Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:14]([CH3:23])[CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]([CH3:23])[CH:15]=[C:16]([C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(C)n2cc(/C=C/c3nc(-c4cccs4)cn3C)nc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)cn3C)nc2n1
Yield: 41.4 %

Procedure:
A solution of 5,7-Dimethyl-2-[(E)-2-(1-methyl-4-thiophen-2-yl-1H-imidazol-2-yl)-vinyl]imidazo[1,2-a]pyrimidine (40 mg, 0.083 mmol) in methanol (2 mL) was passed through a H-Cube® Continuous-flow Hydrogenation Reactor (ThalesNano) at a flow rate of 1 mL/min through a small cartridge of 10% Pd/C (THS01111) with an internal temperature of 40° C. and 30 bar of hydrogen pressure. Evaporation of the volatiles afforded the title compound (11.6 mg, 41%). LC-MS: m/z=338.6 (MH+), tR=0.69 minutes, method A.
Reaction SMILES: [H][H].O.[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([N+:17]([O-])=O)[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]>[Fe].C(O)(=O)C>[C:4]([NH:7][C:8]1[C:9]([O:20][CH3:21])=[C:10]([NH2:17])[C:11]([O:15][CH3:16])=[C:12]([Cl:14])[CH:13]=1)(=[O:6])[CH3:5]
Reactant: [H][H]
Reactant: COc1c(Cl)cc(NC(C)=O)c(OC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(Cl)cc(NC(C)=O)c(OC)c1N
Temperature: 80 °C

