Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].C(N(CC)CC)C.ClC(OCC)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: C1COCCN1
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Cl
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Temperature: -10 °C

Procedure:
20 g (0.058 mol) of 4-amino-β-(4-chlorophenyl)-3,5-dichloro-cinnamic acid (mixture of isomers A and B in the ratio 1:1.5) were dissolved in 700 ml of dry chloroform. 5.93 g (0.058 mol) of triethylamine were added while cooling with ice and stirring, and the mixture was cooled to -10° C. and combined with 6.35 g (0.058 mol) of ethyl chloroformate. After the addition had ended, 25.5 g (0.29 mol) of morpholine were added while further stirring and cooling. The resulting mixture was stirred for 4 hours more at room temperature and then extracted three times with water, and the organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on a silica gel column (silica gel: substance=10:1, eluant: chloroform/ethyl acetate=1:1). The eluates containing substance were combined and evaporated to dryness in vacuo. Colorless crystals were obtained, melting point 140°-144° C., which contained the cis/trans isomer mixture in a proportion of 3:2.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.[ClH:26]>C1COCC1.O>[ClH:26].[C:3]([CH:5]([C:14]1[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: Cc1cc(C(F)(F)F)nc(S(C)(=O)=O)n1
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1nc(C)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1,1,1-trifluoro-2,4-pentanedione (5.00 g; 32.4 mmol) and S-methylisothiourea hemisulfate (4.06 g; 29.2 mmol) in pyridine (3.75 mL) and water (62 mL) was heated at reflux for 1 day. The mixture was cooled to room temperature, extracted with chloroform, and the chloroform extract washed with water to give 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine as an off-white solid (4.60 g, 22.1 mmol). This was dissolved in MeOH (60 mL), and a solution of OXONE® (27.1 g, 44.2 mmol) in water (100 mL) was added over 10 min. The mixture was stirred at room temperature for 4 hr and then extracted with EA. The EA was washed with water, dried, and concentrated to give 4-methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (4.8 g) as a white solid. Sodium hydride (0.16 g of a 60% dispersion in mineral oil; 4.0 mmol) was added to a stirred solution of ethyl cyanoacetate (0.21 mL; 2.0 mmol) in THF (8 mL), and the resulting suspension stirred at room temperature for 15 min. 4-Methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (0.48 g; 2.0 mmol) was then added, and the mixture stirred overnight. Water was added, followed by 1M hydrochloric acid to adjust to pH 3-4. The solid that formed solid was filtered, washed with water, and dried under high vacuum to give ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (0.43 g) as a pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A solution of 1-acetylpiperazine (5 g, 39 mmol) in THF (100 mL) was treated with ethyl acrylate (4.2 mL, 39 mmol) then stirred overnight at r.t. after which an additional 4.2 mL of ethyl acrylate was added. The reaction heated at reflux for 5 h, cooled to r.t. and partitioned between dichloromethane and 1N HCl. The acid wash was basified with NaHCO3 to pH 9-10 and extracted 3 times with dichloromethane. Combined organics were dried, filtered and concentrated to give 4.49 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:14]([O:18][C:19]([N:21]([CH2:23][CH:24]=O)[CH3:22])=[O:20])([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:24][CH2:23][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH3:22])[CH2:3]1
Reactant: CCOC(=O)CC1CCNCC1F
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(CCN(C)C(=O)OC(C)(C)C)CC1F
Reaction time: 24 h
Yield: 55.8 %

Procedure:
