ11.66 (bs, 1H), 10.34 (s, 1H), 8.09 (d, 1H, J=8.8 Hz), 8.07 (s, 4H), 7.55 (d, 1H, J=8.8 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.03 (s, 1H), 2.63 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C:34](C)([CH3:36])[CH3:35])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](O)(=[O:41])C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[O:33][C@H:34]1[CH2:36][CH2:39][O:41][CH2:35]1)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.09 mmol, 50 mg) was dissolved in a 1:1 solution of CH2Cl2/TFA (1 mL) and allowed to stir at room temperature for 1 hour. The solution was then extracted into ethyl acetate, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated to a clear oil. The resulting oil was then dissolved in THF (1 mL) and combined with 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl]carbonate (0.05 mmol, 13 mg) DIEA (0.08 mmol, 14 gL) and allowed to stir for 15 hours. The reaction was neutralized by the addition of acetic acid and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a white solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate), providing 19 mg (37%) of a white solid. H1-NMR (CDCl3): δ7.70 (2H,d), 7.29-7.17 (6H,m), 6.97 (2H,d), 5.1 (1H,s), 4.76 (1H,d), 4.17 (1H,m), 3.86 (3H,s), 3.87-3.70 (6H,m), 3.68-3.60 (1H,m), 3.06 (1H,bs), 2.89 (2H,m), 2.02 (3H,m), 1.89 (1H,m), 1.71 (2H,m),1.28-1.08 (6H,m); MS (ESI): M+Na=585.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].O[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:22]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1 g) in anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under a nitrogen atmosphere. 4-Hydroxybiphenyl (3 g) and triphenylphosphine (4.61 g) were added and the mixture was treated with diisopropylazodicarboxylate (3.46 mL) dropwise. The mixture was stirred at 0° C. for 10 min then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane/ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8 g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200 mg). LCMS System A: Rt=4.2 mins.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].S(O[CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:4]=2[CH:3]=1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCC1(CCOCCOCCOC)c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 60 %

Procedure:
2,7-dibromofluorene (5.0 g, 15.4 mmol) was dissolved in dried THF solution (30 mL). Sodium hydride (1.0 g, 40 mmol) was added to the THF solution at room temperature and refluxed for 5 hours. 1-Tosyloxy-3,6,9-trioxadecane (11.8 g, 37 mmol) in 20 mL of dry THF was added drop-wise to the refluxed solution. The mixture was allowed to refluxed over night, then cooled down, poured into distill water and extracted with chloroform (2×100 mL). The combined organic solutions were washed with saturated NaCI solution (2×100 mL), distilled water (1×100 mL), dried over MgSO4, and concentrated under reduced pressure. Crude oil was further purified by column chromatography using hexane/ethyl acetate (50/50) as eluant. TLC (ethyl acetate/Hexane=1/1) Rf =0.12. The fraction at Rf=0.12 was collected and concentrated to give 5.7 product in 60% yield. 1H NMR (300 MHz, CDCl3), 2.34(t, 4H), 2.77(t, 4H), 3.10-3.60(m, 22H), 7.40-7.60(m, 6H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1F.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Oc2ccc(I)cc2)c(Cl)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4-iodophenol (200 mg) in dimethylsulfoxide (1 ml), 218 mg of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene and 251 mg of potassium carbonate were added, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was cooled, ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed with water and a saturated saline solution and dried over an anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-80/20)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[C:16]=[S:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]1=[S:17]
Reactant: CCNCC(=O)O
Reactant: S=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccccc2Cl)C1=S
Yield: 30.2 %

Procedure:
The title compound was prepared by the; procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.48 g of 2-chlorophenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (3.85 g) was obtained as an orange solid, m.p. 142°-145° C. Anal. Calcd. for. C11H11Cl N2O S: C, 51.87; H, 4.35; N, 11.00. Found: C, 51.96; H, 4.26; N, 10.97. Mass spectrum (EI, M.+) m/z 254.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(O)c1ccccc1COC1CCCCO1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of ethyl 2-oxo-2-[2-(tetrahydropyran-2-yloxymethyl)phenyl]acetate (22.60 g, 77.3 mmol) in methanol (20 ml) was stirred at 0° C., and sodium borohydride (1.46 g, 38.6 mmol) was added to thereto. After 10 minutes, water (100 ml) was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound ethyl α-hydroxy-2-(tetrahydropyran-2-yloxymethyl)phenylacetate (20.47 g, 90.0%) as an oil.