Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14](O)=[O:15])=[C:8]([N+:17]([O-])=O)[CH:7]=1>C(O)C.[Fe]>[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[S:12][CH2:13][C:14](=[O:15])[NH:17][C:8]=2[CH:7]=1
Reactant: O=C(O)CSc1ccc(CCO)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CSc2ccc(CCO)cc2N1
Yield: 46.5 %

Procedure:
A mixture of iron powder (1.24 g, 22 mmol) and sodium chloride (1.24 g, 21 mmol) in 50% aqueous ethanol (25 ml) was heated under reflux for 15 minutes. A solution of crude (g) (0.92 g, 3.6 mmol) in ethanol (5 ml) was then added quickly and the reaction mixture was heated under reflux for 2 hours. The mixture was filtered through keiselguhr and the solution was evaporated to dryness. The residue was dissolved in water and acidified to pH5 with 1M aqueous hydrochloric acid. The precipitate was collected by filtration, washed with water, then dried to give a white solid (0.35 g, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][CH:12](O)[CH3:13].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])=[C:6]([CH:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: COc1c(F)cc(Br)cc1C(C)C
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of 4-bromo-2-fluoroanisole (2.0 g, 9.70 mmol) and 2-propanol (1.2 g, 19.4 mmol) at room temperature was added 80% H2SO4 (10.0 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature, quenched with ice (50 g) and extracted with ether (20 mL×2). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-6-fluoro-2-iso-propylanisole (0.92 g, 38%): 1H NMR (300 MHz, CD3OD): δ 7.36 (d, J=10.5 Hz, 1H), 7.22 (d, J=10.5 Hz, 1H), 3.91 (s, 3H), 3.24 (m, 1H), 1.26 (d, J=6.6 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.50.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
0.8 g (0.00323 mol) of ethyl 1-benzylpiperidine-4-carboxylate was dissolved in a mixture of 5 ml of dioxan, 2 ml of water and 3.5 ml (0.0035 mol) of 1N aqueous NaOH. After stirring for 15 min. 3.5 ml (0.0035 mol) of 1N aqueous HCI were added, the mixture was diluted with 20 ml of water, the dioxan was removed by distillation and the residue which remained was lyophilized. The residue was boiled twice with 100 ml of isopropanol each time and the combined organic phases were filtered and concentrated. The product crystallized out in the cold. 0.586 g (83%) of 1-benzylpiperidine-4-carboxylic acid was obtained as white crystals; m.p. 167°-168°.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C)C=CC=1C(O)=O.CC1C=C(C)C=CC=1C(Cl)=O.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1ccc(C(=O)N=C=S)c(C)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cc1ccc(C(=O)O)c(C)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,4-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,4-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,4-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 97%).
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H:12]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:20][C:21](=[O:28])[NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)([CH2:15][CH2:16]3)[CH2:13]2)=O)C=CC=CC=1.[CH:36]1([C:41]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)([OH:45])[C:42]([OH:44])=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Br-:1].[CH:36]1([C:41]([C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)([OH:45])[C:42]([O:44][C@@H:16]2[CH:17]3[CH2:18][CH2:19][N+:14]([CH2:20][C:21](=[O:28])[NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)([CH2:13][CH2:12]3)[CH2:15]2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(O)C(O)(c1ccco1)C1CCCC1
Reactant: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccco1)C1CCCC1)C2)Nc1ccon1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-Diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (See Example 4) by replacing 2,2′-diphenylpropionic acid with cyclopentyl-furan-2-yl-hydroxy-acetic acid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5](=O)[NH:4][CH:3]=1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Br:1][C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][C:14]=3[C:6]=2[C:5]([Cl:21])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Br)c2[nH]c3ccc(F)cc3c12
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2[nH]c3c(Br)cnc(Cl)c3c2c1
Temperature: 175 °C

