Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11](O)[CH:10]=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:11]1[CH:10]=[N:9][N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13](=[O:14])[CH:12]=1
Reactant: O=c1cc(O)cnn1CC1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1cc(Cl)cnn1CC1CCCCC1
Temperature: 85 °C

Procedure:
To 10.5 g of 2- (cyclohexylmethyl)-5-hydroxy-3(2H)-pyridazinone was added 25 ml of phosphorus oxychloride and this mixture was heated for 4 hours at 85° C. After reaction, the excess phosphorus oxychloride was distilled off under reduced pressure. The residual solution was poured into water and to this solution was added aqueous sodium hydroxide solution to be alkalified and the separated solid was extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and filtered off with silica gel. Benzene was distilled off under reduced pressure to obtain 6.4 g of the intended compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([O:17]CC)=[O:16].[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C=CC=Cc1ccc(OC)c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC=CC(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
A solution of ethyl 5-(2,3-dimethyl-4-methoxyphenyl)-2,4-pentadienoate (2 g, 7.7 mmol) in 10 mL of ethanol was stirred at room temperature under nitrogen and a solution of KOH (1 g) in 2 mL of water was added dropwise. The mixture was stirred at room temperature for 18 hrs. and concentrated in vacuo. The residue was diluted with water and extracted several times with ethyl ether. The aqueous layer was acidified to pH 3 with a 10N HCl solution. The resulting yellow precipitate was extracted into ethyl acetate. The organic solution was washed with brine and dried (Na2SO4). Evaporation in vacuo afforded a yellow powder. Crystallization from ethyl acetate/ethyl ether gave 1.1 g of yellow crystals: MS (CI): 233 (M+1)+, 215.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH2:40][NH2:41]>>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:25])([CH3:26])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:44]([Cl:45])=[C:37]([Cl:36])[CH:38]=2)=[O:23])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(Cc1cccc(CCC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: CC(C)(Cc1cccc(CCC(=O)NCc2ccc(Cl)c(Cl)c2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 64 %

Procedure:
The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl )phenyl]ethyl}amino)-2-methylpropyl]phenyl}propanoic acid (preparation 144) and 3,4-dichlorobenzylamine, using a method similar to that of preparation 38, as a clear oil in 64% yield. 1H NMR (400 MHz, CD3OD) δ: 7.40 (3H, m), 7.18 (1H, m), 7.08 (5H, m), 6.78 (1H, d), 4.61 (3H, m), 4.23 (2H, s), 2.90 (3H, m), 2.60 (5H, m), 1.08 (3H, s), 1.04 (3H, s), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 659 [M+H]+
Reaction SMILES: CS(O)(=O)=O.C(OC([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34](=[NH:36])[NH2:35])[CH:30]=2)[CH:25]=1)=[O:22])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[BrH:45].C(O)(=O)C>C(O)(=O)C>[BrH:45].[BrH:45].[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34](=[NH:35])[NH2:36])[CH:30]=2)[CH:25]=1)=[O:22]
Reactant: N=C(N)c1ccc2cc(OC(=O)C3CCCN3C(=O)OCc3ccccc3)ccc2c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)C3CCCN3)ccc2c1

Procedure:
To a solution of 1.5 g of 6-amidino-2-naphthyl 1-benzyloxycarbonylpyrrolidine-2-carboxylate methanesulfonate in 10 ml of acetic acid, was added 1 ml of anisole. To the mixture, while cooling in ice and stirring, was added 3 ml of a 30% HBr/acetic acid solution. Thereafter the resulting mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed sufficiently with ethyl ether and acetone. Recrystallization from a mixture of methanol and ethyl ether gave 1.1 g of 6-amidino-2-naphthyl pyrrolidine-2-carboxylate dihydrobromide.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36](C)(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].CO.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:47])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 83.5 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 83.5% of theory, C29H31N5O3 (497.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=498; (M+H+Na)++=260.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[S:34][C:33]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1.O>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.COCCOC>[N:36]1([CH2:35][C:33]2[S:34][C:30]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:31][CH:32]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2ccc(CN3CCCC3)s2)c1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)pyrrolidine (0.180 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol) 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 600 sec (very high absorbance). The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.92 min, m/z=447.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.OO.[OH2:36].C[OH:38]>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:10][S:9]([C:7]1[N:8]=[C:3]([O:2][CH3:1])[C:4]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:5]=2[N:6]=1)(=[O:38])=[O:36]
Reactant: CO
Reactant: O
Reactant: COc1nc(SC)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: COc1nc(S(C)(=O)=O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A magnetically stirred mixture of 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide (375 mg, 0.75 mmol) in methanol (20 mL) was cooled in an ice water bath and treated with sodium tungstate dihyrate (135 mg, 0.04 mmol) followed by hydrogen peroxide (30% solution, 10 mL) The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was then poured into water and extracted with methylene chloride. The organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (251 mg, 63%) as a red solid. LRMS for C20H20F3N5O5S2 (M+H)+ at m/z=499. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([SH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].N1CCCCC1>CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([S:17][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S)cc1F
Reactant: CC(C)=CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1F
Temperature: 105 °C
Yield: 101.1 %

