Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3].O.[C:34]([O:38][CH2:39][CH:40]=[CH2:41])(=[O:37])[CH:35]=[O:36].O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[N:19]([C:35](=[O:36])[C:34]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C=O
Reactant: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)/C(C)=C/[C@@H]1CCCN1C(=O)OCC=C

Procedure:
To a solution of (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g) in toluene (150 ml) was added allyl glyoxylate monohydrate (3.68 g). The resulting mixture was heated to reflux with azeotropic removal of water for hours. Evaporation of the solvent gave a residue of allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]glyoxylate, which was dissolved in xylene. After evaporation of the solvent in vacuo, the residue was dissolved in dichloromethane (150 ml). To this solution were added successively 2,6-lutidine (2.75 ml) and thionyl chloride (1.95 ml) at -20° C. After stirring at -20° C. for 15 minutes, the reaction mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) at 5° C. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in degassed N,N-dimethylformamide (80 ml), and to the solution were added 2,6-lutidine (2.75 ml) and triphenylphosphine (1.29 g). After standing for 6 hours at ambient temperature, the reaction mixture was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The separated organic layer was washed in turn with water, cold 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-4:6 V/V) to give allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl- 2-oxo-3-20 butenyl]3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (9.78 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:9]1[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=1
Reactant: CC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
1-(3-tert-Butyl-4-hydroxyphenyl)ethanone (690.9 g, 3.75 mol) was dissolved in acetonitrile (6.05 L), and a solution of N-bromosuccinimide (701.28 g, 3.94 mol) in acetonitrile (5 L) was added dropwise while stirring on ice. After heating to room temperature, the solvent was concentrated to approximately 3 L. For extraction, n-heptane (5 L) and water (5 L) were added, and the solution was separated. The aqueous layer was extracted further with n-heptane (2 L), and the solution was separated. The organic layers were combined, washed with 5% aqueous sodium thiosulfate (1 L) and water (2 L), and concentrated under reduced pressure (35° C.) to obtain 977.0 g of the subject compound as a brownish oily substance (yield: 99.1%, HPLC purity: 95.8%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].O[C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:1][CH2:2][CH2:3][C@H:4]([O:5][C:13]1[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: CC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
(1R)-3-Chloro-1-phenyl-1-propanol (1.000 g, 5.86 mmol), 1-(3-hydroxyphenyl)ethanone (0.797 g, 5.86 mmol), triphenylphosphine (1.54 g, 5.86 mmol) and diethylazodicarboxylate (1.53 g, 8.79 mmol) were combined in a flask, which was immediately flushed with argon. THF (20 mL) was added and the mixture was stirred overnight under argon. THF was removed in vacuo, the crude product was dissolved in 50 mL of CH2Cl2/H2O (1:1) and the organic layer was separated and dried over MgSO4. After removing the solvent in vacuo, the residue was purified by flash chromatography using 10% ethyl acetate/hexane to yield the desired product (900 mg, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.49–7.46 (m, 2H), 7.40–7.26 (m, 6H), 7.07–7.04 (m, 1H), 5.46–5.43 (dd, 1H, J=4.4 Hz, 8.8 Hz), 3.84–3.78 (m, 1H), 3.643.59 (m, 1H), 2.52 (s, 3H), 2.51–2.46 (m, 1H), 2.29–2.22 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>CN(C)C(=O)C>[OH:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(O)cc2s1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of 2-amino-1,3-benzothiazol-6-ol (4.99 g, 30.0 mmol) in N,N-dimethylacetamide (20 mL) was added cyclopropanecarbonyl chloride (4.08 mL, 45.0 mmol) at 0° C., and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed 3 times with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether and collected by filtration to give the title compound (3.22 g, 13.7 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22]([O:10][C:9](=[O:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:21]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
A mixture of (4-fluoro-phenyl)-(3-fluoro-phenylamino)-acetic acid (I83) (510 mg, 1.94 mmol), (R)-quinuclidin-3-ol (246 mg, 1.94 mmol), HOBT (356 mg, 2.32 mmol) and DCC (480 mg, 2.32 mmol) in THF (10 mL) is stirred at RT overnight (UPLC-MS monitoring: complete conversion). The solvent is evaporated, the crude is dissolved in EtOAc and the insoluble is filtered off. The clear solution is washed with 1N K2CO3 and then with brine. The organic layer is dried over Na2SO4, filtered and evaporated. The crude is purified by silica gel chromatography (EtOAc/MeOH=8/2) to give the title compound as a yellow oil (360 mg, 50% yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:9]2[NH:8][C:7](=[O:18])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:18])[CH2:6]1)=[O:4]
Reactant: CCCCI
Reactant: COC(=O)C1CC(=O)NC2=CC(Cl)=CCC2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21

