Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:21]([N:18]1[CH2:17][CH2:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:20][CH2:19]1)[CH2:22][CH2:23][CH3:24]
Reactant: C1=C(c2ccccc2N2CCNCC2)CCCCCC1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccccc2C2=CCCCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.5 %

Procedure:
To a solution of 1-(2-cyclooct-1-enylphenyl)piperazine (11 mg, 0.0407 mmol) produced in Example (46a) in tetrahydrofuran (1 mL) were added butyraldehyde (0.0047 mL, 0.0529 mmol), sodium triacetoxyborohydride (11.2 mg, 0.0529 mmol) and acetic acid (0.0044 mL, 0.0773 mmol), followed by stirring for 14 hours and 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed three times with ethyl acetate. The organic layer was concentrated to produce a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 9.9 mg of 1-butyl-4-(2-cyclooct-1-enylphenyl)piperazine as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc(Br)c2)CC1
Reaction time: 16 h

Procedure:
3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with DCM (50 mL) and TEA (3.6 mL, 26 mmol). After 16 h, reaction was poured into separatory funnel and washed with water. Organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified upon standing (3.6 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:12]([O:30]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(C23CCN(C(=O)OC(C)(C)C)CC2O3)c1
Yield: 94.9 %

Procedure:
4-(3-Methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2 g, 6.9 mmol) was further purified by flash chromatography (100 DCM on Silicagel) to remove baseline impurities (likely waste palladium from Suzuki reaction), then was dissolved in methylene chloride (28.9 mL, 451 mmol) and treated with m-CPBA 70-75% (70:30, m-chloroperbenzoic acid: 3-chlorobenzoic acid, 2.4 g, 9.7 mmol) at room temperature overnight. The reaction was quenched by treatment with a Na2S2O3 aq solution, followed by sat. NaHCO3 aq. solution, and further extracted twice with dichloromethane. The combined organic extracts were dried (MgSO4) and filtered, and the solvent was evaporated under reduce pressure. The product was used without further purification in the next step: (±)-6-(3-methoxy-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (2 g, 95% yield). 1H NMR (CDCl3): δ ppm 7.26 (m, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.90 (br. s., 1H), 6.84 (d, J=8.1 Hz, 1H), 3.93-4.19 (m, 1H), 3.81 (s, 3H), 3.53-3.79 (m, 2H), 3.10-3.24 (m, 2H), 2.38-2.51 (m, 1H), 2.17 (br. s., 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](O)=[O:8])=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][N:13]2[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])[CH:16]=[N:15][C:14]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C@H:54]1[C:59]([F:61])([F:60])[CH2:58][CH2:57][CH2:56][C@H:55]1[NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:65]([O:64][C:63](=[O:69])[NH:62][C@@H:55]1[CH2:56][CH2:57][CH2:58][C:59]([F:61])([F:60])[C@@H:54]1[NH:53][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[C:17]([C:19]([O:24][CH3:25])([O:20][CH3:21])[O:22][CH3:23])[CH:16]=[N:15][C:14]=23)[CH:4]=1)=[O:8])([CH3:66])([CH3:68])[CH3:67]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)O)sc3C)cnn2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)(OC)c1cnc2c(-c3cc(C(=O)N[C@@H]4[C@H](NC(=O)OC(C)(C)C)CCCC4(F)F)sc3C)cnn2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Methyl-4-[6-(trimethoxymethyl)pyrazolo [1,5-a]pyrimidin-3-yl]thiophene-2-carboxylic acid (41.0 mg, 0.113 mmol) and BOP (59.9 mg, 0.135 mmol) were dissolved in DMF (752 μL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (31.1 mg, 0.124 mmol) and diisopropylethyl amine (59.1 μL, 0.338 mmol) and the reaction stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and purified by column chromatography (0-60% EtOAc/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C27H35F2N5O6S) [M+H]+, 596.2; found 596.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.94 min; [M+H]+=478.03.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:12]([CH3:15])([O-])=O>>[NH2:12][CH2:15][CH:8]([OH:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: NCC(O)c1ccc([N+](=O)[O-])cc1