To a solution of ethyl 3-fluoro-4-piperidinylacetate (230 mg, 1.22 mmol) and 2-(N-tert-butoxy carbonyl-N-methylamino)acetaldehyde (211 mg, 1.22 mmol) in THF (5 mL) was added NaBH(OAc)3 (386 mg, 1.82 mmol) and acetic acid (70.0 mL, 1.22 mmol) at room temperature After being sired for 24 hr, the reaction mixture was quenched by the addition of sat. NaHCO3 solution and extracted with EtOAc. The extracts were washed with brine, dried over Na2CO3, and concentrated to dryness. Chromatography of the residue with CHCl3—MeOH (6:1, v/v) as eluent gave ethyl 3-fluoro-1-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-piperidinylacetate (236 mg, 56%) as a reddish oil. 1H-NMR (CDCl3) δ1.25 (t, J=7.1 Hz, 3H), 1.45 (s, 9H), 1.53 1.79 (m, 2H), 1.90-2.09 (m, 2H), 2.15 (dd, J=16.4, 7.1 Hz, 1H), 2.45-2.58 (m, 2H), 2.87 (s, 3H), 2.90-2.99 (m, 2H), 3.20 (m, 1H), 3.24-3.45 (m, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.61, 4.73 (each broad s, 1H); ESI-MS m/z 347.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:20]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21]1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:24]([CH:20]2[CH2:23][CH2:22][CH2:21]2)=[O:25])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC(=O)C2CCC2)c1

Procedure:
An 11.4 g portion of m-aminoacetophenone, 10.9 g of diisopropylethylamine, 10.0 g of cyclobutanecarboxylic acid chloride and 200 ml of dichloromethane were reacted as described in Example 1, giving 14.68 g of N-(3-acetylphenyl)cyclobutanecarboxamide.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)[CH2:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19].O>CS(C)=O>[CH3:19][C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC[C@@H](C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCC[C@@H](C)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
This example illustrates a synthesis of 1-(3-(R)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine (inventive compound no. 1588R). Sodium hydride(95%) (631 mg, 25 mmol) was added to a solution of theobromine (4.14 g, 23 mmol) in dimethylsulfoxide (75 mL). After 20 minutes of stirring, (R)(-)Citronellyl bromide (5.0 g, 22.8 mmol) was added. After 16 hours of stirring at room temperature, the reaction was poured into a separatory funnel containing 500 mL of water and extracted with dichloromethane (3×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% petroleum ether/ethyl acetate eluant, yielding 5.9 g (81.5% yield) 1-(3-(R)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (inventive compound no. 1596R) as a yellowish oil. A solution of 1-(3-(R)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (318 mg, 1 mmol) and m-chloroperoxybenzoic acid (0.52 g; 1.5 mmol) (50% by wt) in dichloromethane (7 mL) was stirred for 5 hours. The reaction mixture was diluted with 40 mL of dichloromethane and washed successively with 20% aqueous sodium sulphite solution (10 mL), saturated sodium bicarbonate solution (10 mL), water and brine solutions. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 5% petroleum ether/ethyl acetate eluant, yielding 0.253 g (76% yield) of 1-(3-(R)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C(Br)Br)[C:12]([Br:18])=[CH:11][C:6]=1C(OC)=O)(=O)[CH3:2].[C:19](=[O:22])([O-])[O-:20].[Ca+2].[C:24](=[O:27])([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCOCC1.O.C(OCC)(=O)C>[Br:18][C:12]1[C:13]([CH:24]=[O:27])=[CH:14][C:5]([O:4][CH2:1][C:2]2[CH:13]=[CH:14][CH:5]=[CH:6][CH:11]=2)=[C:6]([CH:11]=1)[C:19]([O:20][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(C(Br)Br)cc1OC(C)=O
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Br
Temperature: 150 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-(acetyloxy)-5-bromo-4-(dibromomethyl)benzoate (may be prepared as described in Description 23; 1 g, 2.25 mmol) in 1,4-dioxane (5 ml) was added calcium carbonate (0.68 g, 6.74 mmol) and water (5 ml). The mixture was heated at 150° C. for 3 hours, cooled and the solvent was removed in vacuo. The residue was suspended in N,N-dimethylformamide (5 ml) and potassium carbonate (0.78 g, 5.62 mmol) and benzyl bromide (0.59 ml, 4.94 mmol) were added and the mixture was stirred for 18 hours. Ethyl acetate (15 ml) and water (10 ml) were added and the organic layer washed further with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Some starting material was still present. The residue was redissolved in N,N-dimethylformamide (5 ml) and potassium carbonate (0.78 g, 5.62 mmol) and benzyl bromide (0.59 ml, 4.94 mmol) were added and heated at 50° C. for 3 hours, cooled and the solvent was removed in vacuo. Purification by column chromatography (SiO2; 6:1 cyclohexane/ethyl acetate) yielded the title compound as an oil. 956 mg.