Procedure:
The starting material is prepared as follows: -chloro-2,3,4,5 suspension of 6.0 g of 8-chloro--tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester in 125 ml of dimethyl formamide is added portion-wise to that of 2.1 g of a 57% mineral oil suspension of sodium hydride in 300 ml of dimethylformamide while stirring under argon. After stirring for 3 hours at room temperature 4.6 g of n-butyl iodide are added dropwise and stirring is continued over night at said temperature. The pH of the mixture is adjusted to 2 with 3N hydrochloric acid and the whole evaporated. The residue is partitioned between water and chloroform, the organic solution separated and the aqueous solution extracted with chloroform. The combined extract is washed with water, dried, evaporated and the residue taken up in diethyl ether. The mixture is treated with charcoal, filtered hot and the filtrate concentrated, to yield the 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, melting at 89°-90°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O.O>[Si:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
A solution of (4-hydroxyphenyl)acetonitrile (6.01 g, 45.1 mmol) in N,N-dimethylformamide (60 ml) was treated with imidazole (3.81 g, 58.6 mmol), tert-butyldimethylsilylchloride (7.49 g, 49.6 mmol) and N,N-dimethylaminopyridine (20 mg) and the resulting solution left to stir at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The combined organic extracts were washed with sat. aq. sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate:pentane (0:100 changing to 10:90) gave the title compound as a pale yellow oil (9.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].[CH2:31](C([Sn])=C(CCCC)CCCC)[CH2:32]CC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:31]=[CH2:32])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25]
Reactant: COc1ccc(Cn2c(=O)c3cc(I)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(c1)c(=O)n(Cc1ccc(OC)c(OC)c1)c(=O)n2C1CCOCC1
Yield: 57.7 %

Procedure:
A mixture of 3.0 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 3.64 g of tributylvinyltin and Pd(PPh3)4 in 2 ml of toluene is irradiated in a microwave field for 30 minutes at 130° C. The reaction mixture is filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 1.4 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH3:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[P:17]([Cl:20])(Cl)Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[P:17]([Cl:20])([O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[O:16][C:6]1[C:7]([CH3:15])=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1OP(Cl)Oc1c(C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
890.3 g (4 mol) of 2,4-di-tert-butyl-6-methylphenol, 4.2 g of dimethylformamide and 170.0 g of xylene are introduced into a four-neck flask which has been flushed with nitrogen and is fitted with a thermometer, dropping funnel, reflux condenser and distillation attachment. 274.9 g (2 mol) of phosphorus trichloride are added dropwise with stirring over the course of 1.5 hours at a temperature of 50° C. The reaction mixture is warmed to 130° C. and refluxed at this temperature for 1 hour. The reaction mixture is kept at 120° C. for 1 hour under a vacuum of 0.15 bar. Xylene is subsequently removed by distillation under a greater vacuum. After the vacuum has been broken using nitrogen, 959.5 g (1.9 mol) of the title compound are obtained as supercooled, yellow-orange, clear melt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52](O)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1>CN(C)C=O>[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, add 5.5 mmol of 1-[bis(4-fluorophenyl)methyl]piperazine, 5.5 mmol of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and 5.5 mmol of HOBt (hydroxybenzotriazole) in succession to a solution at 0° C. of 5 nmml of 6-hydroxy-1,4-benzodioxin -2-carboxylic acid in 25 cm3 of N,N-dimethylformamide. Stir for 2 hours at 0° C. and then for 12 hours at room temperature, and concentrate the reaction mixture under reduced pressure. Extract the resulting amide with diethyl ether and then, after concentration to dryness, purify the crude product by chromatography on a silica column (eluant:petroleum ether then an increasing gradient of ethyl acetate in petroleum ether). 6-Hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 85%. The product obtained is precipitated from 10 ml of pentane and is then filtered and recrystallised from cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23]Cl.[H-].[Na+].C1(C)C=CC=CC=1>O>[CH3:19][N:20]([CH2:21][CH2:22][CH2:23][O:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:25]
Reactant: CN(C)CCCCl
Reactant: OC(CCCc1ccccc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 5.0 g of 1-(p-fluorophenyl)-4-phenyl-1-butanol, 10 g of γ-dimethylaminopropyl chloride, 2.0 g of sodium hydride (65%) and 100 ml of toluene was heated under refluxing for 30 minutes. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane. M.P., 80°-83° C. (fumarate).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30][NH:31][O:32][CH3:33].Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([N:31]([O:32][CH3:33])[CH3:30])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CNOC
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)-OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. was added MeNHOMe.HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0° C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mL), 1 M HCl (10 mL) and sat. NaCl (2×20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[N+:11]([C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])([O-])=O>C1COCC1>[CH:1]([NH:11][C:14]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][C:15]=1[C:16]([NH:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[O:2]
Reactant: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(C)NC(=O)c1cc(Oc2ccccc2)ccc1NC=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.3 %