Procedure:
253 g of powdered iron which had been reduced with hydrogen were added to 760 ml of water containing 13 ml of acetic acid and which had been previously heated to 80° C., and then 0.46 mole (126.5 g) of 5-acetamido-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step was added gradually with stirring. Upon completion of the additions, the reaction mixture was maintained in a boiling water bath for 15 minutes. After cooling, the reaction mixture was centrifuged. The iron slurries, after being separated from the liquid phase, were extracted with ethyl acetate. The ethyl acetate phase which was washed with water and then dried over sodium sulphate was diluted with 100 ml of a 7N hydrochloric acid solution in absolute ethanol. The expected product, which precipitated in the form of hydrochloride was thoroughly drained. It was dissolved in the minimum amount of water. After neutralization, the expected product precipitated. Recrystallized from alcohol, it melted at 113° C.
Reaction SMILES: [Sn](Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(O)C.O1CCOCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2cccnc2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Tin(II) chloride (11.87 g, 62.6 mmol) was added portionwise over 5 min to a stirred mixture of 3-(2-chloro-5-nitrophenyl)pyridine (3.53 g, 15.1 mmol) in ethanol (100 ml) and 1,4-dioxane (100 ml) at 0° C. The mixture was then stirred overnight, gradually warming to room temperature, and then concentrated under reduced pressure. 20% Aqueous ammonia solution (200 ml) and ethanol (300 ml) were added and again the mixture concentrated under reduced pressure. Ethyl acetate (300 ml) was added and the mixture heated to reflux, the solids were filtered off and the process repeated twice more. The combined organic filtrates were concentrated under reduced pressure to yield the title compound (2.69 g, 87%): 1H NMR (360 MHz, CDCl3) δ 6.65-6.70 (2H, m), 7.26 (1H, dt, J 8.5, 1.1 Hz), 7.33 (1H, dd, J 7.8, 4.8 Hz), 7.77 (1H, dt, J 7.8, 1.9 Hz), 8.59 (1H, dd, J 4.8, 1.6 Hz), 8.66 (1H, d, J 1.8 Hz); MS (ES+) m/z 205, 207 (3:1) [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(Cl)Cl.CO>ClCCl.CS(Cl)(=O)=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][O:16][S:26]([CH3:25])(=[O:28])=[O:27])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)OCc1cc(=O)c(OCc2ccccc2)co1
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To an ice/salt cooled suspension of 5-benzyloxy-2-hydroxymethyl-pyran-4-one (30.0 g, 0.129 mol) in dichloromethane (500 mL) were added, successively, triethylamine (21.0 mL, 0.151 mol) and a solution of methanesulfonyl chloride (8.3 mL, 0.129 mol) in 10 mL of dichlroromethane. The progress of the reaction was monitored by TLC (CH2Cl2/MeOH, 10/1, v/v), and by HPLC Method 1 as described above. An additional methanesulfonyl chloride (0.5 mL, 7.70 mmol) and triethylamine (2.0 mL, 14.2 mmol) were added to the solution after 50 min. Again, an additional methanesulfonyl chloride (1.0 mL, 15.4 mmol) and triethylamine (2 mL, 14.2 mmol) were added an hour later. The reaction was quenched with 150 mL of brine. The organic phase was separated and collected, dried over sodium sulfate and concentrated in vacuo to give an oil. The oil was diluted with 200 mL of hexanes and a precipitate was formed. The solid was collected by suction filtration, and dried in a vacuum oven to give methanesulfonic acid 5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl ester (39 g, 85% yield). HPLC purity (peak area percent) is 82.1% at λ=280 nm using HPLC Method 1 as described above. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 8.32 (m, 1H), 7.43-7.37 (m, 5H), 6.62 (m, 1H), 5.18 (m, 2H2OCH2), 4.98 (m, 2H, OCH2), 3.36 (m, 3H, SCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[Br:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:28][CH2:29][C:30]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:31]
Reactant: O=C(Cl)CBr
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
Product: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.2 mmol) is dissolved in CH2Cl2 (15 ml), DMAP (180 mg, 1.8 mmol) and 2-bromoacetyl chloride (243 mg, 1.55 mmol) are added. The mixture is stirred at RT for 2 hours, then is diluted with CH2Cl2 (50 ml) and quenched with HCl 1N aqueous solution (50 ml). The two phases are separated, and the organic phase is washed with HCl 1N aqueous solution (2×50 ml), dried over Na2SO4 and evaporated under vacuum. The crude contains a mixture of the title compound (bromoacetoxy-derivative) and an undesired compound (chloroacetoxy-derivative), in a cumulative amount of 550 mg. The compound undergoes the next step without any further purification. MS/ESI+ 541.17 [MH]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH2:5][CH2:6][NH2:7].[Br:10][C:11]1[CH:12]=[N:13][C:14](I)=[N:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[N:13][C:14]([NH:7][CH2:6][CH2:5][C:4]([F:9])([F:8])[F:3])=[N:15][CH:16]=1
Reactant: Brc1cnc(I)nc1
Reactant: NCCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)CCNc1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
Sodium hydride (560 mg, 14.0 mmol) was added in portions to a solution of 3,3,3-trifluoro-propylamine (1.59 g, 14.0 mmol) in dry tetrahydrofuran at ambient temperature. The reaction mixture was stirred for 30 min and a solution of 5-bromo-2-iodopyrimidine (2.0 g, 7.0 mmol) in tetrahydrofuran was added. The reaction mixture was stirred for 30 min and then quenched with water (10 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by column chromatography using a gradient of ethyl acetate in hexane to yield 950 mg (48%) of the title compound; 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (s, 2 H), 5.42 (br. s, 1 H), 3.64 (m, 2 H), 2.41 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].O.Cl>CCO.[Fe]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH3:8]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(C)c1O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(C)c1O
Temperature: 95 °C
Yield: 74.4 %

Procedure:
To a solution of 1-(2-hydroxy-3-methyl-4-nitro-phenyl)-ethanone (720 mg, 3.7 mmol) in EtOH (30 mL) are consecutively added Fe powder (4 g, 74 mmol), water (7.2 mL), and conc. HCl (145 μL). The reaction mixture is heated at 95° C. for 4 h. The iron is filtered through celite and the filtrate poured slowly into saturated aqueous NaHCO3. After the bubbling subsides, the mixture is extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried over Na2SO4, and concentrated. The residue is purified by 25% EtOAc/hexane. Obtained is the title compound as a white solid (455 mg). LC-MS (m/e): 166 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.ClC1C(OC)=CC(OC)=C(Cl)C=1C1N=C2NN=C([C:50]3[CH:51]=[C:52]4[C:57](=[CH:58][CH:59]=3)[O:56][CH:55]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:54][CH2:53]4)C2=CN=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:50]3[CH:51]=[C:52]4[C:57](=[CH:58][CH:59]=3)[O:56][CH:55]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:54][CH2:53]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide (Example 2, Step 2). LCMS (M+H)+=495.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].OS(O)(=O)=O.[CH3:24][CH2:25]O>>[CH2:24]([O:13][C:12](=[O:14])[CH:11]([C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:25]
Reactant: CC(C)CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(F)c1
Yield: 97 %

