Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(Cl)nc3)oc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)nc3)oc2C)cc1C
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
A mixture of 3-(4-{2-[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester (41 mg, 0.1 mmol) and phenyl boronic acid (25 mg, 0.2 mmol) and Na2CO3 (22 mg, 0.2 mmol) in toluene (0.5 mL) and water (0.1 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (3 mg) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 45 mg of product.
Reaction SMILES: [Si]([O:8][C@H:9]([C:46]1[CH:47]=[CH:48][C:49]([OH:55])=[C:50]([NH:52][CH:53]=[O:54])[CH:51]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C@@H:30]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:31][CH2:32][N:33]([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:24]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F>CO.O1CCCC1>[NH3:11].[CH:37]([N:33]([CH:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C@@H:30]([C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:46]3[CH:47]=[CH:48][C:49]([OH:55])=[C:50]([NH:52][CH:53]=[O:54])[CH:51]=3)[OH:8])=[CH:15][CH:16]=2)[CH:28]=[CH:27][C:26]=1[OH:29])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([CH3:38])[CH3:39]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Product: N
Reaction time: 8 h

Procedure:
N-{5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(2-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}ethoxy)phenyl]ethyl}amino)ethyl]-2-hydroxyphenyl}formamide (Preparation 46, 180 mg, 0.18 mmol) was dissolved in methanol (5 ml) and tetrahydrofuran (10 ml), and triethylaminetrihydrofluoride (0.18 ml, 1.1 mmol) added. The mixture was stirred overnight and then the solvent removed in vacuo. The residue was dissolved in methanol (10 ml) and 880 ammonia (1 ml) and the solvent removed under reduced pressure. This was repeated and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98/2/0.2 to 80/20/2.0 by volume) to furnish the title compound as a gum, 69 mg.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22](I)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C)C=O>[OH:1][C:2]1[CH:24]=[CH:23][C:22]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 38.3 %

Procedure:
A mixture of 2-hydroxy-5-iodo-N-[3,5-bis(trifluoromethyl)phenyl]-benzamide(compound of Example 81(1); 475 mg, 1 mmol), styrene (130 mg, 1.25 mmol), palladium acetate(4.5 mg, 0.02 mmol), tris(ortho-tolyl)phosphine(12.2 mg, 0.04 mmol), diisopropylamine(388 mg, 3 mmol) and N,N-dimethylformamide(2 mL) was refluxed for 8 hours. After the reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:isopropyl ether=2:1→1:1) to give the title compound (173 mg, 38.3%) as a pale yellow solid.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.Cl.Cl[CH2:24][C:25]1[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[CH:28]=[CH:27][N:26]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:24][S:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:10](=[O:20])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=3)[N:3]=2)[C:30]=1[CH3:31]
Reactant: COc1ccc(-n2c(S)nc3ccc(C)cc3c2=O)cc1
Reactant: COc1ccnc(CCl)c1C
Agent: Cl
Product: COc1ccc(-n2c(SCc3nccc(OC)c3C)nc3ccc(C)cc3c2=O)cc1
Yield: 51.6 %

Procedure:
The title compound was prepared in a yield of 51.6%, using 2-mercapto-3-(4-methoxyphenyl)-6-methyl-4(3H)-quinazolinone in place of 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[S:8](=O)(=[O:11])([OH:10])N>>[CH3:5][C:3]1[O:4][S:8](=[O:11])(=[O:10])[NH:7][C:1](=[O:6])[CH:2]=1
Reactant: NS(=O)(=O)O
Reactant: CC(=O)CC(N)=O
Product: CC1=CC(=O)NS(=O)(=O)O1

Procedure:
cyclizing the acetoacetamide derivative; the process comprises using, as the sulfamic acid derivative in stage (a), a salt of sulfamic acid which is at least partly soluble in the inert organic solvent employed, cyclizing the acetoacetamide-N-sulfonate formed in this stage or the free acetoacetamide-N-sulfonic acid in stage (b) by the action of an at least approximately equimolar amount of SO3, if appropriate in an inert inorganic or organic solvent, to give 6-methyl-3,4-dihydro-1,2,3-oxa-thiazin-4-one 2,2-dioxide, and then, if desired, also neutralizing with a base, in a stage (c), the product obtained here in the acid form.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:14]([C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:5]2=[O:7]
Reactant: Cc1cccc2c1C(=O)OC2=O
Reactant: CC1(N)CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O

