Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2)o1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCCCC3)cc2)o1
Temperature: 170 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.62 mmol) in DMSO (2 mL) was added piperidine (307 μL, 3.11 mmol) and the resulting mixture stirred for 5 h at 170° C. After cooling to ambient temperature the reaction mixture was extracted with aqueous hydrochloric acid (1 N, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=80:0:20 to 50:30:20) afforded the title compound (192 mg, 80%) as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([CH2:37][CH2:38][C:39]#[N:40])[CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH2:37][CH2:38][C:39]#[N:40])[CH2:33][CH2:32]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCC[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a stirred suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (3.17 g) in propan-2-ol (32 mL), trans 3-(4-amino-cyclohexyl)-propionitrile trifluoroacetic acid salt (2.75 g, 10.3 mmol) and diisopropylethylamine (4.09 mL, 23.5 mmol) were added. The mixture was stirred at reflux for 16 hours and then cooled to 0° C. The suspension was filtered, and the solid washed with propan-2-ol (×2) and ether, then air dried to afford 3.83 g (90%) of trans 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexyl]-propionitrile as a bright yellow solid. 1H NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 8.99 (d, 1H), 8.19 (d, 2H), 7.66-7.59 (m, 2H), 7.52 (t, 2H), 6.67 (d, 1H), 3.91-3.80 (m, 1H), 2.40 (t, 2H), 2.24 (m, 2H), 1.96 (m, 2H), 1.66 (q, 2H), 1.55-1.39 m, 3H), 1.23-1.10 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:1]([NH:8][C:10](=[O:11])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)Oc1ccccc1
Reaction time: 72 h

Procedure:
Benzylamine (53.5 g.) is added during 30 minutes to a stirred suspension of phenyl chloroformate (78.3 g.) and anhydrous potassium carbonate (151.8 g.) in dioxan (500 ml.) and the mixture is stirred at laboratory temperature for 72 hours and then poured into water. The mixture is extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulphate and evaporated to dryness. The residue is stirred with petroleum ether (b.p. 60°-80° C.) and the mixture is filtered. There is thus obtained as solid residue phenyl N-benzylcarbamate, which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](O)=O>>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc2c(=O)[nH]cnc2c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 2-amino-4-methylbenzamide (20 g, 133 mmol)and formic acid (120 ml, 3129 mmol) was heated to 100° C. After 6 hours, the reaction was cooled down to to RT and the volatiles were removed under reduced pressure. The residue was then washed carefully with aqueous saturated sodium bicarbonate and then with water. The tan solid was then dried in a vacuum oven at 45° C. overnight to give 7-methylquinazolin-4(3H)-one. MS (M+H)+ 161.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[OH:7][CH2:8][CH:9]1CCC=CO1.C(OCC)(=[O:17])C>C1(C)C=CC=CC=1.[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:1]12([CH2:4][OH:17])[O:5][CH:3]1[CH2:9][CH2:8][O:7][CH2:2]2
Reactant: CCOC(C)=O
Reactant: OCC1CCC=CO1
Reactant: CC(C)(C)OO
Agent: O=[V]([O-])([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCC12COCCC1O2
Reaction time: 0.08 h
Yield: 70 %

Procedure:
Tert-butyl hydroperoxide (5.5M, 4.73 mmoles) was added to a mixture of vanadyl acetoacetonate (0.058 g, 0.22 mmoles) and hydroxymethyldihydro-pyran (0.5 g, 4.38 mmoles) in 16.2 ml of toluene at 85° C. After stirring for 5 minutes, TLC showed the reaction to be complete. The mixture was diluted with ethyl acetate and washed with 1 M hydrochloric acid followed by a wash with a saturated sodium bicarbonate solution. The ethyl acetate layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield a light yellow oil (0.4 g, 70%). 1H NMR (D6 acetone, 400 MHz) δ 3.21 (bs, 1H), 3.36-3.42 (m, 2H), 3.48 (dd, J=6.64 Hz and 12.04 Hz, 1H), 3.6 (dd, J=5.61 Hz and 12.04 Hz, 1H), 3.74 (d, J=13.07 Hz, 1H), 3.87 (dd, J=5.6 Hz and 6.64 Hz, 1H), 4.02 (d, J=13.07 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])(=[O:4])=[O:3].[Cl:14][C:15]1[CH:16]=[N+:17]([O-:40])[CH:18]=[C:19]([Cl:39])[C:20]=1[CH2:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[N+:17]([O-:40])[CH:18]=[C:19]([Cl:39])[C:20]=1[CH2:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[O:12][C:11]([C:7]1[S:8][CH:9]=[CH:10][C:6]=1[NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[O:13]
Reactant: CS(=O)(=O)Nc1ccsc1C(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccsc1C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.6 %