Procedure:
2-(3-Fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.12 mmol) was dissolved in EtOH (100 mL) and H2SO4 (96%, 5 mL) was added. The reaction mixture was refluxed for 3 h and the solvent evaporated. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with saturated NaHCO3 solution (50 mL), water (100 mL) and brine (100 mL), and then dried over MgSO4. Evaporation of the solvent under reduced pressure gave a brown oil (31.0 g, 97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.33-7.26 (m, 2H), 4.17-4.11 (m, 2H), 3.73 (t, J=7.6 Hz, 1H), 2.10-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.0 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.2, 155.3 (d, 1JCF=265.0 Hz), 148.3 (d, 3JCF=8.4 Hz), 136.5, 126.1, 124.1 (d, 3JCF=3.6 Hz), 117.8 (d, 2JCF=21.6 Hz), 61.3, 49.4, 42.3, 25.9, 22.5, 22.1, 14.1.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[N:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16]CC)=[O:15]>CCO>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[N:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cccnc1-c1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaOH (1.65 mL, 2M in water) was added to a solution of ethyl 2-(benzo[d]oxazol-2-yl)nicotinate (290 mg, 0.973 mmol) in EtOH. After stirring for 3 h at room temperature the solvent was removed in vacuo. The residue was dissolved in water (4 mL) and dilute HCl (1.8 mL, 2M in water) was added resulting in pH 2-3 of the mixture. The mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaCl solution and dried over MgSO4. Removal of the solvent provided the title compound (190 mg, 81%); ESI-MS [M+H+]=241.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (41 mg) and morpholine (53 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (34 mg, yield 69%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: [O-][n+]1ccc(Cl)cc1
Product: COc1cc(F)ccc1-c1cc[n+]([O-])cc1
Yield: 87.4 %

