Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:30])=[CH:15][CH:14]=3)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-c2[nH]c3ccc(Cl)cc3c2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(O)cc3)[nH]c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a solution 150 mg (0.34 m mol) of 2-(4-acetyloxylphenyl)-3-(4-methylsulfonylphenyl)-5-chloroindole prepared in Example 94 in 10 ml of THF was added the solution of 20 mg of NaOH in 10 ml of 95% ethanol. The reaction mixture was stirred at room temperature for 4 h, and the solvent was removed. To the residue 10 ml of 0.5N HCl was added and the resulting precipiptate was filtered off, washed with water, dried, recrystallized from 95% ethanol to afford 123 mg of the title compound as white needle crystal, yield 90.7%, m.p. 271-273° C. Analysis via Nuclear Magnetic Resonance provided the following information: 1HNMR (300 MHz, DMSO)δ:3.23 (s, 3H, SO2CH3), 6.78-7.92 (m, 11H, Ar—H), 9.78 (s, 1H, OH), 11.83 (s, 1H, N—H); Anal. Calcd for: C21H16NO3SCl: C 63.39, H 4.05, N 3.52; Found: C 63.31, H 4.24, N 3.51.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[N:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13].C([Li])CCC.[F:26][C:27]([F:34])([F:33])[C:28](OCC)=[O:29].B(F)(F)F>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[N:19]=[C:18]([CH3:20])[O:17][N:16]=2)[CH:5]=[C:6]([CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:28](=[O:29])[C:27]([F:34])([F:33])[F:26]
Reactant: C#CCCCOc1c(C)cc(-c2noc(C)n2)cc1C
Reactant: CCOC(=O)C(F)(F)F
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(C)c(OCCCC#CC(=O)C(F)(F)F)c(C)c2)no1
Temperature: -70 °C
Reaction time: 5 h

Procedure:
A solution of 2.0 g 3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-5-methyl-1,2,4-oxadiazole, prepared by a procedure similar to that described in Example 1(b), in 50 mls anhydrous tetrahydrofuran in an argon atmosphere was chilled to about -70° C. To this solution there was added 3.7 mls butyl lithium followed by ethyl trifluoroacetate and, after ten minutes, 1.5 mls boron trifluoride ethereate. The solution was stirred for five hours at -70° C. and then overnight without cooling, quenched with 20 mls aqueous ammonium chloride solution, diluted with water and extracted with ethyl ether. The ethyl ether extracts were dried (Na2SO4) and concentrated in vacuo. The residue was subjected to column chromatography (silica gel; 20:80 to 40:60 ethyl ether/hexane) to give 497 mg of the title compound as an oil.
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[C:7]([CH2:9][CH2:10][S:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][O:15][C:14]2[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:26][C:13]1=2)#[N:8]>CN(C)C=O>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][O:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:12]([S:11][CH2:10][CH2:9][C:7]3[NH:8][N:5]=[N:4][N:3]=3)[C:13]=2[CH:26]=1
Reactant: N#CCCSC1c2ccccc2COc2ccc(OCc3ccc4ccccc4n3)cc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)COc1ccc(OCc3ccc4ccccc4n3)cc1C2SCCc1nnn[nH]1
Temperature: 120 °C
Reaction time: 10 h
Yield: 20.7 %

Procedure:
0.6 g of ammonium chloride and 0.6 g of sodium azide were added to 1.32 g of 11-(2-cyanoethylthio)-2-(quinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine dissolved in 10 ml of dimethylformamide and the mixture was stirred at 120° C. for 10 hours. After completion of the reaction, the solvent was removed and the residue was washed with water and then applied to silica gel column chromatography to obtain 0.3 g of the title compound as slightly brown powder.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[O:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:17]([O:21]C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C.Cl>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([CH2:1][CH:17]=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7]1
Reactant: Cc1ccc2c(=O)oc3ccccc3c2c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=CCc1ccc2c(=O)oc3ccccc3c2c1
Reaction time: 0.33 h

Procedure:
A solution of 9-methyl-6H-benzo[c]chromen-6-one (100 mg, 0.476 mmol) in dry DMF (2378 μl) Was treated with TERT-BUTOXY BIS(DIMETHYLAMINO)METHANE (99 mg, 0.571 mmol) at 80° C. in a sealed tube for one hour. The solution turned a deep red color and was cooled, diluted with 2M HCl and stirred for 20 minutes. The solution was then extracted with DCM, the combind orgainc layers were dried, filtered and concentrated with out heat. Crude (6-oxo-6H-benzo[c]chromen-9-yl)acetaldehyde was used without further purification. LC-MS (IE, m/z): 239 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH2:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[C:26]1=[O:44])[CH3:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:44])[N:25]([CH2:23][CH3:24])[CH2:34][CH2:33]4)[C:16]2=[CH:15][N:14]=1
Reactant: CCN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: CCN1CCc2cc(-c3n[nH]c4nc(-c5c(Cl)c(OC)cc(OC)c5Cl)ncc34)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=498.1/500.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:27])[CH2:19][C@@H:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23].O.[OH-].[Li+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:5]2[C:18](=[O:27])[CH2:19][C@@H:20]([CH3:26])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)OC)c2cc(Cl)ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCc1c(C(=O)C[C@@H](C)CC(=O)O)c2cc(Cl)ccc2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of Methyl 5-(5-chloro-2-hexyl-1-methyl-1H-indol-3-yl)-3-(R)-methyl-5-oxopentanoate in iso-propanol and water was added lithium hydroxide monohydrate and was stirred at RT for three hours. The product was purified by column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CS(O[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])(=O)=O.C([O-])(O)=O.[Na+].O>C(#N)C>[CH2:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1)[CH2:17][CH2:16][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: CCCC(CCC)OS(C)(=O)=O
Reactant: Cc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCCCCNc1ccc(F)c(C)c1
Yield: 349.5 %