Procedure:
A mixture of 3-(methylsulfonamido)thiophene-2-carboxylic acid (Int. 38) (110 mg, 0.497 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-hydroxyethyl)pyridine 1-oxide (209 mg, 0.497 mmol), EDC (286 mg, 1.491 mmol) and DMAP (30.4 mg, 0.249 mmol) in DCM (25 ml) was stirred at RT for 3 days. The mixture was diluted with DCM and washed with 1N HCl and aqueous NaHCO3; the organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel cartridge (DCM/MeOH=99.5/0.5 to 99/1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(3-(methylsulfonamido)thiophene-2-carbonyloxy)ethyl)pyridine 1-oxide (Int. 39) (95 mg, 0.152 mmol, MS/ESI+623.05 [MH]+, [αD]=−28.6, c=0.3, DCM).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:8][C:7]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30].C(N(CC)CC)C.Cl.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45](Cl)=[O:46]>>[CH3:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)=[N:8][C:7]([N:24]3[CH2:25][CH2:26][N:27]([C:45]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=4)=[O:46])[CH2:28][CH2:29]3)=[N:6][C:5]=2[S:4][C:3]=1[CH3:30]
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1sc2nc(N3CCNCC3)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1sc2nc(N3CCN(C(=O)c4ccccn4)CC3)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].N1C=CC=CC=1>C(Cl)Cl>[Si:6]([O:5][CH2:1][CH2:2][C:3]#[CH:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-butyne-1-ol (5.0 g; 71.3 mmol) in ca. 75 ml of methylene chloride was added tert-butydimethylsilyl chloride (10.8 g; 71.6 mmol) and 7 ml of pyridine. The mixture was allowed to stir overnight at room temperature, diluted with methylene chloride, washed with water, 1M HCl, brine and dried (Na2SO4). Concentration in vacuo afforded the title compound as a colorless liquid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1

Procedure:
A 4.65 g quantity of the N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 1 was dissolved in 90 ml of ethanol, and 0.45 g of 10% palladium carbon powder was added thereto. The mixture was stirred in a hydrogen atmosphere at room temperature for one hour. The catalyst was removed by filtration, and the filtrate was then concentrated under reduced pressure to give 3.7 g of white crystalline N-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: C1(=O)OC(=[O:9])CCCCCC1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([OH:36])(=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28]C1C=CC=CC=1)=[O:27].ClC(OCC)=O>>[CH:16]1[CH:15]=[CH:14][C:13]([NH:12][C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][OH:9])=[O:27])=[O:36])=[CH:18][CH:17]=1
Reactant: O=C1CCCCCCC(=O)O1
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCCCCC(=O)Nc1ccccc1
Agent: CCOC(=O)Cl
Product: O=C(CCCCCCC(=O)Nc1ccccc1)NO

Procedure:
Another process for the preparation of vorinostat has been reported in OPPI Briefs, 2001, vol. 33(4), pages 391-394. The reported process, illustrated in Scheme 6, involves conversion of suberic acid to suberic anhydride, which on treatment with aniline gives suberanilic acid. Coupling of this suberanilic acid with ethyl chloroformate gives a mixed anhydride which upon treatment with hydroxylamine gives vorinostat in an overall yield of 58%. In the first step, there is competition between the formation of suberic anhydride and the linear anhydride and consequently isolation of pure suberic anhydride from the reaction mixture is very difficult. This process step is also hindered by the formation of process impurities and competitive reactions. In the second step, there is formation of dianilide by reaction of two moles of aniline with the linear anhydride. In the third step, suberanilic acid is an inconvenient by-product as the suberanilic acid is converted to a mixed anhydride with ethyl chloroformate, which is highly unstable and is converted back into suberanilic acid. Consequently, it is very difficult to obtain pure vorinostat from the reaction mixture. Although the reported yield was claimed to be 58%, when repeated a yield of only 38% was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].N1C=CC=CC=1.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:29]=[C:28]([N:30]([CH3:31])[C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)C(C)(C)C)cc3Cl)c2n1
Reaction time: 48 h
Yield: 89.6 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (188 mg) in dichloromethane (1.9 ml) were added pyridine (58 mg) and pivaloyl chloride (65 mg) at room temperature and the mixture was stirred for 2 days. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and ethanol was added to the residue to give crude crystals. Ethanol was evaporated, and the residue was recrystallized from acetone-water to give 3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (199 mg) as a white powder.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[OH:10][C@@H:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12]1>CCO>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH2:13][CH2:12][C@H:11]([OH:10])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: N#Cc1cccc2c1CC[C@@H]2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CC[C@@H]2O
Reaction time: 16 h
Yield: 90 %

