Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].CN(C=O)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>O>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][S:2][CH3:1])[CH:11]=1
Reactant: BrCc1cccc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Sodium thiomethoxide (0.616 g, 8.8 mmol) was added to DMF (8 mL) and cooled to 0° C. To this solution was added 1-bromo-3-bromomethyl-benzene (2 g, 8 mmol). The mixture was allowed to warm to rt and stir for 18 h. The mixture was then poured into cold water (50 mL) and extracted with EtOAc (3×20 mL). The organics were combined and dried with sodium sulfate. The solution was concentrated in vacuo to yield the crude product, which was then purified via flash chromatography (5% ethyl acetate—hexanes) to yield 1.3 g (68.5%) of 1-bromo-3-methylsulfanylmethyl-benzene as a pure product. 1H-NMR (methylene chloride -d2) δ 7.48-7.47 (m, 1H), 7.392 (dt, J=7.9, 1.5 Hz, 1H), 7.28-7.207 (m, 2H), 3.64 (s, 2H), 1.99 (s, 3H); LC-MS RT: 3.70, [M+H]+: 354.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[CH3:18]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C=CCCCCCC(=O)O)ccc1F
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CCCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 63 h
Yield: 95 %

Procedure:
To a solution of 8-(4-fluoro-3-methylphenyl)oct-7-enoic acid (0.976 g, 3.899 mmol) in 30 mL of MeOH, was added 10% Pd on C (0.195 g). After stirred at room temperature under H2 (1 atm) for 63 h, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was used directly in the next step without further purification (0.938 g, 95% yield). LC-MS: tR=10.1 min, m/z 253 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])[C:5]2=[CH:4][N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][C@@H:22]1O>>[F:17][C:15]1[CH:14]=[CH:13][C:12]([O:18][CH3:19])=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=1
Reactant: COc1ccc(F)cc1-c1n[nH]c2nc(Cl)ncc12
Reactant: CS(=O)(=O)N1CC[C@H](N)[C@@H](O)C1
Product: COc1ccc(F)cc1-c1n[nH]c2nc(NC3CCN(S(C)(=O)=O)CC3)ncc12

Procedure:
The same procedure as described in Example 25 was used starting from 6-chloro-3-(5-fluoro-2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine, Example 24, (103 mg, 0.37 mmol), and (3S,4S)-4-amino-1-methanesulfonyl-piperidin-3-ol, (115 mg, 0.59 mmol), to give a yellow solid. 70 mg, 46%. MS (M+H)+, 437.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37](C)[CH:36]=C[C:34]=2F)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1.Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:30]=[C:29]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[CH:37][CH:36]=[N:52][CH:34]=2)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[C:11]2=[C:12]([CH3:26])[C:13]([C:15]([NH:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:16])=[CH:14][N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ncnn4cc(C(=O)NCCN5CCOCC5)c(C)c34)c(F)c2)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)c4cccnc4)cc3F)c12
Yield: 39 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 50, 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (30 mg, 0.07 mmol, Compound C of Example 50) was converted the title compound (16 mg, 39%) as a 2.HCl salt. 1H NMR (CD3OD) δ 9.08 (s, 1H), 8.70 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 7.87 (m, 2H), 7.38 (m, 2H), 7.22 (m, 2H), 3.82 (s, 4H), 3.61 (m, 2H), 2.75 (m, 9H); MS(ESI+) m/z 520.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(3-chlorophenyl)piperazine (172.5 mg, 0.88 mmol, 2.00 equiv), and DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) in DMF (4 mL) was placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath, then quenched with water. The resulting solution was extracted with 6×20 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, filtered to remove solids, and concentrated under vacuum. Purification via silica gel column (PE/EA (30:1)) yielded 186.7 mg (89%) of methyl 3-(4-(3-chlorophenyl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available propionyl chloride the title compound is obtained as colorless solid. Alternative the above obtained solid is re-crystalised from ethylene glycol/water mixture (5/1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)OCCO2)OCc1ccccc1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 1,4-benzodioxane-6-acetic acid (5.0 g) and potassium carbonate (2.13 g) in dimethylformamide (20 ml) was added benzyl bromide (4.84 g) at room temperature. After being stirred at the same temperature for 3 hours, the mixture was poured into water (200 ml) and extracted with diethyl ether (150 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford benzyl 1,4-benzodioxane-6-acetate (7.08 g) as an oil.
