Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:23][C@@H:24]2[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:25]2[NH:34][C:35](=[O:37])[CH3:36])[C@@H:16]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[O-2].[Ba+2].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[CH2:60](Br)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:23][C@@H:24]2[O:31][C@H:30]([CH2:32][O:33][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:28]([O:29][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:26]([O:27][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:25]2[NH:34][C:35](=[O:37])[CH3:36])[C@@H:16]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1[C@@H](NC(C)=O)[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: BrCc1ccccc1
Agent: [Ba+2]
Agent: [O-2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCO[C@@H]1[C@@H](NC(C)=O)[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1O[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(C)=O
Reaction time: 24 h

Procedure:
To a solution of benzyl 2-acetamido-4-O-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-D-glucopyranoside (624 mg, 0.97 mmol) in N,N-dimethylformamide (15 ml) are added barium oxide (670 mg), barium hydroxide octahydrate (223 mg), and benzyl bromide (1.04 ml, 8.74 mmol). The reaction mixture is stirred for 20 hours at room temperature at which time additional barium oxide (335 mg), barium hydroxide octahydrate (112 mg) and benzyl bromide (0.52 ml) are added. Stirring is continued for 24 hours at room temperature. The reaction mixture is then diluted with chloroform (100 ml), washed successively with 60% aqueous acetic acid, saturated sodium bicarbonate, and water, dried (sodium sulfate), and evaporated. The residue is applied to a column of silica gel (90 g) that is eluted with 4:1 chloroform-ethyl acetate. Combination and evaporation of the appropriate fractions affords benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-D-glucopyranoside as a white solid; yield 612 mg (69%), [α]D25 +58° (c, 1.1, chloroform). The 300 MHz nmr spectrum in chloroform-d is in accord with the desired structure.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C:23](=[O:25])[NH:22][CH2:21]1)([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.Br[C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].BrC1C=CC(N2CCOCC2=O)=NC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([N:22]2[CH2:21][C@@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:24][C:23]2=[O:25])=[N:28][CH:29]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)[Si](OC[C@@H]1CNC(=O)O1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)[Si](OC[C@@H]1CN(c2ccc(Br)cn2)C(=O)O1)(c1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
Compound 25a (927 mg, 2.73 mmol), 2,5-dibromopyridine (500 mg, 2.1 mmol, cesium carbonate (1.03 g, 3.15 mmol), Pd2(dba)3 (100 mg, 0.1 mmol) and xantphos (73 mg, 0.13 mmol), reacted following the synthetic method of compound 19a to afford 750 mg of viscous liquid, yield 70%.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][O:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[C@@H:22]([NH2:26])([CH2:24][CH3:25])[CH3:23]>O1CCCC1.C(OCC)(=O)C>[CH:22]([NH:26][C:4](=[O:7])[CH:3]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=1)[C:2]([CH3:21])([CH3:1])[CH2:6][OH:5])([CH2:24][CH3:25])[CH3:23]
Reactant: CC1(C)COC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC[C@H](C)N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Reaction time: 192 h

Procedure:
To a stirring solution comprised of (±)-4-(4,4-dimethyl-2-oxo-tetrahydro-furan-3-yloxy)-2-trifluoromethyl-benzonitrile (1.345 g; 4.495 mmol) in tetrahydrofuran (5 mL) at ambient temperature under a nitrogen atmosphere is added (S)-(+)-sec-butylamine (0.4931 g; 6.742 mmol.) The reaction mixture is stirred for eight days. The reaction mixture is diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid and with a brine solution. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo to afford 1.633 of a white solid as a mixture of diastereomers; HPLC UV purity: 94% (two diastereomers.)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1.[I:22]I>C1COCC1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[C:11]=1[I:22]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(I)c1C(F)(F)F
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a freshly prepared solution of LDA (119 mmol) in anhyd THF (250 mL) at −45° C. was added a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzonitrile (21.5 g, 114 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained <−40° C. (became dark brown during addition). The mixture was stirred 30 min at −45° C., cooled to −70° C. and iodine (31.7 g, 125 mmol) was added in one portion (−70° C.→−52° C.). The mixture was stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na2S2O3 (ca. 250 mL) and 1N HCl (ca. 125 mL). The mixture was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) followed by recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.85 (ddd, J=8.6, 5.1, 0.5 Hz, 1H), 7.36 (ddd, J=8.6, 6.6, 0.5 Hz, 1H); MS (GCMS EI) m/z 315 ([M]+, 100%).
Reaction SMILES: C([O:4][CH:5]1[C:10]([OH:14])([CH2:11][CH2:12][CH3:13])[CH:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]1[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)C=C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>C(O)C>[CH2:16]([O:15][CH:9]1[CH:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:5]([OH:4])[C:10]1([OH:14])[CH2:11][CH2:12][CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCOC1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1(O)CCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reaction time: 288 h
Yield: 79.2 %