Procedure:
4-Chloropyridine-N-oxide (305 mg, 2.35 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (450 mg, 87%) as a purple solid: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz, 2H), 7.31 (d, J=6.5 Hz, 1H), 6.80-6.71 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid (3.5 g, 12.4 mmol) in THF (80 mL) were added 4-cyanobenzhydrazide (2.3 g, 14.3 mmol), HOBt (1.70 g, 12.6 mmol), EDC (3.56 g, 18.6 mmol) and Et3N (2.8 mL, 20.1 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-cyanobenzohydrazide (3.47 g, 65%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.72 (b, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 5.55 (d, J=7.2 Hz, 1H), 4.08 (d, J=7.2 Hz, 1H), 2.35 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:42]=[CH:41][C:12]([O:13][C:14]2[CH:15]=[C:16]([NH:34][CH2:35][CH2:36][C:37]([F:40])([F:39])[F:38])[C:17]3[N:21]=[CH:20][N:19]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[C:24]([CH3:32])[CH:23]=4)[C:18]=3[CH:33]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:15]=[C:16]([NH:34][CH2:35][CH2:36][C:37]([F:39])([F:40])[F:38])[C:17]3[N:21]=[CH:20][N:19]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[C:24]([CH3:32])[CH:23]=4)[C:18]=3[CH:33]=2)=[CH:41][CH:42]=1
Reactant: CNC(=O)c1ccc(-n2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(OCc5ccccc5)cc4)cc32)cc1C
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1ccc(-n2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(O)cc4)cc32)cc1C
Temperature: 23 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 17.2 mg (30 μmol) 4-{6-[4-(Benzyloxy)phenoxy]-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-N,2-dimethylbenzamide which was prepared according to example 47 in 0.7 mL ethanol were added 3.19 mg palladium on charcoal (10%) and the mixture was vigorously stirred under an atmosphere of hydrogen for 2 hours at 23° C. After filtration and removal of the solvent the residue was purified by chromatography to give 8.2 mg (54%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].O>C(Cl)Cl.CN(C=O)C>[CH3:20][NH:21][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1oc2ccccc2c1C
Temperature: 2 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methylbenzofuran-2-carboxylic acid (1.0 kg, 5.676 mol) in methylene chloride (5.8 L) and DMF (5 mL) was chilled to ˜2° C. A solution of oxalyl chloride (864 g, 6.81 mol) was added to the reaction mixture keeping the temperature below 10° C., over a period of 2 hrs. A vigorous evolution of a gas was observed. The reaction mixture was stirred overnight under nitrogen at room temperature and then refluxed for 3 hrs. All of the solids were dissolved to give a brown color solution. HPLC analysis of an aliquot indicated that the reaction was complete. The mixture was concentrated on a rotary evaporator and the residual oxalyl chloride was chased with DCM (2 L). The solid product was re-dissolved in DCM (6 L) in a round bottom flask (10 L) and chilled to ˜−5° C. A solution of methyl amine (40% in water, 1.7 L, 3.5 eq, 19.86 mol) was carefully added to the acid chloride solution while keeping the temperature below 8° C. then stirred overnight at room temperature. Analysis of an aliquot indicated that the reaction was complete. Water (8.0 L) was added to the reaction mixture, the layers were separated, the aqueous layer was back extracted with DCM (2×3 L), the combined organic layer was washed with water (4 L) and dried over Na2SO4. The organic layer was filtered, the filtrate was concentrated and traces of DCM were co evaporated with heptanes (2 L). The heptanes slurry was filtered and the cake was washed with heptanes (2×2 L). All the brown color was removed in the heptane filtrate. The solid product was dried under high vacuum overnight to a constant weight. Yield of the title compound was 1.015 kg (94.5%. 1H NMR {CDCl3}: δ (ppm) 8.45 (s, 1H), 7.61 (d, 1H), 7.41 (m, 2 H), 7.30 (m, 1 H), 3.03 (d, 2 H), 2.63 (s, 3 H). HPLC: 99.0 area % (RT=7.91 min)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12](C(F)(F)F)=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20].BrC1C=CC([C:38](C2C=C([N+]([O-])=O)C=CC=2C)=[O:39])=C(Cl)C=1.COC1C=CC=CC=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:39][CH3:38])[CH:5]=[CH:4][C:3]=1[C:19]([C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH3:30])=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Solvent: COc1ccccc1N
Product: COc1ccccc1Nc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.56 mmol) and 2-methoxy-phenylamine (0.56 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: ClC1C=CC(C[O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.[F:36][C:37]([F:41])([F:40])[CH2:38]I>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:31])([F:32])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:38][C:37]([F:41])([F:40])[F:36])=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: FC(F)(F)CI
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCC(F)(F)F)cn1

Procedure:
Compound 12 was prepared in a similar manner to compound 1 from 1,1,1-trifluoro-2-iodoethane to afford a pale yellow solid (23.0 mg, 50%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.27 (s, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.35-7.30 (m, 2H), 7.21 (br s, 1H), 6.78-6.73 (m, 1H), 6.69-6.66 (m, 1H), 5.55 (d, J=14.5 Hz, 1H), 5.12 (d, J=14.5 Hz, 1H), 4.43 (q, J=8.0 Hz, 2H). MS (ESI): m/z 452.1 [M++1]. HPLC: 98.05%.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][OH:25].CN([CH:29]=[O:30])C>C1COCC1>[F:16][C:17]1[C:18]([CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=[CH:21][C:22]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: OCCc1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(CCO)c1F
Temperature: -70 °C
Reaction time: 6 h

Procedure:
2,2,6,6-Tetramethylpiperidine (10.8 mL) was added to a solution of butyllithium (1.6M in hexanes, 40.1 mL) in THF (40 mL) at −70° C. A solution of 2-(2-fluorophenyl)ethanol (3 g) in THF (40 mL) was added dropwise and the resulting mixture stirred for 6 h at −70° C. DMF (8.29 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic solutions were washed with HCl solution (2M, 50 mL), brine (20 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 1.2 g.