Reaction SMILES: [O-:1]Cl.[Na+].[CH3:4][O:5][CH:6]([O:21][CH3:22])[C@@:7]1([CH3:20])[CH:12]=[CH:11][C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1>C(Cl)Cl>[CH3:22][O:21][CH:6]([O:5][CH3:4])[C@@:7]1([CH3:20])[C@H:12]2[O:1][C@H:11]2[C:10]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=2[O:8]1
Reactant: [O-]Cl
Reactant: COC(OC)[C@@]1(C)C=Cc2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To the pre-cooled solution of 0.55 M NaOCl (55 mL, 30.0 mmol) and of 0.05 M Na2HPO4 (21.5 mL) at 0° C., (2R)-2-dimethoxymethyl-2-methyl-6-nitro-2H-1-benzopyran n(2 g, 7.5 mmol) and (R, R) Jacobson's catalyst (477.5 mg, 0.75 mmol) in CH2Cl2 (10 mL) was added. The reaction mixture was stirred at rt for 8 hr and then filtered through Celite to remove the jacobson's catalyst. The layer was separated and the organic layer was washed with brine, dried (Na2SO4), filtered, then concentrated under reduced pressure. The residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=4:1) to give the desired compound (1.64 g, 77%) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[H-].[Na+].Br[CH2:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.C(OCC)(=O)C>[S:27]1[C:26]2[C:21]([CH2:20][N:8]3[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:16])[C:7]3=[O:15])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]=[CH:28]1
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Reactant: BrCc1cccc2ccsc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(O)CCn1c(=O)n(Cc2cccc3ccsc23)c2ccccc21
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (200 mg, 0.91 mmol) in DMA (5 ml) was added sodium hydride (60% oil dispersion, 55 mg, 1.4 mmol). The resulting mixture was stirred for 10 minutes at ambient temperature after which time 7-bromomethyl-benzo[b]thiophene (206 mg, 0.91 mmol) was added. The reaction was heated at 120° C. in a microwave for 20 minutes. Upon cooling to ambient temperature the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.) and brine. The aqueous phase was acidified using 1M HCl and extracted once with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 5% methanol/dichloromethane). The product-containing fractions were combined and concentrated to give 20 mg (6%) of the desired product. LCMS (ESMS): m/z 353.41 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5](F)=[C:6]([CH:14]=[CH:15][C:16]=1[F:17])[C:7]([N:9]([CH2:11][CH2:12][OH:13])[CH3:10])=[O:8].O.[CH3:20]N(C=O)C>>[Cl:3][C:4]1[C:5]2[O:13][CH2:12][CH2:11][N:9]([CH2:10][CH3:20])[C:7](=[O:8])[C:6]=2[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCN1CCOc2c(ccc(F)c2Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (35 mg, 0.913 mmol, 60% dispersion in mineral oil) was added slowly to a solution of 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (220 mg, 0.836 mmol) in DMF (4 mL) and the pale yellow solution was stirred at RT for 16 hours. Water was added to the reaction and the mixture was subsequently extracted with DCM (3×30 mL). The combined organic phases were washed with water (3×20 mL) and saturated brine solution then dried (MgSO4), filtered and evaporated to give the desired product as a colourless oil (180 mg). 1H NMR δ (CDCl3): 1.25 (t, 3H), 3.5 (t, 3H), 3.65 (q, 2H), 4.52 (t, 2H), 6.97 (dd, 1H), 7.72 (dd, 1H). m/z 244 (M+H)+, 242 (M−H)−
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH2:35]Br)=[CH2:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38]C(=O)C)(=O)C.[CH3:42][O-:43].[Na+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:37][OH:38])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH2:35][O:43][CH3:42])=[CH2:34])=[CH:29][CH:28]=1
Reactant: C=C(CBr)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(COC)c1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1

Procedure:
The solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(3-bromoprop-1-en-2-yl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate BA) (110 mg, 0.169 mmol) and 4 mL of 0.3M NaOMe in MeOH (freshly-distilled) was stirred at 70° C. for 2.5 h. Then the reaction was quenched with H2O. After removing the volatiles, the aqueous layer was extracted 3× with AcOEt. The organic portion was washed 1× with a saturated solution of NH4Cl and 1× with brine prior to drying over Na2SO4. Concentration and purification of the crude product by preparative TLC gave intermediate BA (48 mg).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[N:13]1[CH:17]=[CH:16][C:15]([C:18](=[N:20][OH:21])[CH3:19])=[CH:14]1>CO.Cl>[OH:21][NH:20][CH:18]([C:15]1[CH:16]=[CH:17][N:13]([C:7]2[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:6]=2[CH3:5])[CH:14]=1)[CH3:19]