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[K+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[K+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Potassium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to room temperature, diluted with water, froze to a solid, and lyophilized to dryness to afford potassium (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 5.97 (s, 2H), 2.31 (s, 3H), 1.92-1.82 (m, 211), 1.81-1.65 (m, J=13.8, 5H), 1.54-1.48 (m, 1H), 1.47-1.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 31-1). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:12][Br:14])[O:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCC(O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc(C2CCC(CBr)O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A mixture of 7.4 g of 1-(4-fluorophenyl)-4-penten-1-ol and 8.0 g of N-bromosuccinimide in 100 ml of chloroform is stirred at room temperature for 3 hours. The reaction mixture is then washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant to give 9.8 g of 2-(4-fluorophenyl)-5-(bromomethyl)tetrahydrofuran as colorless oil, nD27 1.5218.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:28])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:21][C:22]=2[F:27])[CH:38]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2F)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=534.1 [M+H]+.
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O>[Br:1][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: OCCc1cccc2ccccc12
Reactant: Br
Solvent: O
Product: BrCCc1cccc2ccccc12

Procedure:
A mixture of hydrobromic acid (50 ml, 46% w/v) and 1-(2-hydroxyethyl)naphthalene (10.0 g, 0.058 mol) was stirred and heated under reflux for 4 h. After cooling, the reaction mixture was diluted with water (150 ml), and the resulting precipitate was extracted with ether (3×150 ml). The ether extracts were combined and dried (MgSO4), when the ether was evaporated under reduced pressure, to afford 1-(2-bromoethyl)-naphthalene which was used without further purification.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([NH:11][C@H:12]([C:16]([O:18][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A suspension of 3.40 g (13.5 mmol) of Cbz-valine and 1.56 g (13.5 mmol) of N-hydroxysuccinimide in 200 ml of dichloromethane was treated with 2.86 g (14.9 mmol) of N-ethyl-N'-(dimethylaminopropyl)carbodiimide hydrochloride and stirred at ambient temperature for 4 h. The resulting solution was washed sequentially with 10% citric acid, aqueous NaHCO3, and water; dried over Na2SO4, and concentrated in vacuo to provide 4.00 g (85%) of the desired compound.
Reaction SMILES: S([O-])([O:4][CH3:5])(=O)=O.[CH3:7][N:8]1[C:13](=[O:14])[NH:12][C:11](=O)[O:10][C:9]1=[O:16]>O.C(Cl)(Cl)(Cl)Cl>[CH3:11][N:12]1[C:13](=[O:14])[N:8]([CH3:7])[C:9](=[O:10])[O:16][C:5]1=[O:4]
Reactant: Cn1c(=O)[nH]c(=O)oc1=O
Reactant: COS(=O)(=O)[O-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)oc(=O)n(C)c1=O
Yield: 92 %

Procedure:
The process disclosed in example 1 is used, except that the solvent is not distilled. 15.1 g of methyl sulfate (0.12 mole) are added to the solution of 3-methyl-1,3,5-oxadiazine-2,4,6-trione. The solvent is evaporated after 10 minutes of reaction at a temperature of 25° C. After washing with water and carbon tetrachloride, 14.6 g of 3,5-dimethyl-1,3,5-oxadiazine-2,4,6-trione (yield: 92%) which is a symmetrical disubstituted 1,3,5-oxadiazine trione are obtained.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@@H:28]([OH:40])[C@@H:27]([CH2:41][OH:42])[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]>CN(C)C1C=CN=CC=1.ClCCCl.C(Cl)(Cl)Cl>[N:19]([C@@H:22]1[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C@@H:28]([OH:40])[C@@H:27]([CH2:41][O:42][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:26][C@H:23]1[S:24][CH3:25])=[N+:20]=[N-:21]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](SC)[C@@H]2N=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of t-butyldiphenylsilyl chloride (151 mg, 0.54 mmol), 4-dimethylaminopyridine (90 mg, 0.73 mmol) and methyl 2-azido-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (15) (130 mg, 0.36 mmol) in dry 1,2-dichloroethane (8 mL) was stirred at 80° C. for 2 hours. The resulting clear solution was cooled to room temperature, diluted with CHCl3 (20 mL), washed with H2O (3×20 mL), brine solution (20 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane—ether 2:1 as the mobile phase to give methyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside (16) (142 mg, 68%).