Procedure:
4-Methyl-2-(2,6-dioxo-3-methyl-(3-piperidyl))isoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-methylphthalic anhydride (0.27 g, 1.7 mmol), 3-amino-3-methylpiperidine-2,6-dione hydrogen chloride (0.30 g, 1.7 mmol) and sodium acetate (0.15 g, 1.8 mmol) in acetic acid (10 mL). The product was a white solid (0.13 g, 27 % yield); mp, 248.0-250.0° C.; 1H NMR (DMSO-d6) δ1.89 (s, 3H, CH3), 2.01-2.08 (m, 1H, CHH), 2.49-2.70 (m, 3H, CHH, CH2), 2.55 (s, 3H, CH3), 7.62-7.74 (m, 3H, Ar), 10.99 (br s, 1H, NH); 13C NMR (DMSO-d6) δ17.0, 21.0, 28.6, 29.1, 58.6, 120.7, 127.5, 131.5, 134.2, 136.8, 137.2, 167.7, 168.6, 172.1, 172.3; Anal. Calcd. for C15H14N2O4+0.3 H2O: C, 61.77; H, 5.05; N, 9.60. Found: C, 62.05; H, 4.94; N, 9.20.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:8]2[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21

Procedure:
A mixture of 9.95 g (0.0412 mole) of 1-isobutyl-1H-imidazo [4,5-c]quinolin-5-oxide (from Example 54) and 100 ml of phosphorus oxychloride was heated at its reflux temperature for 2.5 hours, and was then cooled and poured into ice with stirring. Basification (to pH 9-10) with 50% aqueous sodium hydroxide solution was followed by extraction with dichloromethane. The extracts were dried over sodium chloride and sodium bicarbonate, and were then evaporated to provide a solid residue. A sample of the residue was recrystallized from diethyl ether to provide 4-chloro-1-isobutyl-1H-imidazo [4,5-c]quinoline, m.p. 134°-136° C. Analysis: Calculated for C14H17ClN3 : %C, 64.7; H, 5.4; %N, 16.2; Found: %C, 64.3; %H, 5.3; %N, 16.3.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1I)([CH3:4])[CH3:3].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)#[N:19].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(N(CC)CC)C.C1COCC1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH2:9].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:17])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:27]#[C:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccccc1I
Reactant: C#Cc1ccc(C#N)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NCC(O)COc1ccccc1C#Cc1ccc(C#N)cc1
Product: O
Yield: 75 %

Procedure:
A solution of 6.6 g (19 mmoles) of 1-[(1,1-dimethylethyl)amino]-3-(2-iodophenoxy)-2-propanol, the product of Example 12b., 2.5 g (19.7 mmoles) of p-cyanophenylacetylene, 0.44 g (0.38 mmole) of (Ph3P)4Pd and 0.07 g (0.78 mmole) of copper (I) iodide in 40 ml of deoxygenated triethylamine and 20 ml of deoxygenated THF was stirred under nitrogen for 18 hr. A precipitate was removed by filtration and discarded. The solvent was evaporated from the filtrate in vacuo. Trituration of the residue with ether gave a crystalline solid which was collected by filtration. Evaporation of the ether filtrate gave a second crop of crystalline product. The combined crystalline material was dissolved in MeOH and fumaric acid (0.5 equivalent) was added. There was obtained 5.6 g (75%) of crystalline 4-[2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]phenylethynyl]benzonitrile (E)-2-butenedioate hydrate (50:25:17), mp 198°-200° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26].N1C=CC=CC=1>C(Cl)Cl>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:21][CH:20]=3)[N:13]=2)=[CH:10][N:9]=[C:8]1[CH3:26]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N)cc3)n2)n1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ncc(-c2ccnc(Nc3ccc(NS(C)(=O)=O)cc3)n2)n1C
Temperature: 4 °C
Yield: 65.4 %