Procedure:
The method of Schoenenberger, Archiv. der Pharmazie, 1975, 308(9), 717-719 can be employed. 4-Nitrobenzaldehyde can be reacted with nitromethane and base, followed by selective reduction of the aliphatic nitro group to yield 1-amino-2-hydroxy-2-(4-nitrophenyl) ethane. This substance can be reacted with 2,6-dichlorobenzaldehyde to yield a mixture of cis-(±) and trans-(±)-2-(2,6-dichlorophenyl)-5-(4-nitrophenyl)-1,3-oxazolidines. The nitrophenyl group can be reduced with tin (II) dichloride or iron powder and ammonium chloride to yield the corresponding aniline. This aniline can be reacted with 2,2-dichloroacetyl chloride and triethylamine to yield a mixture of cis-(±) and trans-(±)-2,2-dichloro-N-[4-[2-(2,6-dichlorophenyl)-5-(1,3-oxazolidinyl)]phenyl]acetamides.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=1)(=[O:19])=[O:18])[CH3:2].[Br:29]Br>>[Br:29][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([CH3:28])[CH:21]=3)(=[O:19])=[O:18])[CH:3]([CH2:1][CH3:2])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[CH:9]=1
Reactant: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Reactant: BrBr
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)c(C)c1

Procedure:
The title compound was prepared from 6-ethyl-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine and excess bromine according to the procedure and in the same manner as described in Example 19, step a and yielded, after crystallization from a mixture of ethyl acetate-hexane, 2-bromo-6-ethyl-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine as a colorless, crystalline, solid, which was characterized by LCMS (ES+, FA, CV=5) and 1H NMR;
Reaction SMILES: [BrH:1].[F:2][C:3]([F:16])([F:15])[C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1N.N([O-])=O.[Na+]>O.[Cu]>[F:2][C:3]([F:16])([F:15])[C:4]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:5]=1[Br:1]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Br
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(C(F)(F)F)c(Br)c1

Procedure:
A suspension of the HBr salt of 2,5-bis-trifluoromethylaniline (1.0 gm, 4.4 mmol) was prepared by addition of 48% HBr (3 gm, 17.5 mmol) and 5 mL of water. This was cooled in an ice bath while a solution of sodium nitrite (335 mg, 4.8 mmol) in 1 mL of water was added dropwise. The reaction was stirred a farther 0.5 hr at which time copper powder (1 gm) and another 3 gm portion of 48% HBr were added. The reaction was heated to reflux and after 10 min the distillate was collected until no organic material was evident with the water. The distillate was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford the title compound as an oil. NMR (CDCl3): δ 7.68 (d, 1H, J=8 Hz), 7.81 (d, 1H, J=8 Hz), 7.96 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][S:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(F)cc1
Reactant: Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
163 g of 2-(4-fluorophenyl)ethenesulfonyl chloride were dissolved in 1.5 l of toluene and, at RT, 69.64 g of phenol were added. Subsequently, at RT, 103 ml of triethylamine were added dropwise, during which the temperature rose to 44° C. The mixture was then stirred at RT for 90 minutes, left to stand for 16 hours and stirred at RT for a further 2 hours. The solvent was then removed in vacuo, and the crude product was taken up in 2.5 l of EA. Washing 3 times with 750 ml of a saturated aqueous NaHCO3 solution was followed by washing 3 times with 750 ml of 2 N aqueous HCl solution each time. After drying over Na2SO4, the solvent was removed in vacuo. The product was then stirred in 350 ml of HEP for 1 hour and, on cooling, the product crystallized and was washed with HEP and dried under medium vacuum. 145.0 g of white crystals were obtained, mp 108° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:10]=1[C:11]([OH:13])=[O:12]>C1COCC1.CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:15][N:16]=[CH:17][C:9]=1[Br:8].[Br:8][C:9]1[CH:17]=[N:16][CH:15]=[C:14]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(O)c1c(Br)cncc1Nc1ccccc1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(Br)cncc1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
(Trimethylsilyl)diazomethane (8.1 mL, 2M in THF, 16.2 mmol) was added to a solution of 3-bromo-5-(2-fluoro-phenylamino)-isonicotinic acid (4.2 g, 13.5 mmol) in THF/MeOH (72 mL, 9/1, v/v) and stirred for 2 h at room temperature. The reaction solution was quenched with acetic acid, and then concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 50% EtOAc in hexanes to afford the desired product (4.1 g, 94%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[CH3:10])=[CH:4][N:3]=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:9]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[F:20])[C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH3:10])=[CH:4][N:3]=1
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)c(F)c1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)Nc2ccccc2)C(C)c2cnc(Cl)nc2)c(F)c1
Reaction time: 2.5 h