Procedure:
A solution of formic acid (0.02 mL, 0.56 mmol) and acetic anhydride (0.05 mL, 0.56 mmol) was heated to 50° C. for 2 hours under an argon atmosphere. The resulting mixture was diluted with THF (0.2 mL) and added dropwise to a solution of 34B (50 mg, 0.19 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The resulting solution was concentrated to dryness and purified by chromatography (SiO2, 40% EtOAc in hexane) to afford 44A (58 mg, 100%).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@H](O)c1ccccc1
Yield: 91.2 %

Procedure:
A solution of 85.1 g (559 mmol) of D-mandelic acid, 65 ml (628 mmol) of benzyl alcohol, and 1.01 g (5.35 mmol) of p-toluenesulfonic acid in 700 ml of benzene was refluxed for 6.5 hours. The mixture was washed with water and concentrated. The residue was recrystallized from ether to give 123.5 g of the aimed compound D-2 in 91% yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=1>>[C:19]([C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:4]2[S:3][C:2]([NH:1][C:26]3[CH:27]=[CH:22][N:23]=[C:24]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=3)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)=[CH:11][CH:12]=1)([CH3:18])[CH3:17])#[N:20]
Reactant: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(N)s2)cc1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Product: CC(C)(C#N)c1ccc(-c2cc(C(N)=O)c(Nc3ccnc(OCC[Si](C)(C)C)n3)s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[4-(1-cyano-1-methylethyl)phenyl]thiophene-3-carboxamide (100 mg, 0.350 mmol) and 4-chloro-2-[2-(trimethylsilyl)ethoxy]pyrimidine (81 mg, 0.350 mmol) (see J. Het. Chem., 1994, 989-995) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[C:17]2[C:4]=1[C@H:5]1[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:23])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:27])([CH3:26])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1.B(Br)(Br)Br.Cl[CH2:33]Cl>>[OH:21][C:19]1[CH:18]=[C:17]2[C:4]([C@@:5]3([CH3:33])[C@H:14]([CH2:15][S:16]2(=[O:24])=[O:23])[C@:13]2([CH3:25])[C@H:8]([C:9]([CH3:27])([CH3:26])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]3)=[C:3]([O:2][CH3:1])[CH:20]=1
Reactant: ClCCl
Reactant: COc1cc(OC)c2c(c1)S(=O)(=O)C[C@H]1[C@H]2CC[C@H]2C(C)(C)CCC[C@]12C
Agent: BrB(Br)Br
Product: COc1cc(O)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2(=O)=O
Reaction time: 60 h
Yield: 60 %

Procedure:
To a suspension of compound 23 (5.00 g, 12.3 mmol) in dichloromethane (20 mL) at 0° C. under argon was slowly added boron tribromide (1.0 M in DCM, 12.5 mL, 12.5 mmol). The mixture was stirred for 60 h then concentrated. The residue was dissolved in ethyl acetate (50 mL), quenched with water (250 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with brine (2×250 mL) then dried (MgSO4) and concentrated to afford a brown foam. The crude product was purified by column chromatography on silica gel (hexanes:ethyl acetate, 2:1) to afford compound 57 (2.90 g, 60%) as a pale solid. 1H NMR (CDCl3): δ 7.00 (d, J=2.6 Hz, 1H), 6.54 (d, J=2.5 Hz, 1H), 6.20 (s, 1H), 3.79 (s, 3H), 3.36-3.16 (m, 3H), 2.27 (d, J=11.4 Hz, 1H), 1.72-1.00 (m, 10H), 1.38 (s, 3H), 0.95 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H). 13C NMR (CDCl3): δ 159.7, 157.0, 139.3, 127.8, 105.4, 102.4, 56.2, 56.1, 53.4, 46.3, 41.9, 39.8, 39.0, 38.1, 33.7, 33.5, 21.7, 19.2, 19.1, 18.8, 17.8, 17.7. MS m/z 393 (C22H32O4S+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][CH2:12][CH2:13]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:11][CH2:12][CH2:13][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1]
Reactant: COc1ccccc1N
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCNc1ccccc1OC
Yield: 64.8 %

Procedure:
A suspension of 24.6 g (200 mmol) o-anisidine M10, 20.8 g (220 mmol) chloroethyl methyl ether M11, 30.4 g (220 mmol) K2CO3 and 18.3 g (110 mmol) KI in 110 ml DMF was heated at 95° C. for 24 hours. DMF was evaporated, and the residue was digested with 100 ml CHCl3, filtered, and the precipitate washed with 2×50 ml CHCl3. The solvent was evaporated to give 41.2 g crude oil. This oil was purified by a plug packed with 184 g silica gel 100 with CHCl3/cyclohexane (1:1, v/v) as eluant, to afford 23.5 g pure product (yield: 65%).