Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Si:7]([O:24][C@H:25]([CH3:41])[C@H:26]([NH:36][CH2:37][C@@H:38]([OH:40])[CH3:39])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:7]([O:24][C@H:25]([CH3:41])[C@H:26]([N:36]1[CH2:37][C@H:38]([CH3:39])[O:40][C:2](=[O:3])[C:1]1=[O:5])[C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=1)([C:20]([CH3:22])([CH3:23])[CH3:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](O)CN[C@H](c1cc(F)c(F)c(F)c1)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN([C@H](c2cc(F)c(F)c(F)c2)[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(=O)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (45 μl) was added dropwise to a solution of (S)-1-[(1R,2R)-2-tert-butyldiphenylsilanyloxy-1-(3,4,5-trifluorophenyl)propylamino]propan-2-ol (171 mg), TEA (0.17 ml), and 4-(N,N-dimethylamino)pyridine (8 mg) in methylene chloride (2 ml) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred at the same temperature for two hours. Ice water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=9:1 to 3:1) to obtain 96 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11](N)=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH-:15].[K+].Cl>CCO.O>[CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:15])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: [OH-]
Reactant: Cc1cc(C)c2c(C(N)=O)nsc2c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(C(=O)O)nsc2c1
Temperature: 85 °C

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid amide (20 mg, 0.097 mmol) in EtOH (10 mL) and H2O (2 mL) was added KOH (11 mg, 0.19 mmol). The solution was heated to 85° C. for 48 hours. The solution was cooled and was placed in an ice bath. Conc. HCl was added to adjust the pH of the solution to 2. The solid that precipitated out from the solution was collected by filtration. The white solid was dried and was confirmed to be the title compound (15 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[F:15][C:16]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:19]2=[N:20][O:21][N:22]=[C:18]2[CH:17]=1.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:24]2[C:16]([F:15])=[CH:17][C:18]3=[N:22][O:21][N:20]=[C:19]3[CH:23]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Reactant: CC1(C)OB(c2cc3nonc3cc2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2cc3nonc3cc2F)nc(N)c1OC
Temperature: 115 °C
Yield: 40.9 %

Procedure:
Methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (400 mg, 1.838 mmol), 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (789 mg, 2.390 mmol), bis(triphenylphosphine)palladium(II) chloride (129 mg, 0.184 mmol), and cesium fluoride (558 mg, 3.68 mmol) were combined in 4 mL 1:1 ACN-water and heated at 115° C. for 30 min in a microwave reactor. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried, and evaporated. The product was purified by flash chromatography (SiO2, eluting with 5-30% ethyl acetate in dichloromethane) to provide the title compound (240 mg, 39%).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of from 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 116 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6b (182 mg, 71%); mp: 209-211° C.; mp: 140-142° C.; 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 8.19 (dd, J=3.0, 1.5 Hz, 1H), 7.81 (dd, J=3.0, 1.5 Hz, 2H), 7.52-7.47 (m, 3H), 7.20 (d, J=9.0 Hz, 2H), 6.83 (t, J=7.5 Hz, 4H), 6.55-6.51 (m, 1H), 5.41 (s, 2H), 4.58 (d, J=4.5 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); MS (ESI m/z): 463 [M+H]+ Yield: 71%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11](O)=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:3]=1[Cl:19].[Cl:20]P(Cl)C1C=CC=CC=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([Cl:20])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:3]=1[Cl:19]
Reactant: ClP(Cl)c1ccccc1
Reactant: COC(=O)c1nc(-c2ccc(O)nc2)cc(N)c1Cl
Product: COC(=O)c1nc(-c2ccc(Cl)nc2)cc(N)c1Cl
Temperature: 50 °C
Yield: 34.6 %

Procedure:
Methyl 4-amino-3-chloro-6-(6-hydroxy-3-pyridinyl)pyridine-2-carboxylate (0.30 g, 1.07 mmol) was suspended in neat dichlorophenylphosphine (2.5 mL, 1.84 mmol) and the mixture was heated to 50° C. for 1 hr. The volatiles were removed in vacuo and the residue purified by column chromatography (1:1, Hexanes/EtOAc) to give of methyl 4-amino-3-chloro-6-(6-chloro-3-pyridinyl)pyridine-2-carboxylate (0.11 g, 0.37 mmol).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[OH:40]>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][C:15]([O:40][C:34]3[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=3[F:32])=[N:16][C:17]=2[O:19][CH2:20][C@H:21]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]2)[NH:12][N:11]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CC1(C)OC[C@H](COc2nc(S(C)(=O)=O)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Agent: [K+]
Agent: [OH-]
Product: CC1(C)OC[C@H](COc2nc(Oc3ccc(F)cc3F)nc3[nH]nc(-c4ccccc4Cl)c23)O1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Powdered KOH (1.0 g) was taken up in 4 mL of 2,4-difluorophenol, and the resulting mixture was heated at 120° C. for 15 minutes. (S)-3-(2-Chloro-phenyl)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidine (1.34 g, 0.305 mmol) was added, and the reaction mixture was stirred for one hour at 120° C. The reaction mixture was cooled to room temperature, partitioned between water (100 mL) and EtOAc (300 ML0, and the layers were separated. The organic layer was washed three times with 2N aqueous NaOH, once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative scale TLC (50% MeOH in methylene chloride to provide 1.395 mg of (S)-3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=489. Mp.=70.1-75.9° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15](Cl)Cl)=[CH:10][CH:9]=1.[N:18]1([CH2:24][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[C:11]1([NH:14][C:15]2[O:34][C:33]([NH:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:37]=[CH:38][CH:39]=[C:25]([CH2:24][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:26]=3)=[N:35][N:36]=2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: ClC(Cl)=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(Nc2nnc(NCCCOc3cccc(CN4CCCCC4)c3)o2)cc1
Temperature: 25 °C