Reaction SMILES: [C:1]1([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:15]=[C:14]([NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:75][CH2:74]OCCOCCOCCOCCOC1>[Cu].C1(C)C=C(C)C=C(C)C=1>[C:44]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:46][C:41]([N:11]([C:12]2[CH:13]=[C:14]([N:29]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:50]3[CH:51]=[CH:52][C:47]([C:44]4[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=4)=[CH:48][CH:49]=3)[CH:15]=[C:16]([N:18]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[C:1]3[CH:10]=[CH:5][C:4]([C:75]4[CH:74]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:3][CH:2]=3)[CH:17]=2)[C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:42][CH:43]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: c1ccc2c(Nc3cc(Nc4cccc5ccccc45)cc(Nc4cccc5ccccc45)c3)cccc2c1
Reactant: Ic1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cc(C)cc(C)c1
Product: c1ccc(-c2ccc(N(c3cc(N(c4ccc(-c5ccccc5)cc4)c4cccc5ccccc45)cc(N(c4ccc(-c5ccccc5)cc4)c4cccc5ccccc45)c3)c3cccc4ccccc34)cc2)cc1
Reaction time: 17 h
Yield: 110.3 %

Procedure:
2.0 g of 1,3,5-tris(1-naphthylamino)benzene, 5.0 g of 4-iodobiphenyl, 3.7 g of potassium carbonate, 2 g of copper powder, 0.3 g of 18-crown-6 (or 1,4,7,10,13,16-hexaoxacyclooctadecane) and 10 mL of mesitylene as a reaction solvent were placed in a 100 mL capacity glass flask and the reaction was carried out at a temperature of 170° C. for 17 hours under a nitrogen atmosphere. After the reaction, the resultant reaction mixture was extracted with toluene and the toluene solution was subjected to silica gel chromatography to fractionate the reaction product. The reaction product was then purified by recrystallization from a mixed solvent of toluene/hexane and then by sublimation to provide 1.2 g of the desired 1,3,5-tris(N-(4-biphenylyl)-N-(1-naphthyl)amino)benzene (TBNAB). The yield was 32%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[NH4+:11].C1COCC1>O>[Br:1][C:2]1[C:3]([NH2:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2,4-dichloropyrimidine (10.0 g, 44 mmol), concentrated ammonium hydroxide (100 mL) and THF (150 mL). The resulting mixture was magnetically stirred at room temperature for 12 h. Work-up: the reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 11 g (quantitative) of the product as a white solid. MS m/z: 208 (M+H+).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[S:16][C:15]([CH2:17][C@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:19]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:21]2[CH2:22][C@H:18]([CH2:17][C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)[CH2:19][C@H:20]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)s2)CN1C(=O)Cn1ccnn1
Yield: 65 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4S)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 65, (2S,4S)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-((5-chlorothien-2-yl)methyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (60.2 mg, 65%). 1H-NMR (400 MHz, CDCl3): σ 8.95 (s, 1H), 7.77 (d, 2H), 7.43 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 6.76 (d, 1H), 6.63 (d, 1H), 5.30 (d, 1H), 5.17 (d, 1H), 4.80 (d, 1H), 3.79 (dd, 1H), 3.30 (t, 1H), 3.04-2.93 (m, 2H), 2.87-2.78 (m, 1H), 2.68 (dd, 1H), 1.75-1.68 (m, 1H). MS (EI) for C26H23ClFN5O3S. found 540.1 (MH+).