Procedure:
20 (0.30 g, 0.48 mmol) was dissolved in 20 mL aqueous ethanol (90%). 93 mg (0.101 mmol) Wilkinson catalyst and 50 μL diisopropylethyl amine were added and the mixture was heated to reflux for 12 hours. After cooling to room temperature 30 μL triflouro acetic acid was added and the solution was allowed to stir for 12 days by when the starting material had disappeared. The solution was dried in high vacuum and the residue was dissolved in t-butylmethyl ether and washed with 0.5 M phosphate buffer pH=7 and brine. The organic phase was filtered after being dried over Na2SO4 and the filtrate was dried under reduced pressure. Further purification was accomplished by preparative HPLC (89% MeOH, 40 m/min, tRet=21.40 min) to give 220 mg of 21 (0.38 mmol, 78.4% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH3:18])[C:6]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:45][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>O.[OH-].[Na+].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[CH2:12][CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:45])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(Br)ccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCCC1CCn1c(-c2ccc([N+](=O)[O-])cc2)cc2cc(N)ccc21
Temperature: 25 °C
Yield: 24 %

Procedure:
Compound 19 (0.5 g, 1.167 mmol) and tris(dibenzylideneacetone) dipalladium (0) (53.4 mg, 0.058 mmol) were charged to an argon-purged flask fitted with a magnetic stirbar and condenser. Anhydrous tetrahydrofuran (15 mL) was added and stirring begun. Tri-tert-butylphosphine (0.358 mL, 0.1167 mmol, 10 wt % in hexanes) and lithium bis(trimethylsilyl)amide solution (3.501 mL, 3.501 mmol, 1.0 M in THF) were added and the mixture heated to reflux for 2 hours. The solution was cooled to room temperature overnight, diluted with water (15 mL) and 3M sodium hydroxide solution added to adjust pH to 9. Ethyl acetate added and the mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine, dried over magnesium sulphate, filtered, concentrated and the crude residue purified twice via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to afford dark red solid 20 (102 mg, 24.0%); 1H NMR (DMSO-d6) δ 8.33 (d, 2H, J=8.7 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 6.72 (d, 1H, J=1.8 Hz), 6.63 (m, 1H), 6.49 (s, 1H), 4.64 (brs, 2H), 4.25-4.12 (m, 2H), 2.88-2.78 (m, 1H), 1.99 (s, 3H), 1.91 (q, 1H, J=8.8 Hz), 1.84-1.72 (m, 2H), 1.64-1.55 (m, 1H), 1.52-1.35 (m, 3H), 1.30-1.16 (m, 1H); ESI-MS (m/z, %): 365 (M+1, 100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[CH3:4].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>C1COCC1.[Cl-].[Na+].O>[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]1)=[O:18])[CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCC1CCC(C(=O)CC(=O)OCC)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C(=O)C(CC(=O)c2ccccc2)C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
To a stirred slurry of 0.92 g (23 mmol) NaH, 60% dispersion in mineral oil, in 30 mL anhydrous THF, cooled 0° C. in ice, 5.12 g (21.3 mmol) 3-oxo-3-(4-propyl-cyclohexyl)-propionic acid ethyl ester from Step 2 was added dropwise over the course of 60 min. The reaction was stirred at 0° C. for 1 hr. 2-bromoacetophenone (5.57 g, 28 mmol) in 12 mL anhydrous THF was then added dropwise at 0° C. and the reaction was allowed to stir at room temperature over 5 days. The reaction was poured into brine, extracted with ethyl acetate, dried over MgSO4, and concentrated to afford 8.85 g (24.6 mmol, 115% yield) 4-oxo-4-phenyl-2-(4-propyl-cyclohexanecarbonyl)-butyric acid ethyl ester as an oil. The product was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:19]([CH2:20][C@@H:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)[CH2:22][CH3:23])[CH2:18][O:17]C1(C)C)=O)(C)(C)C>O.C(#N)C.[OH-].[Na+]>[NH2:15][C@@H:19]([CH2:20][C@@H:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH2:22][CH3:23])[CH2:18][OH:17]
Reactant: CC[C@@H](C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)Oc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: CC[C@@H](C[C@H](N)CO)Oc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 100.6 %