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (1.23 g, 12.33 mmol), 3-fluoro-4-methoxy thiophenol (Compound 200, 1.95 g, 12.33 mmol), and piperidine (314.8 mg, 3.70 mmol). This mixture was heated to 105° C. for 23 hours, cooled to room temperature and dissolved in EtOAc (100mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded 3.22 g of a clear yellow oil which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ: 7.32 (2H, m), 6.94 (1H, t, J=8.4 Hz), 3.92 (3H, s), 2.54 (2H, s), 1.41 (6H, s).
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:28]I>O1CCCC1>[C@H:1]([N:5]([CH3:28])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (R)-methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran (9 mL). sodium hydride (132 mg, 3.3 mmol, 10.00 equiv, 60%) was added. The resulting solution was stirred for 1 h at room temperature. This was followed by the dropwise addition of a solution of CH3I (922.5 mg, 6.50 mmol, 20.00 equiv) in tetrahydrofuran (2 mL) with stirring at 0° C. The resulting solution was stirred for overnight at 20° C. The resulting mixture was concentrated under vacuum and diluted by 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration. This resulted solid in 67 mg (59%) of (R)-3-(sec-butyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][O:16][C:17](=[O:22])[C:18](Br)([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[C:18]([CH3:20])([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:19]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 0.026 mol), 2-bromo-2-methylpropionic acid methyl ester (3.50 mL, 0.0270 mol), Cs2CO3 (12 g, 39 mmol) in DMF (200 mL) was heated at 90° C. overnight. Reaction mixture was concentrated in vacuo, water was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a light yellow solid. MS (ES+): m/z 295.13, 296.16 (100, 50) [MH+]. HPLC: tR=3.35 min (ZQ3 polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:24][CH3:25].C(N(CC)CC)C.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH3:25][O:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[NH:1][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]2[CH:19]=[CH:20][CH:21]=[C:10]2[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 60 mg of triethylamine followed by a solution of 56 mg of n-butylsulfonyl chloride in 0.5 ml of methylene chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue which is dissolved in methyl alcohol, stirred for 1 hour and evaporated in vacuo to a residue which is treated with 2 ml of NH4Cl and extracted with 15 ml of ethyl acetate. The organic extract is washed with saturated NaHCO3, brine, dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated to a residue. The residue is stirred with ether-hexanes to give 0.14 g of light yellow solid. MS(CI): 454(M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([N:26]1[CH:29]([C:30]([CH3:34])([CH3:33])[CH:31]=[CH2:32])[CH2:28][C:27]1=[O:35])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[C:36](N1C=CN=C1)(=[O:38])[CH3:37]>O1CCCC1>[Si:19]([N:26]1[CH:29]([C:30]([CH3:34])([CH3:33])[CH:31]=[CH2:32])[CH:28]([C:36](=[O:38])[CH3:37])[C:27]1=[O:35])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C=CC(C)(C)C1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=CC(C)(C)C1C(C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium in hexane (4.10 mmol) is added by syringe to a solution of diisopropylamine (4.10 mmol) in anhydrous tetrahydrofuran (16 ml) at -78° C. The resulting solution is stirred at -78° C. for 15 min. prior to the addition of a solution of 1-(t-butyldimethylsilyl)-4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one 3 (2.0 mmol) in anhydrous tetrahydro uran (2 ml). After an additional 15 min. at -78° C., the reaction mixture is added via a Teflon tube to a mixture of N-acetylimidazole (4.1 mmol) in anhydrous tetrahydrofuran (16 ml) at -78° C. The resulting yellow reaction mixture is stirred at -78° C. for 15 min., then quenched by addition of saturated aqueous ammonium chloride solution (10 ml). The reaction mixutre is diluted with ether (100 ml) and washed with 2.5N hydrochloric acid solution (25 ml) water (25 ml) and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to yield crude products. This material is chromatographed on silica gel (2:1 petroleum ether:ether) to yield 4.
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH:8]([CH3:10])C)=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:8]([O:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH3:10]
Reactant: CC(C)Oc1ncc(Br)s1
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Product: CCOc1ncc(-c2cc(-c3ccccc3C)c3nccn3c2)s1

