Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(Cl)Cl.Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])=[CH:22][CH:21]=1)[C:11](=[NH:14])OC.[NH3:38]>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:28](=[O:37])[C:29]3=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]3[C:31]2=[O:32])=[CH:22][CH:21]=1)[C:11]([NH2:14])=[NH:38]
Reactant: N
Reactant: COC(=N)c1ccc(OCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c(OC)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=N)N)ccc1OCc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
To a mixture of 100 ml of chloroform and 100 ml of anhydrous methanol, was added 3.0 g of methyl 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzimidate hydrochloride followed by 16 ml of a methanol solution of anhydrous ammonia (22 mg/ml). The mixture was stirred for 24 hours and then evaporated to dryness. The residue was dissolved in methanol, then poured into a large volume of chloroform, and filtered from precipitated colorless solids. The filtrate was evaporated to dryness and the residue was recrystallized from methanol to yield 1.4 g of 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzamidine; m.p. 228°-230° C. To obtain a methanesulfonate, the above benzamidine compound was suspended in methanol and admixed with an excess of methanesulfonic acid. Upon addition of ether to the resulting solution, there was obtained a colorless solid which was recrystallized from methanol to yield colorless needle crystals of 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzamidine methanesulfonate; m.p. 174°-176° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=O)[C:11]=3[C:20]([O:22]CC)=[O:21])=[CH:4][C:3]=2[O:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)[CH:11]2[C:20]([OH:22])=[O:21])=[CH:28][CH:27]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (5 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 4-fluorophenyl magnesium bromide (0.62 mmol). After stirring for 45 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacua, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (45 mg, 35%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[NH2:33][CH:34]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:35]#[N:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([CH:34]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)#[N:36]
Reactant: N#CC(N)Cc1ccccc1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CC(Cc1ccccc1)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-3-phenylpropanenitrile hydrochloride (8.47 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide (R/S)-N-(1-cyano-2-phenylethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.012 mmol, 26.2% yield) as a mixture of diastereomers: LCMS=546.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.17 (2 H, m), 7.18-7.72 (12 H, m), 5.08-5.15 (1 H, m), 5.02 (1 H, t, J=7.70 Hz), 3.11-3.27 (2 H, m); HPLC peak RT=11.0 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]=O)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)[CH:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:21]=[C:27]2/[C:26](=[O:28])[NH:25][C:24](=[O:29])[S:23]/2)=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:9]2)[CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2C=O)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cc(Cl)ccc2/C=C2\SC(=O)NC2=O)C1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A 100 mL round bottom flask was charged with a magnetic stir bar, (S)-tert-butyl 1-(5-chloro-2-formylphenyl)pyrrolidin-3-ylcarbamate (Method 78) (1.100 g, 3.39 mmol), thiazolidine-2,4-dione (0.397 g, 3.39 mmol), and ethanol (11.29 ml). Piperidine (0.034 mL, 0.34 mmol) was added and the reaction was heated to reflux for 2 h. Once the reaction was judged to be complete by LCMS, it was allowed to cool to ambient temperature and conc. in vacuo to afford the title compound (1.310 g, 91%) which was used in the next step without further purification; m/z 425.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1>O.C(O)C.[Na].[Hg]>[NH2:1][C:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc(-c2cc(N)nc3ccc(Cl)cc23)cc1
Agent: [Hg]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC1=Nc2ccc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
6.76 g of sodium amalgam were added over the course of one hour to a solution of 255 mg of 2-amino-6-chloro-4-(4-aminophenyl)quinoline in 3.4 ml of water and 22 ml of ethanol while stirring. The mixture was stirred overnight and decanted off from the Hg precipitate, and the solvent was removed by distillation under reduced pressure. After carrying out an MPLC column chromatography in a mixture of 10 parts by volume of ethyl acetate, 5 parts by volume of methanol, 5 parts by volume of n-heptane, 5 parts by volume of dichloromethane and 1 part by volume of ammonia (concentrated) and acidification with a little concentrated hydrochloric acid, the solvent was removed by distillation and the residue was induced to crystallize with a little ethyl acetate.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C[O:14][B:15](OC)[O:16]C.O>CCOCC>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([B:15]([OH:16])[OH:14])[CH:8]=1
Reactant: COB(OC)OC
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: OB(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To -78° C. cooled n-BuLi (61 ml; 2.5 M hexane solution) was added 3-bromopyridine (20.0 g), dissolved in Et2O (-78° C.) (100 ml) by cannula during 5 minutes. After 10 minutes, a precooled (-78° C.) solution of trimethyl-borate (17.1 g) in Et2O (80 ml) was added. The reaction mixture was stirred at -78° C. for 1 hour, warmed to room temperature during 1 hour, and stirred at room temperature for 1/2 hour. To the reaction mixture was added 20 ml water and stirring continued. The resulting solid percipitate was collected and the supernatent concentrated to a residue. To the residue was added ethyl alcohol (100 ml) and acetic acid (8 ml) followed by heating at reflux for 35 minutes, cooling to room temperature and concentrating to dryness to give a pale yellow foamy material. The crude product was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13]1.C(N(CC)CC)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:13]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: c1ccc(C2CCCNC2)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCCC(c3ccccn3)C2)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-6-chloronicotinic acid (1.6 g, 9.248 mmol) in N,N-dimethylformamide (41 mL) was added 2-(piperidin-3-yl)pyridine (1.82 g, 11.098 mmol) and triethylamine (25.455 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the residue was purified via column chromatography to afford 2-amino-6-(3-(pyridin-2-yl)piperidin-1-yl)nicotinic acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][C:24]=1[CH3:25])=[CH:16][CH:15]=3.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn(C(=O)C(C)(C)C)nc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.14 g (0.32 mmol) of compound from Example 53, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one is dissolved in 5 ml of pyridine. 0.2 ml (1.6 mmol) of pivaloyl chloride is added. The mixture is stirred at ambient temperature for 2 hours. The reaction medium is poured into water, and extracted with EtOAc. Washing with a saturated NaCl solution, drying over Na2SO4 and then adsorbing onto silica are performed. Purification is carried out by chromatography on a silica column, elution being carried out with a 75/25 EtOAc/cyclohexane mixture and then with pure EtOAc.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:13])[C:4]1=[O:14])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.COC(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:13][C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([N:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c(=O)c(C)nc2ccccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: CCn1c(=O)c(CBr)nc2ccccc21
Yield: 40.3 %