Procedure:
To a solution of trifluoroacetic acid (0.07 ml) in water (6 ml) was added dropwise a solution of (S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (135 mg) in acetonitrile (1 ml). The mixture was heated for 4 h at 80° C. with mechanical shaking. The mixture was then cooled to room temperature and diluted with 1 N aqueous sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate and concentrated in vacuo to give (2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (94 mg, quant.) as a light yellow viscous oil. MS (ISP): 316.1 ([M+H]+).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2[N+]([O-])=O)CCCCC1.[Cl:31]Cl.[BH4-].[K+]>[Fe](Cl)(Cl)Cl.[Cu]Cl.O>[Cl:31][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH2:13]
Reactant: O=[N+]([O-])c1ccc(C2CCCCC2)cc1
Reactant: ClCl
Agent: Cl[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: O=[N+]([O-])c1ccccc1C1CCCCC1
Solvent: O
Product: Nc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.0 g (5 mmol) of 4-cyclohexyl-nitrobenzene and 0.1 g of iron(III) chloride was heated to 60°. After the cyclohexyl-nitrobenzene had melted chlorine gas was conducted through the well-stirred mixture for 15 minutes. Then, 20 ml of ice-water were added and the mixture was extracted with ether. The ether was distilled off and the residue was dissolved in 60 ml of methanol. Then, the solution was treated with 2.5 g (25 mmol) of copper(I) chloride and portionwise with 1.6 g (29 mmol) of potassium borohydride. After stirring for 30 minutes the mixture was poured into 0.5 l of water and extracted with ether. Drying over sodium sulfate, distillation of the ether and chromatography over silica gel with hexane/ethyl acetate 9:1 gave 0.68 g of oil. MS: m/e (% basic peak)=209 (M+, 75), 166 (100), 140 (78), 131 (62).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17](Br)=[C:18]([Br:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:3]=1[Br:50].Cl.C(O)(=O)C.C(O)C>[Zn].C1(C)C=CC=CC=1>[Br:50][C:3]1[C:4]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][CH:17]=[C:18]([Br:34])[C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)[S:6][CH:2]=1
Reactant: CCCCCCCCCCCCCCc1c(-c2nc3sc(-c4sc(Br)c(Br)c4CCCCCCCCCCCCCC)nc3s2)sc(Br)c1Br
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCc1c(Br)csc1-c1nc2sc(-c3scc(Br)c3CCCCCCCCCCCCCC)nc2s1
Temperature: 100 °C

Procedure:
To a 50 mL round bottom flask were added to 0.800 g of 2,5-bis(5,4 dibromo-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole, 0.500 g Zn dust, 3 mL 3 M HCl, 2 mL acetic acid, 15 mL ethanol, and 15 mL toluene. The flask was heated to 100° C. for 3 hours. The reaction mixture was then filtered and the solvents were removed by rotary evaporation. The residue was purified by column chromatography using a mixture of hexane and dichloromethane to give the desired compound. The NMR data were obtained and were consistent with those of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[CH3:26].[N:27]([O-])=O.[Na+].NC(N)=O.C1(C)C=CC=CC=1>C(O)(=O)C.O>[CH:15]1([O:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:9][C:8]=2[C:5]2[CH:4]=[C:3]3[C:2](=[CH:7][CH:6]=2)[NH:1][N:27]=[CH:26]3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)CCc1ccc(OC2CCCC2)c(-c2ccc(N)c(C)c2)c1
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCc1ccc(OC2CCCC2)c(-c2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of Intermediate 72 (760 mg) in acetic acid (4 ml) was added with an aqueous solution (0.7 ml) of sodium nitrite (156 mg) under ice cooling, and stirred for 30 minutes. This reaction mixture was added with urea (350 mg), warmed to room temperature, stirred for 30 minutes, then added with toluene (8 ml) and water (4 ml), and further stirred for 60 hours. The reaction mixture was extracted with toluene (50 ml×2). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. V-57, 411 mg).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([CH3:21])[CH:13]=1.BrC1C=CC(N)=CC=1Cl.FC(F)(F)C1C=CC(B(O)O)=CC=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:9][CH3:10])=[C:14]([CH3:21])[CH:13]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: COc1cc(N)ccc1Br
Agent: Nc1ccc(Br)c(Cl)c1
Agent: OB(O)c1ccc(C(F)(F)F)cc1
Product: COc1cc(N)ccc1-c1ccc(Cl)cc1C