Procedure:
4-Bromo-8-fluoro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (1 gram) was suspended in 10 mL POCl3 and heated to 175° C. for 15 minutes in a microwave. The crude reaction mixture was poured over ice, neutralized with 12 M NaOH, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to dryness. The title compound was used without further purification.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]1([CH3:26])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.C(O)(C)C.O>CC(C)=O>[CH3:26][C:16]1([C:15]([OH:3])=[O:14])[O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: CC1(CO)COc2ccccc2O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC1(C(=O)O)COc2ccccc2O1

Procedure:
Jones' reagent (33.3 ml.) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxan (5 g.) in acetone (300 ml.) at 5° C., then the reaction was allowed to attain room temperature. Isopropanol (10 ml.) was then added followed by water (200 ml.), the solution extracted with chloroform and the extracts evaporated in vacuo. The residual oil was taken up in chloroform (200 ml.) then extracted with dilute sodium bicarbonate solution and the aqueous phase further washed with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (MgSO4) and evaporated in vacuo ti give 2-methyl-1,4-benzodioxan-2-carboxylic acid (1.7 g.). A sample was recrystallized from toluene, m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[C:17]([OH:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:15][C:14]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C=CC>O.C(O)C.CCCCCC.C(OCC)(=O)C>[OH:5][CH2:4][CH:3]1[O:18][C:17]2=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:15][C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]2[O:12][CH2:1]1
Reactant: CCOC(=O)c1sc(C(=O)OCC)c(O)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1sc(C(=O)OCC)c2c1OCC(CO)O2
Temperature: 25 °C
Yield: 55 %

Procedure:
7.7 mL (0.0902 mol) of epibromohydrin and 1.92 g (0.0139 mol) of potassium carbonate were dissolved in 100 mL water and added to a refluxing mixture of 16.11 g (0.0694 mol) diethyl 3,4-dihydroxythiophene-2.5-dicarboxylate in 350 mL ethanol. After heating to reflux for 1 hour, an additional 5.3 mL (0.0624 mol) epibromohydrin was added and the reaction heated to reflux overnight. Upon cooling to room temperature the reaction was concentrated by evaporation and then poured into 500 ml water. The mixture was acidified and then extracted with methylene chloride until the organic wash no longer indicated product was present. The organic fractions were washed with saturated brine then dried with magnesium sulfate. The solvent was removed under reduced pressure to give a yellow solid. Column chromoatography was performed using 60% ethyl acetate in hexane to give a 70:30 mixture of the product and propylene isomer in 55% yield as a white solid. Structure and purity were confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][C@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:20]CN(C(C)C)C(C)C.CI.O>CN(C=O)C>[CH3:20][O:10][C:9](=[O:11])[C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)s1)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Esterification. To a solution of (S)-3-(5-bromo-thiophen-2-yl)-2-ter t-butoxycarbonylamino-propionic acid in DMF (50 mL) was added DIEA and methyl iodide. The reaction mixture stirred at rt for 2.5 h and was poured onto EtOAc and water. The organic layer was washed with 1 N HCl and 10% sodium carbonate, dried over sodium sulfate and concentrated to furnish (S)-3-(5-bromo-thiophen-2-yl)-2-tert-butoxycarbonylamino-propionic acid methyl ester. This product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)[C:20]([NH2:22])=[O:21].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:22][C:20](=[O:21])[C@@H:19]([NH:18][C:15]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 118.4 %