Procedure:
4,2 g (22,3 mM) of 1-ethyl-3-methyl-quinoxalin-2(1H)-one, 3.97 g (22,3 mM) of N-bromosuccinimide and 53,3 mg of benzoylperoxide in 220 ml of carbon tetrachloride were refluxed for 4 h. The reaction mixture was filtered and the solvent was removed under vacuum. The residue was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (70/30) as eluant to give a solid, which was taken up in methylterbutyloxide. After filtration, 2,4 g of 3-(bromomethyl)-1-ethyl-quinoxalin-2(1H)-one were obtained as a tan solid. Yield: 40,3%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1.Br[C:12]1C=C(C)C(I)=C(C)C=1.C[Si](C)(C)C=C>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:12])[C:5]([CH:8]=[CH2:9])=[C:4]([CH3:10])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1C
Reactant: Cc1cc(Br)cc(C)c1I
Agent: C=C[Si](C)(C)C
Product: C=Cc1c(C)cc(Br)cc1C
Yield: 94 %

Procedure:
Using a procedure analogous to that used to prepare 30A, 5-bromo-2-iodo-1,3-dimethylbenzene (15.6 g, 48 mmol) was reacted with trimethyl(vinyl)silane in a pressure vessel at 160° C. for 1 h to yield 32A (10.0 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.26 (s, 6 H) 5.24 (dd, J=17.86, 1.92 Hz, 1 H) 5.55 (dd, J=11.54, 2.20 Hz, 1 H) 7.18 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:40])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:40])[C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3,5-bis-trifluoromethyl-benzamide as prepared in the previous step, using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([O:11][C:21]([O:20][CH3:19])=[O:22])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: COC(=O)Cl
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 24 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 22 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1,3-bis (methoxycarbonyloxy)adamantane (yield 90%) was formed.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26]OS(C)(=O)=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CNc3ccccc3)cc(OC)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 20 mg (0.039 mmol) of methanesulfonic acid 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-ylmethyl ester in DMF is added aniline (excess) and the reaction is stirred for 1 h at 60° C. The reaction mixture is extracted with sat. NaHCO3/water. The organic layer is evaporated and the residue is purified via reversed phase RP18-chromatographie to give 3.3 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.S(Cl)([Cl:13])=O>ClC(Cl)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([Cl:13])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-chloro-pyridine-2-carboxylic acid (2.0 g, 12.8 mmol) in dichloroethane (43 mL) was added thionyl chloride (2.8 mL, 38.5 mmol) and DMF (2-3 drops). The suspension was warmed to 85° C. After 1 h, the resulting clear, yellow solution was cooled to rt and concentrated. The residue was dissolved in DCE and concentrated. This process was repeated two additional times to give a yellow liquid which crystallized upon standing to give a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:22][O+](C)C>>[CH3:22][O:16][C:14]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:15]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCC(CCCc2ccccc2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(CCCc2ccccc2)CCC1