Procedure:
Methanesulphonyl chloride (0.055 ml, 0.711 mmole) was added to a solution of 4-(1,2-dimethylimidazol-5-yl)-2-(4-aminoanilino)pyrimidine (Example 165; 0.18 g, 0.64 mmole) and pyridine (0.052 ml, 0.64 mmole) in DCM (2.0 mL) cooled at 4° C. The mixture was allowed to warm to ambient temperature. The mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution and EtOAc. The organic layer was separated, the volatiles evaporated and the residue purified by column chromatography on silica gel eluting with DCM/7M methanolic ammonia (96:4) to give the title compound (0.15 g, 65%) as a solid. NMR: 2.36 (s, 3H), 2.90 (s, 3H), 3.91 (s, 3H), 7.06 (d, 1H), 7.14 (d, 2H), 7.57 (s, 1H), 7.64 (d, 2H), 8.33 (d, 1H), 9.37 (br s, 1H), 9.42 (s, 1H); m/z 359.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.Cl>ClC(Cl)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCO2
Temperature: 5 °C

Procedure:
A suspension, cooled to 0° C., of 120 g of 2,3-di-hydrobenzofuran and 128 g of aluminum chloride in 260 ml of dichloroethane is added to a mixture of 96 g of succinic anhydride and 260 g of aluminum chloride in 512 ml of dichloroethane. The temperature is maintained at approximately 5° C. The reaction medium, maintained for 2 hours at this temperature, is then poured into a solution of 3 liters of water containing 400 ml of concentrated hydrochloric acid. After separation following settling, and extraction with methylene chloride, the organic phase is exhaustively extracted with 1N sodium hydroxide. The combined basic phases are acidified in the cold with 6N hydrochloric acid and the oil formed is extracted with methylene chloride. The organic phase is washed to neutrality and then dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH4+:38]>>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]2[NH:38][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:15]=2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Product: CCOC(=O)c1nc(-c2ccc(OCc3ccccc3)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate, 4-benzyloxybenzaldehyde and ammonium acetate are reacted and treated in the same manner as in Example 22 to give ethyl 2-(4-benzyloxyphenyl)-5-(4-chlorophenyl)imidazole-4-carboxylate. Ethyl 2-(4-benzyloxyphenyl)-5-(4-chlorophenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-benzyloxyphenyl)-5-(4-chlorophenyl)-imidazole-4-carboxylic acid. 2-(4-Benzyloxyphenyl)-5-(4-chlorophenyl) imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 2-(4-benzyloxyphenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:18])=[O:19]
Reactant: NS(=O)(=O)c1cc(C(O)c2ccc(F)cc2)ccc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A solution of 65 mg of 2-chloro-5-((4-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide in 1 mL of acetone is stirred at room temperature as 0.2 mL of 3 M Jones' reagent is added. The reaction mixture is stirred at room temperature for 30 minutes then diluted with ethyl acetate, filtered through celite, the filtrate is concentrated in vacuo. The crude product is purified by silica gel chromatography to give 48 mg of the title compound as white foam. 1H NMR (CDCl3): 5.15 (br, 2H), 7.12-7.30 (m, 3H), 7.70 (d, J=8 Hz, 1H), 7.80-7.90 (m, 2H), 7.90-8.0 (dd, 1H), 8.5 (d, J=2 Hz, 1H). MS (m/z): 312 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[C:4]([CH3:17])[C:3]=1[OH:18].Br[CH2:20][CH2:21][CH3:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:17][C:4]1[CH:5]=[C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[O:18][CH2:20][CH2:21][CH3:22]
Reactant: CCCBr
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(C)cc(B2OC(C)(C)C(C)(C)O2)cc1C
Temperature: 25 °C

Procedure:
A mixture 2,6-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (500 mg, 2.02 mmol, 1 eq.), 1-bromopropane (793 mg, 6.45 mmol, 3.2 eq.), and K2CO3 (334 mg, 2.42 mmol, 1.2 eq.) in acetone (20 mL) is heated at 65° C. for 4 days. After cooling to room temperature, the reaction is concentrated, diluted with EtOAc and sequentially washed with H2O and saturated aqueous NaCl. The organic solution is dried over Na2SO4 and concentrated to give 2-(3,5-Dimethyl-4-propoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as a clear oil.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C([Sn](CCCC)=O)CCC.[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44])=[O:38])[CH2:34][C:32]=2[N:33]=1>C1(C)C=CC=CC=1>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH:19]1[NH:27][C:28]1[N:29]=[CH:30][C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH2:41][CH2:42][C:43]3[NH:44][N:3]=[N:2][N:1]=3)=[O:38])[CH2:34][C:32]=2[N:33]=1
Reactant: N#CCCCOC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(OCCCc1nnn[nH]1)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 100 °C
Yield: 8.8 %