Reactant: CC(=NO)c1ccn(-c2c(C)cccc2C)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C)c1-n1ccc(C(C)NO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Two mole-equivalents of sodium cyanoborohydride is added to a mixture of 1-(2,6-dimethylphenyl-3-acetyl-1H-pyrrole oxime in methanol and ethanolic hydrochloric acid is added to adjust to pH 3. The reaction mixture is stirred at room temperature overnight, poured over ice, rendered basic and extracted with ether. The ether extract is washed with brine, dried and evaporated to dryness. The residue is chromatographed over silica gel by gradient elution with methylene chloride/methanol, to yield N-hydroxy-1-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Br:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23]>>[Br:17][C:18]1[CH:19]=[C:20]([S:24]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:26])=[O:25])[S:21][C:22]=1[Cl:23]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3cc(Br)c(Cl)s3)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)phenyl}acetamide (63 mg) and 4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described in the synthetic METHOD B to give a white solid (11.7 mg) with purity >80%: MS (pos) m/z 491.9, 493.9.
Reaction SMILES: [Br:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:38]([F:42])([F:41])([F:40])[F:39]>C(OCC)C>[F:39][B-:38]([F:42])([F:41])[F:40].[Br:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(C)c(C)c1C
Reactant: Cc1ccc(S(=O)CBr)cc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CBr)c2cc(C)c(C)c(C)c2C)cc1
Reaction time: 0.5 h

Procedure:
1-((Bromomethyl)sulfinyl)-4-methylbenzene (200 mg, 0.86 mmol) of example 35 was dissolved in dry diethyl ether (6 mL) under an argon atmosphere. 1,2,3,4-tetramethylbenzene (0.127 g, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −60° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.145 mL, 1 eq) was slowly added maintaining the same temperature. After 30 minutes, HBF4 in diethyl ether was added (54%, 0.209 mL, 1.5 eq). The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and dried under vacuum. 0.309 g (82%) of the desired product was obtained as a white solid. mp: 238° C. 1H NMR (DMSO-d6, 400 MHz): δ 7.98 (2H, d, J=8.4 Hz), 7.78 (1H, s), 7.58 (2H, d, J=8.2 Hz), 6.8 (2H, ABQ, J=9.08 Hz), 2.51 (3H, s), 2.42 (3H, s), 2.36 (3H, s), 2.26 (3H, s), 2.25 (3H, s). 13C NMR (DMSO-d6, 100 MHz): δ 145.7, 142.8, 138.4, 137.3, 136.8, 131.6, 130.6, 126.2, 121.4, 120.5, 35.0, 20.9, 20.4, 17.1, 16.4. FT-IR (KBr): 3048, 2967, 1494, 1446, 1392, 1284, 1261, 1218, 1195, 1085, 1051, 1031, 862 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])[O-]
Reactant: Fc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-bromo-2,4-difluorobenzene (0.512 g, 2.65 mmol, Aldrich, used as received) in conc. H2SO4 (5.0 mL) at 0° C., KNO3 (0.275 g, 2.72 mmol) was added in one lot. The resulting solution was allowed to warm to 28° C. and stirred at that temperature overnight. It was then poured into ice (50 g) and extracted with ethyl acetate (50 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the resulting oil dried further under vacuum to afford 0.576 g (91%) of the pure (1H NMR) title compound as a light red oil; 1H NMR (CDCl3); δ7.141 (dd, 1H, J1 =10.2 Hz, J2 =7.8 Hz), 8.375 (t, 1H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](OCC)=[O:16])=[N:6]1.[C-]#[N:25].[Na+].N.CO>>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]([NH2:25])=[O:16])=[N:6]1
Reactant: CCOC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of ethyl 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate (Intermediate-3, 0.78 mmol) and sodium cyanide (0.1 equiv) in ammonia/MeOH (7N, 30 equiv, 3.4 mL) in a seal tube was heated at 90° C. for 24 h. The reaction mixture was cooled to room temperature, conc. and dried in vacuo to afford 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxamide as a tan solid (>99% yield).