Procedure:
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3(s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes:ethyl acetate, to give 2.56 g (35%) of a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>CN(C)C=O.O>[N:1]1([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C(=C/c1nc(COc2ccc(CCCn3ccnc3)cc2)co1)\c1ccccc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of imidazole (70 mg) in N,N-dimethylformamide (5 ml) was added, at 0° C., sodium hydride (60%, in oil, 50 mg). The mixture was stirred for one hour. To the reaction mixture was added 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate (350 mg). The mixture was stirred for 1.5 hour at 70° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The resulting crystalline product was recrystallized from ethyl acetate-hexane to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole (200 mg, 61%) as colorless prisms, mp 127-128° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[NH:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>CN(C=O)C.O>[NH:29]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=2)=[N:30]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)c1nc(Cl)c2ccc(I)cc2n1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccc(I)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of ethyl 4-chloro-7-iodoquinazoline-2-carboxylate (0.138 g, 0.38 mmol) in DMF (2 mL) at rt under argon were added potassium iodide (0.069 g, 0.42 mmol), DIEA (0.079 mL, 0.45 mmol), and 1H-pyrazol-3-amine (0.038 g, 0.46 mmol). The mixture was stirred at rt overnight then diluted with H2O (15 mL). The precipitate was collected by filtration, washed with H2O, and dried under high vacuum for several hours to afford ethyl 4-(1H-pyrazol-3-ylamino)-7-iodoquinazoline-2-carboxylate as a yellow solid (0.130 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ1.34 (t, 3H), 4.38 (q, 2H), 7.14 (m, 1H), 7.72 (m, 1H), 7.94 (d, 1H), 8.28 (d, 1H), 8.48 (d, 1H), 10.92 (s, 1H), 12.58 (s, 1H); LC-MS (ESI) m/z 410 (M+H)+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=O)=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[CH:14]1[CH2:16][CH2:15]1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.4 %

Procedure:
Methoxylamine hydrochloride (2.004 g) was added to (4-chlorophenyl)(cyclopropyl)methanone (2.71 g) in pyridine (60 mL) at 25° C. The resulting solution was stirred at 25° C. for 24 hours. The pyridine was removed in vacuo, and the residual solid extracted with ether. Filtration and evaporation of the solvent gave the crude (4-chlorophenyl)(cyclopropyl)methanone O-methyl oxime (2.75 g, 87%) as a yellow oil. This material was used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[N:37]1([C:43]([C:45]2[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=2)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(#N)C.C([O-])(=O)C.[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:40]1[CH2:41][CH2:42][N:37]([C:43]([C:45]2[CH:46]=[CH:47][C:48]([C:2]3[C:6]4[C:7]([O:11][CH:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:8][CH:9]=[CH:10][C:5]=4[N:4]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:3]=3)=[CH:49][CH:50]=2)=[O:44])[CH2:38][CH2:39]1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.170 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (48 mg, 0.204 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (13.9 mg, 0.017 mmol) were charged in a microwave vial equipped with a stir bar. Acetonitrile (1.0 mL) and 1.0 M potassium acetate in water (0.41 mL) were then added, the reaction mixture was degassed with nitrogen for 5 min and then heated to 150° C. under microwave irradiation for 40 min. The crude mixture was filtered through Celite®, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:29]([NH:36][CH2:37][CH2:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([O:18][CH3:19])=[C:11]([N:41]3[CH2:42][CH2:43][CH:39]([CH2:38][CH2:37][NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:40]3)[CH:12]=[CH:13]2)=[C:8]([CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2c(OC)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(CC)c2c(OC)c(N3CCC(CCNC(=O)OC(C)(C)C)C3)ccn2c1=O
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Ethyl-8-chloro-1-ethyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate (Precursor A) (0.151 g) and triethylamine (0.5 ml) are dissolved in acetonitrile (6 ml). To this solution 3-(N-boc-aminoethyl)pyrrolidine (Precursor D) (0.215 g) is added and the solution stirred at 40° C. for 18 hours. The solvent is evaporated and the residue dissolved in dichloromethane, washed with 1N hydrochloric acid and dried over sodium sulfate. The desired product is obtained by evaporation of the solvent.
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]3[CH:18]([OH:19])[CH2:17][CH2:16][N:15]([CH3:20])[C:14]3=[O:21])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH:1]1([C:8]2[S:12][C:11]([N:13]3[CH:18]([O:19][C:22](=[O:24])[CH3:23])[CH2:17][CH2:16][N:15]([CH3:20])[C:14]3=[O:21])=[N:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC(O)N(c2nnc(C3CCCCCC3)s2)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CCCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([NH:8]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3]1.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[ClH:31].[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3][C@@H:2]1[OH:1]
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)C3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](N)[C@@H](O)C3)c2c1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl ((3S,4R)-3-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (223 mg) was dissolved in DCM (2 ml) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (2 ml). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give the title compound as a pale yellow solid (209 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.B(Br)(Br)Br.O.C(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a -65° C. solution of 8.6 g (53.4 m mol) 5-methoxy-2-methyl indole in 110 mL of CH2Cl2 was added dropwise 30.4 g (117 m mol) of boron tribromide. The reaction was allowed to warm to room temperature and stirred for 30 minutes. After cooling the mixture to 5° C., 200 mL of 50% water/chloroform was cautiously added. The aqueous layer was separated and the pH adjusted to 5.8 with aqueous sodium hydroxide. Extracting the mixture twice with 100 mL of ethyl acetate, followed by drying (Na2SO4), filtering and concentrating provided 5.3 g of the product as a yellow solid, mp 124°-126° C. 1H NMR (60 MHz, 20% DMSO d6 /CDCl3) δ 8.05 (s, 1H, NH), 7.05 (d, J=8 Hz, 1H), 6.80 (d, J=2 Hz, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 5.90 (broad s, 1H, indole CH), 2.40 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([C:13](OCC)=[O:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Oc2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc(Oc2ccccc2)s1
Yield: 52.1 %