Procedure:
(±)-[1-(2,4-Dichloro-pyrimidin-5-yl)-ethyl]-(2-fluoro-4-methoxy-phenyl)-amine (0.45 g; 1.41 mmol) (from Example 8b supra) and phenyl isocyanate (165 μL; 1.52 mmol) (Aldrich) were combined in toluene (5 mL) and heated in an oil bath at 110–120° C. for 2.5 hours and then at 130° C. for 2.5 hours. After cooling, the reaction mixture was concentrated and triturated with hexanes. The solid residue was purified by flash chromatography (Biotage 40S; 30:70 ethyl acetate-hexanes) to give the intermediate (±)-1-[1-(2-chloro-pyrimidin-5-yl)-ethyl]-1-(2-fluoro-4-methoxy-phenyl)-3-phenyl-urea. (Yield 0.27 g; 43.2%).
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][N:20]([CH3:30])[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:13][CH:12]=1>>[CH2:1]([NH:7][C:8]([C:19]1[N:20]([CH3:30])[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:18]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C

Procedure:
Using essentially the same procedure as Example 33, but using n-hexyl isocyanate (0.040 mL, 0.30 mmol), 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C was converted to the title compound after purification twice by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16](=[O:22])[CH2:17][C:18](=O)[CH2:19][CH3:20])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH2:19]([C:18]1[NH:8][CH:9]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]=1[C:16](=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:20]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: C1=C(c2ccccc2)N1
Solvent: CCO
Product: CCc1[nH]cc(-c2ccccc2)c1C(=O)c1ccccc1
Reaction time: 8 h

Procedure:
The preparation is carried out in accordance with the general procedure in Example 1. The reactants are 2-phenylazirine and 1-phenylpentane-1,3-dione. The reaction product is dissolved in 150 ml of hot ethanol and the solution is allowed to stand overnight at room temperature. The precipitated crystals are filtered with suction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Biphenylboronic acid was prepared differently than described in the literature (see Yabroff, D. L.; Branch, G. E.; Bettman, B. J. Am. Chem. Soc. 1934, 56, 1850-1857). To a solution of 4-bromobiphenyl (2.00 g, 8.58 mmol) in THF (20 mL) at −78° C. was added n-butyllithiurn (4.0 mL of 2.5 M in hexanes) in a slow stream via syringe. After 15 minutes, triisopropylborate (3.0 mL, 13 mmol) was added in a slow stream via syringe. After 10 minutes, the resultant homogeneous solution was allowed to warm to ambient temperature over 45 minutes and partitioned between EtOAc (50 mL) and 10% aqueous HCl (50 mL). The aqueous layer was separated and extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a crude product which was triturated with hexanes to yield 1.53 g (90%) of 4-biphenylboronic acid as a white solid. 1H NMR (DMSO-d6): δ 8.05 (s, 2H), 7.83 (d, 2H, J=8.5 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.4 Hz), 7.33 (t, 1H, J=7.2 Hz). Anal. C12H11BO2: C, 72.78; H, 5.60. Found: C, 72.51; H, 5.62.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OC1CCCCC1
Product: C=CCOC(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 85 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclohexanol to afford the title compound as a mixture of diastereomers (pale yellow oil) (4.62 g, 85% yield). Flash column chromatography using hexanes/EtOAc (90/10 to 80/20) gave 394 mg (7% yield) of the syn diastereomer of the title compound. 1H NMR (500 MHz, CDCl3) δ 1.11-2.09 (m, 10H), 2.35-2.61 (dd, 1H), 2.72-2.98 (dd, 1H), 3.60-3.83 (m, 1H), 4.32-4.72 (m, 3H), 5.06-5.43 (m, 2H), 5.60 (d, 1H), 5.82-6.03 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24]C)=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([OH:24])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1