Procedure:
To hydroxylamine hydrochloride (0.87 g, 12.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in EtOH (20 mL) was added (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-2 (1.59 g, 10 mmol) in one portion and the solution was heated to reflux. After 16 h, the reaction was cooled and filtered to remove the solids. The EtOH was removed and the compound purified by chromatography (MeOH/DCM) to give 1.74 g (90%) of (S)—N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-3 as a white foam. LCMS-ESI (m/z) calculated for C10H12N2O2: 192.1; found: 193.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m, 2H), 5.22 (t, J=6.5, 1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H), 2.49 (dddd, J=11.4, 8.0, 7.0, 4.4, 1H), 2.02-1.88 (m, 1H). (R)—N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide is made in an analogous fashion from (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.[CH3:16]O>>[ClH:3].[CH3:16][O:14][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH2:5])[CH2:12][CH2:11]1)=[O:15]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)[C@H]1CC[C@H](CN)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (7 ml, 96 mmol) was added to a solution of trans-4-aminomethyl cyclohexanecarboxylic acid (5.00 g, 31.8 mmol) in methanol (50 ml) and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and the obtained solid was washed with diethyl ether (50 ml). Trans-4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride (6.49 g, 98%) was obtained by separating by filtration and drying in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: COc1cc(NS(=O)(=O)c2ccccc2N)cnc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2C(=O)Nc3ccccc3S2(=O)=O)cnc1OC
Yield: 49 %

Procedure:
The title compound (257 mg, 0.77 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)benzenesulfonamide (486 mg, 1.57 mmol), 1,1′-carbonyldiimidazole (1.02 g, 6.29 mmol) and triethylamine (0.44 mL, 3.14 mmol) in DMF (3 mL) using the methods of (IntA14), step 3.
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3cc(C)on3)cc(OCc3ccccc3C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2cc(OCc3ccccc3C)cc(C(=O)Nc3ccc(C(=O)O)cn3)c2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Methyl 6-{[3-(2-methylbenzyloxy)-5-(5-methylisoxazol-3-ylmethoxy)benzoyl]amino}-3-pyridinecarboxylate (98 mg, 0.201 mM) was dissolved in THF (4 ml) and a solution of NaOH (24 mg, 0.603 mM) in water (0.24 ml) was added. Water (4 ml) was added to the reaction mixture until it became monophasic. The reaction was stirred for 16 hours at ambient temperature and was then acidified to pH=1 with 1N aqueous HCl. The white solid which precipitated from the mixture was isolated by filtration and was dried ‘in vacuo’ to give the title compound as a white solid (67 mg, 70% yield); H1 NMR δ (d6-DMSO) 2.30 (3H s) 2.39 (3H s) 5.16 (2H s) 5.22 (2H s) 6.33 (1H s) 6.91 (1H s) 7.11–7.42 (6H m) 8.30 (2H s) 8.87 (1H s). MS [MH]+ 474
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.OB(O)[C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
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: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C(=O)O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-(dihydroxyboryl)thiophene-2-carboxylic acid (205 mg, 1.19 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (4 mL) was heated in a microwave reactor at 100° C. for 6 h. The material was dry-loaded onto silica gel for column chromatography. The crude product was eluted with 20% MeOH/DCM. The fractions containing the product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.54 (q, J=6.9 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 7.41 (dd, J=9.0, 4.9 Hz, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.92 (s, 1H), 8.27 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-:9].[K+].N#N.F[C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>CS(C)=O.C1C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:9][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [OH-]
Reactant: Oc1cccc(Br)c1
Agent: N#N
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=C(c1ccc(Oc2cccc(Br)c2)cc1)c1ccc(Oc2cccc(Br)c2)cc1
Yield: 72 %

Procedure:
A reaction mixture was prepared with 3.8g (22 mmol) of m-bromophenol, 20 ml of methanol, and 20 ml of benzene. To this reaction mixture, 20 ml of 1 N KOH was added while N2 gas was passed into the mixture, and the methanol and water were removed at a temperature of 100° C. or below. To the resultant, 20 ml of benzene was added and benzene was distilled off at a temperature of 100° C. or below. Subsequently, 2.18 g (10 mmol) of 4,4'-difluorobenzophenone and 30 ml of dimethylsulfoxide (DMSO) was added and reacted at 140° C. for 4 hours to obtain 3.8 g of 4,4'-bis(3-bromophenoxy) benzophenone. The yield was approximately 72%. The following is the reaction formula of this synthesis. ##STR7##
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:20]Br.O>C(O)(=O)C>[BrH:20].[Br:20][CH:12]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)=[O:19]
Reactant: CC(C)(C)c1ccc(C(=O)Cc2ccncc2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Br
Product: CC(C)(C)c1ccc(C(=O)C(Br)c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.2 %

Procedure:
1-[4-(1,1-Dimethylethyl)phenyl]-2-(4-pyridyl)ethanone (10 g, 39 mmol) was dissolved in acetic acid (40 mL) and bromine (2.0 mL, 39 mmol) was added. The mixture was stirred at 80° C. for 3 h. The reaction mixture was cooled with iced water and the precipitated crude crystals were collected by filtration. The crude crystals were washed with ethyl acetate to give the title compound (9.6 g, yield 81%).