Procedure:
A solution of 12 g of the product of Step A in 100 ml of tetrahydrofuran was added dropwise to a mixture of 2.8 g of lithium aluminum hydride in 200 ml of tetrahydrofuran and the mixture was refluxed for 24 hours. Excess hydride was destroyed by addition of ethyl acetate and aqueous 2N hydrochloric acid was added thereto. The mixture was filtered and the aqueous phase was extracted with ether. The combined organic phases were evaporated to dryness to obtain 5.2 g of (2-phenoxy-5-thiazolyl)-methanol.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C[C:11]([N:13](C)C)=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.[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[N:13]
Reactant: Cc1cccc(F)c1I
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 5 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (2.4 L) and degassed under vacuum and purged with N2 three times. Tetrakis was added to the mixture (35 g, 30.3 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (230 g, 974 mmol) and zinc cyanide (68.7 g, 585 mmol) were added and the mixture was degassed under vacuum and purged with N2 three times. The mixture was heated to 80° C. for 16 hrs and allowed to cool to RT. The solution was added to 2.0 L aqueous solution of 1N NH4OH, which was then extracted three times with 1.5 L EtOAc, washed with 2 L brine, dried over Na2SO4, filtered, concentrated and purified by silica chromatography (PE/EA=10:1) to give the title compound.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:19]=[C:20]([Si:24]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:43][C:39]1[CH:38]=[C:37]([Si:24]([C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([C:4]3[C:5]4[O:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[CH:36]=2)([C:20]2[CH:19]=[CH:18][CH:23]=[CH:22][CH:21]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(Br)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1cccc([Si](c2ccccc2)(c2ccccc2)c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
A mixture solution of dibenzo[b,d]furan-4-yl boronic acid (2.5 g, 11.79 mmol), bis(3-bromo-phenyl)diphenylsilane (14.57 g, 29.5 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and K2CO3 (3.26 g, 23.58 mmol) in 150 mL of toluene and 50 mL water was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was separated and evaporated to dryness. The residue was purified by column chromatography on silica gel with hexane:DCM (9.5:0.5, v/v) as eluent to yield (3-bromophenyl)(3-(dibenzo[b,d]furan-4-yl)phenyl)diphenylsilane (4.4 g, 64%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].B(Br)(Br)Br.BrC1C=C2C(C=CN=C2)=CC=1O>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:17])[F:18]
Reactant: COc1ccc2cncc(CCCC(F)(F)F)c2c1
Agent: BrB(Br)Br
Agent: Oc1cc2ccncc2cc1Br
Product: Oc1ccc2cncc(CCCC(F)(F)F)c2c1
Yield: 42.4 %

Procedure:
1.02 g of 6-Methoxy-4-(4,4,4-trifluoro-butyl)-isoquinoline (87) were treated with boron tribromide as described for the synthesis of compound 1 to give 410 mg of the desired product 88. LCMS Method # 1, retention time 1.04 min, detected mass 256.00 [M+H]+