Procedure:
1.4 ml (10 mmol) of triethylamine and 0.7 ml (5 mmol) of phenyl isocyanide dichloride are added to 1.5 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide in 30 ml of THF and the mixture is stirred at room temperature until the reaction is quantitative. Solid triethylammonium chloride is filtered off, the filtrate is concentrated by evaporation under vacuum, and the solid residue is recrystallised from ethanol. The analytical values are summarized in Table II.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCO
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NCCO)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 55.4 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 30 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)#[N:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:9]([C:11]1([C:17]2[N:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:27]=[N:28][N:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=4)[C:30]=3[CH3:31])=[O:25])=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:14]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:15][CH2:16]1)#[N:10]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(CC(=O)C(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8.5 h

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (88 μl) was added to a suspension of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (227 mg) and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 8.5 hours. Water was added to the reaction solution, the precipitated solid was filtered, and washed with water and ethanol to give the titled compound (271 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[C:10]1[CH:17]=[CH:16][C:13]([C:14]2[NH:31][C:26]3[CH:25]=[C:24]([N:21]4[CH2:22][CH2:23][O:18][CH2:19][CH2:20]4)[CH:29]=[CH:28][C:27]=3[N:30]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2ncc(CO)cc2Cl)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
0.50 g of 4-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)benzaldehyde (3) (2.02 mmol) prepared in Example 1 and 0.39 g of 4-morpholinobenzene-1,2-diamine (18) (2.02 mmol) prepared in Example 12 were dissolved in nitrobenzene (5.5 mL), and refluxed under heating for 2 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.68 g of {5-chloro-6-[4-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-phenyl]-pyridin-3-yl}-methanol (yield 80%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[SH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(SCC(=O)c2ccccc2)cc1

Procedure:
To bromoacetophenone (322.8 mg, 1.62 mmole) and anhydrous K2CO3 (896 mg, 6.48 mmole) in ethanol (20 ml), 250 mg (1.62 mmole) 4-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The basic aqueous solution was extracted with ethyl acetate to remove unreacted bromoacetophenone. The aqueous layer was acidified to yield a precipitate which was filtered and dried (356 mg). m/z 271 (M−1)+1H NMR (DMSO) δ 4.75 (2H, s, —CH2-), 7.35-7.72 (5H, m, 5×ArH), 7.82 (2H, d, 2×ArH), 8.05 (2H, d, 2×ArH).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>>[NH:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8]
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Ic1ncc[nH]1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc[nH]1
Yield: 77 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (79 mg, 0.43 mmol) was converted (using 2-iodo-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 83 mg, 77%) which was obtained as an off-white solid. MS: m/e=250.2 [M+H]+.
Reaction SMILES: B(F)(F)F.[N:5]1[O:6][CH2:7][CH:8]2[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:10][C:9]=12.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:23]1([C:9]23[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:12][CH:8]2[CH2:7][O:6][NH:5]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Reactant: Br[Mg]c1ccccc1
Agent: FB(F)F
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Boron trifluoride (30.8 mL, 244 mmol) is added to a −50° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (40 g, 162 mmol) in tetrahydrofuran (200 mL). The mixture is stirred for 10 minutes and the solution is added to phenyl magnesium bromide (325 mL, 325 mmol, 1 M in tetrahydrofuran) at −50° C., warmed to 0° C., and stirred for 4 hours. The reaction is quenched with saturated ammonium chloride (200 mL) and the aqueous layer is separated. The organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel using a 5 to 50% ethyl acetate/hexanes gradient to give the title compound (31 g, 59%). ES/MS (m/e): 325 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][C:4]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:18][C:4]1[CH:5]=[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1
Reactant: CC1(C)OB(c2ccc(CBr)c(F)c2)OC1(C)C
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(CN3CCC(O)C3)c(F)c2)OC1(C)C
Yield: 91.8 %

