Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10]F.N#N.FF>FC(F)(F)C(O)=O>[F:10][C:2]1([CH3:1])[CH:7]=[N:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]
Reactant: FF
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: CC1(F)C=NC(=O)NC1=O
Temperature: 14 °C
Reaction time: 2 h

Procedure:
5-methyluracil (1.00 g) in trifluoroacetic acid (10 ml) was treated with gaseous fluorine-nitrogen mixture. The reaction began at an initial temperature of 0° C. and during the fluorination the reaction temperature was raised to 14° C. and the reaction continued until completion for 120 minutes. The mole ratio of fluorine to 5-methyluracil was 2.56. The solvent was evaporated at about 50° C. under reduced pressure leaving a brown solid, which upon extracting with acetone gave 5-fluoro-5-methyluracil (0.21 g) whose structure was confirmed by NMR analysis.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[C:15]([CH3:27])=[N:16][C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[C:15]([CH3:27])=[N:16][C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)nc(C)n3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)nc(C)n3c21
Yield: 39.2 %

Procedure:
Manganese dioxide (67 mg, 0.77 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4,8-dimethyl-2,3-dihydro-1H-imidazo[1,5-a]pyrrolo[3,2-e]pyrimidine (58 mg, 0.15 mmol) in toluene (10 mL), followed by heating under reflux for three days. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane), to give the title compound (22 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:52]1(=[O:58])[NH:56][C:55](=[O:57])[CH:54]=[CH:53]1>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([O:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:56]3[C:52](=[O:58])[CH:53]=[CH:54][C:55]3=[O:57])=[O:17])=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Reactant: O=C1C=CC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C=CC(=O)N1C(=O)c1ccc(C(OCCCc2ccccc2)(c2ccccc2)c2cccc(OCCO)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of trityl acid 8 (280 mg, 0.42 mM) in dry THF (6 mL) was added dicyclohexyl carbodiimide (DDC, 400 mg, 1.95 mM). The reaction mixture was stirred for 30 min at r.t., and maleimide (100 mg, 1.1 mM) and a catalytic amount of DMAP was added and allowed to stir for overnight. The solvent was removed under rotaevaporator and the solid obtained was dissolved in dry ether. The precipitated DCU was filtered and the solvent ether was evaporated. Part of the product was purified by preparative TLC. Yield: 12 mg. 1H-NMR (500 MHz, CDCl3) δ ppm: 1.78 (m, 2H), 1.95 (m 2H), 2.9 (s, 4H), 3.51 (m, 2H), 3.93 (t, 2H), 4.02 (t, 2H), 6.8 (m, 5H), 7.25 (m, 5H), 7.29 (m, 5H), 7.37 (m, 3H), 7.48 (d, 2H), Mass: 561.3 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CN(C)C=O>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: BrCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(SCCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
To 1,7-dibromoheptane (23 g) and potassium carbonate (10 g) in dry dimethylformamide (100 ml) was added 4-chlorothiophenol (4.3 g) dropwise with stirring at 25° C. After 6 h, the mixture was filtered and the solvent removed under reduced pressure. Chromatography of the residue on silica gel using hexane as eluent gave 1-bromo-7-(4-chlorophenylthio)heptane (9.6 g). 1H-NMR (CDCl3) δ 1.2-1.55 (6H, m), 1.55-1.75 (2H, m), 1.8-2.0 (2H, m), 2.89 (2H, t), 3.40 (2H, t) and 7.2-7.4 (4H, m).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.COC(=O)C([N:45]([C:53]1C=CC=[C:55](N)[CH:54]=1)[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])C>>[C:49]([O:48][C:46](=[O:47])[N:45]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:53][CH2:54][CH3:55])([CH3:52])([CH3:51])[CH3:50]
Reactant: COC(=O)C(C)N(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 2-[(3-amino-phenyl)-tert-butoxycarbonyl-amino]-propionic acid methyl ester (prepared in two steps from 3-nitro-N-tert-butoxycarbonylaniline) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41, step b. 1NMR (DMSO-d6) 9.53 (1H, s), 7.50 (2H, m), 7.25 (2H, m), 6.98 (2H, m), 6.73 (1H, d), 6.30 (1H, d), 5.00 (3H, br s), 4.79 (2H, s), 4.25 (1H, m), 3.91 (2H, m), 2.86 (1H, m), 2.00-1.00 (10H, m), 1.33 (3H, d), 1.13 (9H, s). Found: C, 60.48; H, 6.77; N, 11.18%; C31H39N5O5.HCl.H2O requires: C, 60.43; H, 6.87; N, 11.37%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C)C=O>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4][C@H:3]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
In 250 ml of dimethylformamide is dissolved 13.9 g of trans-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, and 2.3 g of 60% sodium hydride is added to the solution. After the mixture is stirred at room temperature for 20 minutes, 80 ml of a solution containing 10 g of tert-butyl bromoacetate in dimethylformamide is added thereto dropwise. The mixture is stirred at room temperature for 3 hours and then concentrated under reduced pressure. Water is added to the residue, and the organic substance is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried. Thereafter the solvent is distilled off under reduced pressure to give 18.6 g of tert-butyl trans-3-amino- 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate in the form of white crystals, m.p. 172°-174° C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21].COC1C2C(=C([N+]([O-])=O)C=CC=2)N=C(C([NH:29]C2NN=NN=2)=O)C=1>>[NH2:29][C:4]1[CH:5]=[C:6]2[C:19](=[CH:2][CH:3]=1)[N:18]=[C:9]([C:10]([NH:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:11])[CH:8]=[C:7]2[O:20][CH3:21]
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12
Reactant: COc1cc(C(=O)Nc2nnn[nH]2)nc2c(N)cccc12
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccc(N)cc12