Procedure:
Add azidotrimethylsilane (3.5 mL; 9.7 equiv; 26.27 mmoles) and dibutyloxostannane (0.163 g; 0.25 equiv; 0.66 mmoles) to a solution of 3-cyanopropyl 2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (0.98 g; 1.0 equiv; 2.70 mmoles) in toluene (20.4 mL). Heat the reaction mixture to 100° C. for 18 hours. Concentrate the solution and purify by reverse phase chromatography followed by silica gel chromatography (0 to 15% methanol in chloroform) to afford the desired 3-(1H-tetrazol-5-yl)propyl 2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (0.097 g; 9%) as a brown solid: MS (m/z): 407(M+1).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]=[C:9]1[S:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH3:31])(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:30][CH3:31])=[C:21]([CH:26]=1)[CH2:20][S:19][C:9]1[N:8]([CH2:7][C:6]([OH:32])=[O:5])[C:12]2[CH:13]=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[N:10]=1)(=[O:29])[CH3:28]
Reactant: COc1ccc(C(C)=O)cc1CSc1nc2cc(C=O)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1CSc1nc2cc(C=O)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of tert-butyl[2-(5-acetyl-2-methoxy-benzylsulfanyl)-5-formyl-benzoimidazol-1-yl]-acetate (Precursor 5-HCO—H-11b, 16 mg, 0.035 mmol) in TFA/dichloromethane (1:1, 4 ml) is allowed to stir overnight at rt. The solvents are removed under a stream of air and the resulting products are dried under high vacuum. This yields the title compound (14 mg) in 100% as a yellow solid: tR=0.94 min (LC-3), ESI-MS (pos.): m/z 398.86 [M+H]+, ESI-MS (neg.): m/z 397.06 [M−H]+; 1H-NMR (DMSO-d6): δ (ppm) 2.46 (s, 3H, COCH3), 3.88 (s, 3H, OCH3), 4.59 (s, 2H, SCH2), 4.96 (s, 2H, CH2CO2), 7.11 (d, 1Harom), 7.65 (d, 1Harom), 7.74 (d, 1Harom), 7.90 (dd, 1Harom), 8.06 (d, 1Harom), 8.12 (d, 1Harom), 10.01 (s, 1H, CHO).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:29])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][N:8]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:6]=2[N:7]=1.[NH:30]([CH2:33][CH3:34])[CH2:31][CH3:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.CCCCCC.CN(C=O)C>[CH2:31]([N:30]([CH2:33][CH3:34])[C:15](=[O:17])[CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:29])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:18][C:19]2[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=2)[CH:9]=1)[CH3:32]
Reactant: CCNCC
Reactant: COc1c(C)cnc(Cn2cc(C#CCCC(=O)O)c3c(Cl)nc(N)nc32)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)CCC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-pent-4-ynoic acid (see previous example, 25 mg), Et2NH (100 μL), EDCI (87 mg), HOBt (50 mg), and DMF (1 mL) was stirred at rt for 16 h. Preparative plate chromatography (EtOAc/hexane 2:1) gave the title compound. tR=5.33 min. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.01 (s, 1H), 5.32 (s, 2H), 4.98 (s, 2H), 3.76 (s, 3H), 3.42 (q, 2H), 3.33 (q, 2H), 2.78 (dd, 2H), 2.64 (dd, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.20 (t, 3H), 1.13 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:22]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][CH:7]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1-c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2[N+](=O)[O-])c1
Reaction time: 0.75 h

Procedure:
2-(3-Hydroxyphenyl)nitrobenzene, as described above in Step B, (8.07 g, 37.52 mmol), imidazole (7.66 g, 112.56 mmol) and tert-butyldimethylsilyl chloride (6.22 g, 41.27 mmol) were dissolved in DMF (30 mL) and stirred for 0.75 hour. The DMF was removed in vacuo and the resulting residue was taken up in water and dimethyl ether and extracted with dimethyl ether (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of 0% to 4% EtOAc in hexanes, to yield the above-titled compound.