Procedure:
The title compound was prepared as described in Example 159 substituting 4-bromo-3-methoxyaniline and (4-chloro-2-methylphenyl)boronic acid for 4-bromo-3-chloroaniline and (4-(trifluoromethyl)phenyl)boronic acid, respectively.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[CH3:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH3:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-dimethylpropanoyl chloride (20 mg, 164 mmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.9 mg, 81% of theory).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O.O>C(OCC)(=O)C>[O:1]=[C:2]1[N:3]([NH:8][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[CH2:4][CH2:5][CH2:6][N:7]1[C:24]([NH2:23])=[O:25]
Reactant: O=C(NN1CCCNC1=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)N1CCCN(NC(=O)OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a suspension of (tetrahydro-2-oxo-1(2H)-pyrimidinyl)carbamic acid, phenylmethyl ester (35.5 g, 135.9 mmol) in 500 ml ethyl acetate, chlorosulfonyl isocyanate (24.0 g, 169.9 mmol) was added. The resulting solution was stirred for one hour and hydrolyzed by adding 175 ml water. The phases were separated, the organic phase washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent and trituration of the residue with ether yielded 38.0 g of the desired product, melting point 135.6° C.
Reaction SMILES: COC[O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8]([C:19]2[O:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][C:23](=[O:25])[CH:24]=2)=[CH:7][CH:6]=1.[I-].[Na+].Cl.[OH-].[Na+]>CC(C)=O>[OH:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8]([C:19]2[O:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][C:23](=[O:25])[CH:24]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=c1cc(-c2ccc(O)c3c2Sc2ccccc2S3)oc(N2CCOCC2)c1

Procedure:
To a solution of 2-(4-Methoxymethoxy-thianthren-1-yl)-6-morpholin-4-yl-pyran-4-one (1.1 g, 2.42 mmol) in acetone (50 ml) was added sodium iodide (0.40 g, 2.66 mmol) and concentrated HCl (3 ml). The dark suspension was stirred at room temperature for 72 hours before the careful addition of 1M sodium hydroxide solution until pH 12 was attained. The mixture was washed with EtOAc (2×50 ml) and then acidified with concentrated HCl until pH 1 whereupon a brown precipitate formed which was filtered off (0.90 g, 90%) and corresponded to the title compound. m/z (LC-MS, ESP): RT=4.39 min, (M++1)=456
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:18][C:19]([O:21]CC)=[O:20])[O:3]1.[Li+].[OH-]>C1COCC1.CO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:18][C:19]([OH:21])=[O:20])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OCC(=O)NC)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.2 %

Procedure:
The mixture of ethyl 2-(1-hydroxy-4-methyl-6-(2-(methylamino)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (321 mg, 1 mmol), LiOH (119.5 mg, 5 mmol) in THF/MeOH/H2O (5 ml/5 ml/10 ml) was stirred at room temperature for 4 hrs. The reaction mixture was quenched with 3N HCl. Filter the precipitate and washed with water. Dried to give desired product 150 mg as white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 9.14 (s, 1H), 7.97 (s, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 5.42 (d, J=9.6 Hz, 1H), 4.42 (s, 2H), 3.20 (dd, J=15.6, 2.4 Hz, 1H), 2.63 (d, J=3 Hz, 3H), 2.48 (s, 3H), 2.05 (dd, J=9.6, 15.6 Hz, 1H). MS (ESI) m/z=292 [M−H]−.