Procedure:
A solution of 2-[4-(bromomethyl)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 0.95 mmol), pyrrolidin-3-ol (99 mg, 1.1 mmol), and potassium carbonate (160 mg, 1.1 mmol) in acetonitrile (5 mL) was heated to 50° C. for 3 h. The reaction mixture was cooled, filtered and the filtrate was concentrated to afford the desired product (280 mg, 92%) as a red oil: ESI MS m/z 322 [C17H25BFNO3+H]+.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:21])=[C:8]([S:13]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[Cl:22])=[O:31])=[C:7]([OH:21])[C:8]=1[S:13]([NH:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)(=[O:14])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)NCC2CC2)c1O
Yield: 21.1 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 3-amino-6-chloro-N-cyclopropylmethyl-2-hydroxybenzenesulfonamide (0.23 g, 0.77 mmol) and 2-chlorophenylisocyanate(95 μL, 0.79 mmol) were coupled to form the desired urea (0.07 g, 21%). LC-MS m/z 430 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
6-Amino-9-benzyl-2-(2-methylbutyl)thiopurine (60 mg, 0.18 mmol) and bromine (0.4 ml) were dissolved in 90 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (39 mg, yield 53%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH3:15])=[CH:7][N:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH3:15])=[CH:7][N:6]=1
Reactant: CCCOc1cnc(CN=[N+]=[N-])cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1cnc(CN)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-azidomethyl-5-propoxy-pyridin-4-ol (9.70 g, 46.6 mole), is then suspended in 120 mL of tetrahydrofuran and treated with triphenylphosphine (12.22 g, 46.6 mmole) after stirring for 10 mins at ambient temperature water is added (12.6 mL, 15 equivalents) and the reaction mixture is stirred at ambient temperature overnight. The solids gradually dissolved followed by the formation of a precipitate. The resulting solid is filtered, washed with fresh 10:1 tetrahydrofuran:water and dried to give, 5.92 g, (69%), mp 159-60° C.; MS (ES+): m/z 183.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[BH4-].[Na+].O>CO>[CH2:19]([O:18][C:16](=[O:17])[C:15]([CH3:21])([CH3:22])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([OH:23])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:25])([CH3:24])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Reaction time: 2 h
Yield: 91.3 %

Procedure:
7-Oxo-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (9.2 g, 25 mmol) was dissolved in methanol (200 mL) and the solution was cooled in an ice-water bath. Sodium borohydride (0.95 g, 25 mmol) was added. After 2 h, another portion of sodium borohydride (0.95 g, 25 mmol) was added and stirring was continued for 2 h. The reaction mixture was hydrolyzed with water (200 mL). The aqueous solution was extracted with dichloromethane (3×150 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the product (8.5 g, 92%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 4H, J=7.0 Hz), 3.60-3.50 (m, 1H), 1.66-1.32 (m, 11H), 1.24 (pseudo-t, 12H, J=7.0 Hz), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 71.7, 60.1, 42.1, 40.6, 37.3, 26.0, 25.1, 24.9, 14.2. HRMS (LSIMS, nba): Calcd. for C21H41O3 (MH+): 373.2954. found: 373.2936. HPLC: 88.90% purity.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:33])[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=[C:10]([Br:30])[C:9]=1[O:31][CH3:32]>C1COCC1.CO>[Br:30][C:10]1[C:9]([O:31][CH3:32])=[C:8]([NH:7][CH2:6][C:5]([OH:33])=[O:4])[CH:13]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:11]=1
Reactant: COC(=O)CNc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(Br)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1NCC(=O)O
Reaction time: 4 h
Yield: 63.7 %

Procedure:
Aqueous potassium hydroxide (1N, 0.64 mL, 0.64 mmol)was added to a stirred room temperature solution of [3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-acetic acid methyl ester (0.180 g, 0.320 mmol) in THF (2.5 mL), methanol (1.5 mL). After 4 h, the solvent was removed and water was added. The suspension was acidified and extracted with ether. Silica gel was added. The ether was removed and the adsorbate was flash chromatographed (Gradient: 7:3pet. ether:ethyl acetate to ethyl acetate to 9:1 ethyl acetate:methanol) to provide the title compound as a white solid (0.112 g, 64%): mp>190° C. (dec): NMR (DMSO-d6); 8.16 (d, J=8 Hz, 1H), 7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.48 (ddd, J=8, 6, 1 Hz, 1H), 6.72 (d, J=2 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 5.74 (broad s, 1H), 3.83 (s, 3H), 3.46 (s, 2H), 2.42 (s, 3H), 1.71 (s, 3H); MS (FAB+): 2 bromine isotope pattern 547, 549, 551; Anal. Calc. for C23H19Br2NO3S: C, 50.29, H, 3.49, N, 2.55. Found: C, 49.54, H, 3.73, N, 2.26.