Procedure:
4-(tert-Butoxycarbonylamino)tetrahydro-2H-pyran-4-carboxylic acid (0.801 g), (S)-2-amino-3-(4-iodophenyl)propanamide (Example 1, step (ii), 0.947 g) and N-ethyl-N-isopropylpropan-2-amine (1.422 mL) were dissolved in DMF (10 mL) and to the solution was added TBTU (1.573 g). The reaction mixture was stirred, at room temperature, for 2 days. The reaction mixture was evaporated to dryness dissolved in dichloromethane (20 mL) and evaporated onto silica. The silica was put on the top of a silica column and eluted with 20% ethyl acetate in isohexane then 50% ethyl acetate in isohexane then 100% ethyl acetate followed by 10% then 20% methanol in ethyl acetate to afford the sub-titled compound (2.00 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:24])([CH3:23])[C:7](=[O:22])[N:8]2[C:11]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1.[CH:25]([C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]1)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:24])([CH3:23])[C:7](=[O:22])[N:8]2[C:11]([NH:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][N:18]([CH2:25][C:27]3([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]3)[CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C=O)CCC1
Reactant: CC1(C)C(=O)N(C(=O)NCC2(O)CCNCC2)c2cc(F)ccc21
Product: COC(=O)C1(CN2CCC(O)(CNC(=O)N3C(=O)C(C)(C)c4ccc(F)cc43)CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 2 from 6-fluoro-N-[(4-hydroxypiperidin-4-yl)methyl]-3,3-dimethyl-2-oxoindoline-1-carboxamide and methyl 1-formylcyclobutanecarboxylate (step 4 of Example 22) and methyl 1-formylcyclobutanecarboxylate (Davis, Charles R. et al., J. Org. Chem., 1993, 58, 6843).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:19][CH2:18]2)[C:12]([O:14]C)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([S:32](NC(CC=C)C(OC)=O)(=O)=O)=[CH:28][CH:27]=1.O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]([OH:19])[CH2:18][S:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)[C:12]([OH:14])=[O:13])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(CC(O)CSc1ccccc1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
Methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4,5-epoxypentanoate: To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.N.O>CO>[N:12]1([C:15]2[CH:21]=[CH:20][C:18]([NH:19][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10][O:9][CH2:14][CH2:13]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Nc1cc(Cl)ncn1
Agent: N
Solvent: CO
Solvent: O
Product: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Temperature: 25 °C

Procedure:
The title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 4-morpholinoaniline. The semi-solid reaction mixture received after cooling to room temperature is dissolved in warm methanol, basified with conc. aqueous ammonia solution and the mixture concentrated to half of its volume. The precipitate obtained after addition of H2O is filtered off, washed with H2O and dried in vacuo to afford the title compound. Faintly violet solid, ESI-MS: 272.3 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH2:10]O.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>ClCCl>[Br:13][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: COc1cccc(C)c1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(C)c1CBr
Temperature: -10 °C
Reaction time: 8 h

Procedure:
[2-Methyl-6-(methyloxy)phenyl]methanol (for a preparation see Intermediate 56)(300 mg, 1.971 mmol) in dichloromethane (4.5 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (186 μl, 1.97 mmol) in DCM (4 ml) was then added dropwise over about 15 min and the solution stirred for a further 30 min at this temperature. The solution was allowed to warm up to ambient temperature. After a few hours, saturated aqueous sodium bicarbonate (approximately 5 ml) was added and the mixture stirred vigorously. The suspension was stored in freezer overnight. The phases were separated and the aqueous phase extracted further with chloroform. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as yellow solid (424 mg); LCMS: (System 4) No MH+, tRET=3.01 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCCCCCc1cccnc1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: Cc1ccc(-c2ccc(C(=O)NCCCCCCc3cccnc3)cc2)cc1C

Procedure:
The title compound was prepared from 7.0 g of 3',4'-dimethyl[1,1'-biphenyl]-4-carboxylic acid and 6.1 g of 3-pyridinehexanamine according to Example 3 to give 6.2 g of 3,'4'-dimethyl-N-[6-(3-pyridinyl)hexyl][1,1'-biphenyl]-4-carboxamide. mp 81°-82° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9]O.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C.[F:29]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:29][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(CO)c1ccccc1F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CF)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-hydroxyethanone [CAS 218771-68-7; WO9857925, ex. 16) (2.77 g, 18.0 mmol) in dichloromethane (42 ml) was treated consecutively at 0° C. with triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and nonafluoro-n-butanesulfonyl fluoride (8.48 g, 26.9 mmol). The tube was sealed and the reaction mixture stirred overnight at room temperature. For the workup, the dark red solution was poured on a saturated solution of sodium hydrogencarbonate and ice, then extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel (Telos Flash Silica) using dichloromethane as the eluent to give the 2-fluoro-1-(2-fluoro-phenyl)-ethanone (1.23 g, 61% yield) as a yellow semisolid.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[C:9]=2[S:17]([CH3:20])(=[O:19])=[O:18])=[O:7])[CH2:3][CH2:2]1.[CH2:22]([O:24][CH:25](OCC)OCC)[CH3:23]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:21])[C:5](=[CH:25][O:24][CH2:22][CH3:23])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH3:16])[C:9]=2[S:17]([CH3:20])(=[O:19])=[O:18])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: COc1c(F)ccc(C(=O)CC(=O)C2CC2)c1S(C)(=O)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(F)c(OC)c1S(C)(=O)=O)C(=O)C1CC1
Yield: 95.9 %