Procedure:
The title compound is prepared from 3 g (8.9 mmol) of the compound from Example XXIII and 12 ml of 1N sodium hydroxide solution analogously to the procedure of Example XV.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]([N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([O:1][CH2:2][CH2:3][O:4][CH:5]([N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c(=O)n(C(OCCO)c2ccc3c(c2)OCO3)cc1F
Solvent: c1ccncc1
Product: CC(=O)OCCOC(c1ccc2c(c1)OCO2)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[α-(2-Hydroxyethoxy)-3,4-methylendioxybenzyl]-5-fluorouracil obtained in Example 10 was dissolved in acetic anhydride (20 ml) and pyridine (20 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting oil was extracted with chloroform (100 ml). The extract was washed with hydrochloric acid and then water, dried over magnesium sulfate and evaporated under reduced pressure to remove chloroform. The residue was treated with ligroinacetone to give 4.3 g of crystalline 1-[α-(2-acetoxyethoxy)-3,4-methylenedioxybenzyl]-5-fluorouracil.
Reaction SMILES: [CH:1]1([C:7]2[S:8][C:9]3[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([O:18]C)[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Ce+4].[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH:1]1([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH:14]=[CH:13][C:12](=[O:18])[C:10]=3[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(OC)c2sc(C3CCCCC3)nc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1C=CC(=O)c2sc(C3CCCCC3)nc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
1 g (3.61 mmol) of 2-cyclohexyl-4,7-dimethoxy-1,3-benzothiazole is put into suspension in an acetonitrile/water mixture (3/1) at 0° C. then 4.36 g (7.96 mmol; 2.2 eq.) of cerium (IV) and ammonium nitrate are added to the suspension. The reaction mixture is maintained for 1.5 hours under stirring at ambient temperature, then 0.78 g (yield=88%) of 2-cyclohexyl-1,3-benzothiazole-4,7-dione is obtained after filtration, washing with cold water and drying under reduced pressure.
Reaction SMILES: [H-].[Na+].[C:3]([C:6](=[C:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH3:4].[CH3:27]I>>[C:3]([C:6](=[C:12]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CC(NCc1ccccc1)=C(C(C)=O)C(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(C)=O)=C(NCc1ccccc1)C(C)C(=O)OCC

Procedure:
In the same manner as in Reference Example 4-2-(1) but using 60 % sodium hydride (88 mg; 2.2 mmole), diethyl 2-acetyl-3-benzylamino-2-pentenedioate (333 mg; 1 mmole) and methyl iodide (156 mg; 1.1 mmole), there was produced diethyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioate.
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:59])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH:33][C:34]3[CH:35]=[C:36]4[C:41](=[CH:42][CH:43]=3)[C:40]([N:44]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:39][CH:38]=[CH:37]4)C(O)=O)=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)=O)C1C=CC=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:48]([O:47][C:45]([N:44]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[C:40]1[C:41]2[C:36](=[CH:35][C:34]([NH:33][CH:29]3[C:26]4=[CH:27][CH:28]=[C:23]([CH:24]=[CH:25]4)[O:22][CH2:21][C:20](=[O:59])[NH:19][C:15]4=[CH:14][C:13](=[CH:18][CH:17]=[CH:16]4)[CH2:12][NH:11][C:9]3=[O:8])=[CH:43][CH:42]=2)[CH:37]=[CH:38][N:39]=1)=[O:46])([CH3:49])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC(C(=O)O)c3ccc(OCC(=O)Nc4cccc(CNC(=O)OCc5ccccc5)c4)cc3)ccc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(NC3C(=O)NCc4cccc(c4)NC(=O)COc4ccc3cc4)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
A solution of 66D (55 mg, 0.082 mmol) in 10 mL DMF was added to a solution of PyBOP (88 mg, 0.17 mmol), DMAP (49 mg, 0.4 mmol), and TEA (40 mg, 0.4 mmol) in CH2Cl2 (30 mL) dropwise through syringe pump over 3 h. The solution was stirred at rt for 16 h. The solution washed with 1M H3PO4, sat NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 80% EtOAc in hexanes) to give 66F (8.5 mg, 16%). MS (ESI) m/z 654.8 (M+H)+.