Reaction SMILES: [CH:1]([CH:4]([S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:9])[C:5](O)=[O:6])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>>[CH:1]([CH:4]([S:8]([O:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:9])[C:5]([Cl:24])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1OS(=O)(=O)C(C(=O)O)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)c1ccccc1OS(=O)(=O)C(C(=O)Cl)C(C)C

Procedure:
2,6-Diisopropylphenoxysulfonyl acetic acid (prepared as described in Example 3) was reacted with oxalyl chloride to provide 2,6-diisopropylphenoxysulfonyl acetyl chloride. The acid chloride was reacted with 2,6-diisopropylphenol in dichloromethane to provide, following evaporation of the reaction solvent, 2,6-diisopropylphenyl (2,6-diisopropylphenoxycarbonyl)methyl sulfonate, mp 90°-92° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[CH:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:30]([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 24 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-methoxyphenyl)indole-3-carboxylic acid ethyl ester (153 mg, 0.40 mmol and 4-isopropoxyphenylboronic acid (108 mg, 0.60 mmol). Yield 111 mg, 52%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][CH:22]([OH:24])[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:25]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:20]2[CH2:23][CH:22]([O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:21]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.581 mL of triethylamine and 0.185 mL of methanesulfonyl chloride were added to chloroform (15 mL) solution of 500 mg of N-(diphenylmethyl)-3-hydroxyazetidine, and stirred at room temperature for 3 hours. Aqueous sodium carbonate solution was added to the reaction liquid, extracted with chloroform, dried with sodium sulfate, and evaporated under reduced pressure to obtain crude N-(diphenylmethyl)-3-(methanesulfonyloxy)azetidine. 433 mg of 1-(4-nitrophenyl)piperazine and 433 mg of potassium carbonate were added to DMSO (10 mL) solution of the compound obtained in the above reaction, and heated at 100° C. for 3 hours. Water was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with saturated saline water. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the crude product was purified through column chromatography (ethyl acetate/hexane=2/1). A catalytic amount of trifluoroborane ether solution was added to acetic anhydride (6 mL) solution of the obtained diphenylmethyl compound, and heated at 90° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, sodium hydrogencarbonate was added to the residue, and extracted with chloroform. The organic layer was dried with sodium sulfate, and then concentrated under reduced pressure. The crude product was purified through column chromatography (methanol/chloroform=1/10), and then solidified from ethyl acetate/hexane to obtain 160 mg of the entitled compound as a yellow solid.
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][C:6]([NH:10][C:11]([N:4]([O:5][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:3])[CH3:2])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(C)(C)N=C=O
Reactant: CC(=O)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(OC(=O)NC(C)(C)C)C(=O)NC(C)(C)C

Procedure:
Acetohydroxamic acid (7.5 grams), tert-butyl isocyanate (22 grams) and a few drops of triethylamine were stirred in 80 ml of methylene chloride for about 48 hours. After stirring, the solvent was removed under vacuum leaving a residue which was recrystallized from a solution containing methylene chloride and hexane. A subsequent recrystallization from methylene chloride left the desired, N-(((1,1-dimethylethyl)amino)carbonyl)-N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide, m.p. 111°-113° C.