Procedure:
A mixture of 3-cyclopropyl-1-(4-fluoro-3-methoxy-2-methylsulphonylphenyl)propane-1,3-dione (5.4 g) and triethylorthoformate (4.8 g) in acetic anhydride (4.5 g) was heated under reflux for 4 hours. The mixture was evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(4-fluoro-3-methoxy-2-methylsulphonylphenyl)propane-1,3-dione (6.1 g) as a red oil, which was used directly in the next stage.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5](C(OC(C)(C)C)=O)[N:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1n[nH]c2ncccc12

Procedure:
A solution of 250 mg (0.80 mmol) of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (1-1) and sodium azide (55 mg; 0.85 mmol) in 1 mL anhydrous DMF was heated at 90° C. for 5 hours. The reaction was cooled, diluted with water, and extracted twice with 25 mL portions of EtOAc. The combined EtOAc extracts were washed with brine, dried (anhydrous MgSO4) and concentrated to give a dark oil. The oil was purified by reverse phase preparative HPLC on a Gilson apparatus to give the title compound as a tan solid. MS M+1=152.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:15][C:16]([NH:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[O:17])[CH:12]=[CH:13][CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C[O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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].ClCCl>[F:21][C:20]([F:23])([F:22])[CH2:19][NH:18][C:16]([NH:15][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:24]=[CH:25][C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([OH:29])=[O:27])=[CH:31][CH:32]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH:14]=[CH:13][CH:12]=1)=[O:17]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(Br)ccc32)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4ccc(C(=O)O)cc4)ccc32)c1
Temperature: 25 °C

Procedure:
A mixture of N-[3-(5-bromo-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (250.0 mg, 0.6050 mmol) (prepared by the procedure for Example 1, step 4), [4-(methoxycarbonyl)phenyl]boronic acid (160 mg, 0.91 mmol, Aldrich, Cat. No. 594539), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (30 mg, 0.04 mmol, Aldrich, Cat. No. 379670) and sodium carbonate (130 mg, 1.2 mmol) in 1,4-dioxane (5 mL) and a few drops of water was heated at 120° C. overnight under nitrogen. After the reaction was cooled to r.t., 1.0 M sodium hydroxide in water (2.4 mL,) was added to the above mixture. The reaction mixture was heated at 100° C. for 2 h, then cooled to r.t. The reaction mixture was diluted with ethyl acetate, and extracted with 1N NaOH aqueous solution twice. The combined aqueous phases were acidified to pH˜2 with 6 M HCl aqueous solution, and then extracted with ethyl acetate twice. The combined organic phases (only the extracted portion with acidic aqueous solution) were washed with brine, dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired product. LCMS (M+H)+: m/z=455.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([OH:14])=[C:11]([C:15]([O-:17])=[O:16])[CH2:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[CH2:13][C:12]([OH:14])=[C:11]([C:15]([O:17][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH2:10][C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccccc1
Reactant: O=C([O-])C1=C(O)CN(Cc2ccccc2)C(=O)C1
Product: O=C(OCc1ccccc1)C1=C(O)CN(Cc2ccccc2)C(=O)C1
Yield: 81.5 %

Procedure:
A solution of 1-benzyl-5-hydroxy-2-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate 4 (14 g, 50.9 mmol) in benzyl alcohol (27.5 g, 255 mmol) was heated at about 170° C. for about 16 hours. The solvent was removed in vacuo, and the resulting residue was re-crystallized from ether to give the title product as a yellow solid (14 g; yield=85%). LC-MS: m/z=338 (M+H)+.