Procedure:
8-Amino-4-methoxy-N(1H-tetrazol- 5-yl)quinaldamide, m.p. 276° (d), was prepared by the hydrogenation of 4-methoxy-8-nitro-N(1H-tetrazol- 5-yl)quinaldamide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[O:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[O:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(Oc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the compound of Example 54 (0.5 g) in THF (10 ml) and ethanol (20 ml) at room temperature was added sodium hydroxide (2N). The reaction mixture was stirred overnight at room temperature. The solution was evaporated under vacuo and then redissolved in H20. To the resulting solution was added acetic acid (1 ml). The yellow solid was filtered to give the title compound.
Reaction SMILES: [K].Br[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[P:13](=[O:18])([OH:17])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1.[F-:19].[K+].[Br-].[K+]>O.O1CCOCC1.C(O)COCCO>[F:19][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[P:13](=[O:18])([OH:17])[O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=1
Reactant: [F-]
Reactant: O=P1(O)Oc2ccccc2-c2cc(Br)ccc21
Agent: [Br-]
Agent: [K+]
Agent: [K]
Solvent: OCCOCCO
Solvent: O
Solvent: C1COCCO1
Product: O=P1(O)Oc2ccccc2-c2cc(F)ccc21
Temperature: 25 °C

Procedure:
Into a 200 ml capacity 3-neck flask equipped with a thermometer, a reflux condenser and a stirrer are fed 50 g of potassium salt of 9,10-dihydro-6-bromo-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide (CA-B6-K), 30 g of potassium fluoride and 100 g of diethylene glycol, and the flask is heated with stirring so that the contents boil slowly. Dioxane and water are formed little by little to reduce the temperature of the contents. Thus, while they are taken out, the initial boiling temperature is maintained to carry out the reaction for 8 hours. The reaction mixture is cooled down to room temperature to deposit an excess amount of potassium fluoride and potassium bromide formed by the reaction, which are then filtered off. To the resulting filtrate are added 100 ml of water and thereafter 30 ml of 10 N hydrochloric acid to deposit an acid, which is then filtered, dried and recrystallized from ethanol to give about 20 g of 9,10-dihydro-6-fluoro-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide, exhibiting a phosphorus content of 12.3% (theoretical value: 12.4%), an acid value of 224 (theoretical value: 224.3) and a melting point of 240° C. or higher, which will be hereinafter referred to as CA-F6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:9](=[O:10])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:11][CH:12]=2)[CH:3]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 4-chlorophthalic anhydride (25 g) in benzene (200 ml) was added aluminum chloride (36.5 g), and the mixture was stirred at room temperature for 1 hr. and subsequently refluxed for 30 min. After cooling the reaction mixture, it was diluted with ethyl acetate (200 ml) and poured into ice water. Conc. hydrochloric acid (20 ml) was added and the mixture was stirred at room temperature for 30 min. After separating the organic layer, the layer was washed successively with 4N hydrochloric acid, water and brine, dried over sodium sulfate and concentrated until the crystals precipitated. The crystals were collected by filtration and washed with isopropyl ether to give 4-chloro-2-benzoylbenzoic acid (16 g) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:20][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1
Reactant: Fc1ccc(F)nc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Temperature: 110 °C
Yield: 21.7 %

Procedure:
Potassium carbonate (16.75 g, 128.1 mmol) was added to a solution of 2,5-difluoropyridine (4.91 g, 42.7 mmol) and 2,4-dimethoxybenzylamine (6.85 g, 42.7 mmol) in DMSO (30 mL). The mixture was heated to 110° C. for 16 hours, cooled to room temperature and poured into water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with two further portions of ethyl acetate (25 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10 to 30% ethyl acetate in heptanes to afford the title compound as a white solid (2.43 g, 22%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:18])[NH:16][CH3:17])[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])[C:15]([NH:16][CH3:17])=[O:18]
Reactant: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C3 (step B) from (3-chloro-2-fluoro-5-methylcarbamoyl-benzyl)-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH2Cl2. MS (LC-MS): 217.0 [M]+; tR (HPLC conditions c): 2.39 min.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][O:31][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Reactant: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)=O)c(C)c2Cc2ccc(SCC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-acetyl-4-[(4-ethylthiophenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.03 g) in 2,4,6-trimethylpyridine (0.5 mL) was added ethyl chloroformate (0.012 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution (5 mL), and the resulting mixture was stirred at room temperature overnight. The resulting precipitatse were collected by filtration and washed with 10% aqueous citric acid solution and water to give 1-acetyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole (0.020 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:52])[C@@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)/[CH:26]=[CH:27]/[CH2:28][C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:53](I)[CH:54]=[CH2:55]>C1COCC1>[CH2:55]([C@@H:28](/[CH:27]=[CH:26]/[C@H:25]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=1)[C:24]([N:19]1[C@@H:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:52])[C:29]([N:31]1[C@@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][O:33][C:32]1=[O:43])=[O:30])[CH:54]=[CH2:53]
Reactant: C=CCI
Reactant: O=C(C/C=C/[C@H](Cc1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](/C=C/[C@H](Cc1ccc(F)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A solution of NaHMDS (1.0 M in THF, 1.34 mL, 1.34 mmol) was slowly added dropwise over 10 min to a −78° C. solution of (S,E)-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-fluorobenzyl)hex-3-ene-1,6-dione (763 mg, 1.34 mmol) in THF (4.8 mL). After the addition, the reaction mixture was allowed to stir for another 30 min at −78° C. and then a solution of allyl iodide (225 mg, 1.34 mmol) in THF (0.5 mL) was added dropwise. The reaction temperature was then warmed to −40° C. and stirred at −40° C. for 45 min. Then the reaction was warmed to 0° C. and stirred at 0° C. for an additional 1 hr. The reaction was quenched by the addition of saturated NH4Cl. The mixture was then partitioned between EtOAc and water. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4 and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (2S,5S,E)-2-allyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-(4-fluorobenzyl)hex-3-ene-1,6-dione (470 mg, 0.770 mmol, 57.6% yield) as a foam. Anal. Calcd. for C36H35FN2O6 m/z 610.2. found: 611.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH:9]([N:11]([CH3:13])[CH3:12])[CH3:10])=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[C:9]([N:11]([CH3:13])[CH3:12])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)c1ccc(F)cc1)N(C)C
Reactant: BrCc1ccccc1
Solvent: CC(=O)N(C)C
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(F)cc1
Temperature: 105 °C