Procedure:
Example 190 was prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropyloxy)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.63 min.; (M+H)': 336.31.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[C:22]1([Si:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[Br:16][C:9]1[C:10]2[C:15]([C:2]([Si:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:3]3[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1c2ccccc2c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 12 g (35.7 mmol) of 9,10-dibromoanthracene, and 300 ml of tetrahydrofuran (THF) were added to a round-bottom flask. Next, 14.4 ml (35.7 mmol, 2.5M) of n-butyl lithium was added dropwise slowly into the round-bottom flask at −78° C. After mixing and reacting for 30 min, 12 g (40.7 mmol) triphenylsilyl chloride with 50 ml THF were added dropwise slowly into the round-bottom flask at −78° C. After reacting at room temperature for 24 hours, the resulting mixture was subjected to extraction with a mixed solvent (ethyl acetate:H2O), dried over anhydrous MgSO4, filtered, and condensed, then the crude product was purified by column chromatography (n-hexane/acetyl acetate=15/1), A 9.0 g of pure 9-bromo-10-triphenysilyl anthracene was collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:27][C:26]([CH3:29])([CH3:28])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]CC)=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9].O.[OH-].[Li+].[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[CH2:27][C:26]([CH3:28])([CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=2)[NH:19]1)(=[O:10])=[O:9]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1F)N2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(C(=O)O)cc21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 2-(2-(2-fluorophenylsulfonamido)phenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (crude 0.62 mmol) in ethanol was added a solution of lithium hydroxide monohydrate (129 mg, 3.08 mmol) and sodium hydroxide (50 mg, 1.23 mmol) in water (1.5 mL) at room temperature. The reaction mixture was stirred at 85° C. overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water, adjusted pH=3˜4 by 1M aqueous hydrochloric acid, extracted with ethyl acetate. The combined organic layer was washed by brine, dried over anhydrous Sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give 2-[2-(2-fluoro-benzenesulfonylamino)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid LC/MS m/e obsd. (ESI+) [(M+H)+] 455.20.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[CH:3]1.[Cl:9]N1C(=O)CCC1=O>O1CCOCC1>[Cl:9][C:5]1[N:4]=[CH:3][N:2]([CH3:1])[C:6]=1[CH2:7][OH:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cncc1CO
Solvent: C1COCCO1
Product: Cn1cnc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (1-methyl-1H-imidazol-5-yl)methanol (1.14 g, 10 mmol) in dioxane (50 mL), in a 250 mL round bottom flask, was added 1-chloropyrrolidine-2,5-dione (1.38 g, 10 mmol). The resulting mixture was stirred at room temperature overnight. Dioxane was removed under vacuum to provide (4-chloro-1-methyl-1H-imidazol-5-yl)methanol. The crude (4-chloro-1-methyl-1H-imidazol-5-yl)methanol was dissolved in 40 mL of chloroform, followed by addition of tribromophosphane (1.9 mL, 20 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was evaporated to provide 5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)C>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:25]2)[O:4]1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A suspension of 9-[(3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (5.00 g, 16.3 mmol), benzyl 3-(3-oxocyclobutyl)-propanoate (4.17 g, 18.0 mmol) and acetic acid (0.85 ml, 14.8 mmol) in DCE:iPrOH (7:2) (90 ml) was stirred at r.t. for 2 h. Sodium triacetoxyborohydride (4.40 g, 20.8 mmol) was added in portions and the mixture left to stir for 18 h at r.t. The reaction mixture was quenched with 1M Na2CO3 solution (10 ml) and the product was extracted with DCM (3×30 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel flash column chromatography eluting with 1% 7M NH3 in MeOH:99% DCM gave the product as a yellow oil (5.25 g, 55%, 89% pure): MS (ESI+) for C27H34N6O5 m/z 523.6 [M+H]+; LC purity 89% (ret, time, 1.60 min); 1H NMR (500 MHz, CDCl3) δH 8.35 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.30-7.39 (m, 5H), 6.01 (dd, J=3.0 Hz, 1.6, 1H), 5.72 (br. s., 2H), 5.50 (dt, J=6.4 Hz, 3.3, 1H), 5.10 (d, J=3.8 Hz, 2H), 4.98-5.04 (m, 1H), 4.31-4.38 (m, 1H), 2.97-3.34 (m, 1H), 2.72-2.85 (m, 2H), 2.22-2.35 (m, 3H), 2.14 (td, J=8.3, 4.3 Hz, 1H), 1.73-1.90 (m, 4H), 1.64-1.71 (m, 1H,), 1.62 (d, J=1.4 Hz, 3H), 1.39 (s, 3H), 1.10-1.27 (m, 1H).