Procedure:
11.2 g of sodium hydride (66%) are washed with hexane to remove oil, and added to 200 ml of dry dimethylacetamide. 50.0 g (0.256 mol) of 1-(4-fluorophenyl)-2-dimethylamino-propan-1-one (prepared by the method described in U.S. Pat. No. 5,534,629) are dissolved in 50 ml of dry dimethylacetamide and added dropwise to the above described solution. Successively, 48.2 g (0.282 mol) of benzyl bromide are slowly added dropwise with stirring and warmed up to 105° C. When the mixture has been stirred at this temperature for 12 h, the reaction mixture is poured to 500 ml of ice/water and extracted with toluene. The organic phase is washed with water, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (1:20) as eluent. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.17 (s,3H), 2.33 (s,6H), 2.96 (d, 1H), 3.39 (d, 1H), 6.87 (m,2H), 7.03-7.13 (m,5H), 8.55 (m, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:14]1[CH2:15][CH2:16][N:11]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH2:12][CH2:13]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: C#CCCCOS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCCCN1CCN(c2ncccn2)CC1
Yield: 66.4 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), 2-(piperazin-1-yl)pyrimidine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 2-(4-(pent-4-ynyl)piperazin-1-yl)pyrimidine (0.95 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>C1(C)C=CC=CC=1.CC(O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH:17]([CH3:22])[CH3:18])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(I)ccc1O
Reaction time: 24 h

Procedure:
2-Hydroxy-5-iodobenzoic acid (I 84 g, 0.7 mol), isopropanol (50 ml), conc sulfuric acid (5 ml) and p-toluenesulfonic acid (10 g) in toluene (1 1) was refluxed using a water separator. Portions of isopropanol was added intermittently to compensate for loss of 2-propanol by dehydration. After 24 h, the solution was cooled and washed with water. The toluene was evaporated partially. Iso-octane was added, and precipitated 2-hydroxy-5-iodobenzoic acid (106 g) filtered off. The solution was taken to dryness and the residue recrystallized from methanol. Yield 64 g, (71%), corrected for recovered starting material).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:22])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=2)=[C:7]([O:20][CH3:21])[CH:6]=1.[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:33])[F:32])[C:29]=1[CH3:30])#[N:24]>C(O)C.C1COCC1>[C:23]([C:25]1[C:26](=[C:41]([C:44]#[N:45])[C:42]#[N:43])[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:31]([F:34])([F:32])[F:33])[C:29]=1[CH:30]=[CH:18][C:16]1[S:17][C:13]([CH:12]=[CH:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][OH:1])[CH3:22])=[CH:6][C:7]=2[O:20][CH3:21])=[CH:14][CH:15]=1)#[N:24]
Reactant: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=O)s1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N(C)CCO)ccc1C=Cc1ccc(C=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)s1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of ethanol (15 ml) and THF (5 ml) were dissolved 5-(2-{4-[(2-hydroxyethyl) methylamino]-2-methoxyphenyl}vinyl)thiophene-2-carbaldehyde (0.5 g, 1.58 mmol) and 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-5H-furan-2-ylidene)malononitrile (0.50 g, 1.58 mmol). The mixture was stirred at room temperature for 18 hours and further at 50° C. for 3 hours. The mixture was cooled and the solid was collected. The solid was washed with cold ethanol (40 ml) 3 times to give a reddish brown crystal (yield: 0.91 g (93.8%)).