Procedure:
The product of Example 99 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:11][CH3:12])[O:9][CH3:10])=[C:4]([F:13])[CH:3]=1.[O:14]1CCC[CH2:15]1.C([Li])CCC.CN(C)C=O>O>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[O:14])=[CH:3][C:4]=1[F:13]
Reactant: C1CCOC1
Reactant: COC(OC)c1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1ccc(C=O)cc1F
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of 4-bromo-1-dimethoxymethyl-2-fluorobenzene (4.53 g, 18.2 mmol) in 1 tetrahydrofuran (50 mL) were added n-butyllithium (1.6 mol/L in hexanes; 15 mL) and dimethylformamide (2.1 mL, 27 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted twice with ether. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6:1 Hexane/ethyl acetate) to afford 4-dimethoxymethyl-3-fluorobenzaldehyde (2.26 g, 63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C=O.[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][NH:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCCC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h

Procedure:
Tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (1.0 g, 4.38 mmol) was dissolved in DCM (40 ml) and treated with 36.5% formaldehyde solution (326 μl, 4.38 mmol) followed by acetic acid (1 drop). The reaction mixture was stirred for 20 mins and treated with sodium triacetoxyborohydride (93 mg, 0.438 mmol). The resulting mixture was stirred at ambient temperature for 16 hrs and quenched with 2M NaOH (40 ml). The mixture was extracted with DCM (2×100 ml) and the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give tert-butyl 4-(2-(methylamino)ethyl)piperidine-1-carboxylate as an oil;
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH:12]([Cl:14])[CH3:13]>C(O)C>[Cl:14][CH:12]([CH3:13])[CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: Oc1ccccc1Br
Reactant: CC(Cl)CBr
Agent: [Na]
Solvent: CCO
Product: CC(Cl)COc1ccccc1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hour, cooled to 0°, and treated, dropwise, with 157.5 g of 1-bromo-2-chloropropane. The last addition requires about 1 hour. The mixture is stirred at 0° for about 2 hours and slowly warmed to reflux during about 2 hours, heated under reflux for about 2 hours, filtered from the precipitated sodium bromide, and the filtrate is concentrated in vacuo at 40° to give about 240.2 g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[N:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:25])C=1.CO>C(Cl)(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([S:9]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc(Sc2cncc[n+]2[O-])s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=[N+]([O-])c1cnc(S(=O)c2cncc[n+]2[O-])s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of 1.0 g (0.004 mol) of Compound 2 in 50 ml of chloroform was gradually added 2.0 g (0.010 mol) of 85% m-chloroperbenzoic acid. The reaction mixture was stirred overnight at room temperature and then filtered. The filtrate was washed with water, dilute bicarbonate and brine, and dried over MgSO4. Evaporation of the solvent afforded a yellow oil that solidified on standing. This crude product was recrystallized from CHCl3 /hexane and a second crop of crystals was recrystallized from methanol for a total yield of 0.3 g (28% yield) of yellow crystals, m.p. 139°-141° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1>C(#N)C>[CH3:2][CH:1]([NH:4][C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([F:13])([F:12])[F:14])[N:10]=1)[CH3:3]
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: CC(C)N
Solvent: CC#N
Product: CCOC(=O)c1sc(NC(C)C)nc1C(F)(F)F
Yield: 42.2 %

Procedure:
By the procedure of Example 39, a stirred mixture of 10 ml acetonitrile, 2.28 g (38.6 mmol) of iso-propylamine, and 5 g (19.3 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 16 hours. The product was separated and then recrystallized in hexane to yield 2.30 g of a beige solid product (m.p.=94°-97° C.) identified in Table 1.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH:3]([CH2:4][CH3:5])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: CC/C=C/C(=O)OC
Product: CCC(CC(=O)OC)N1CCCC1
Temperature: 100 °C

Procedure:
A mixture of 171 g of methyl 2-trans-pentenoate and 106.5 g of pyrrolidine was heated for 20 hours at 100° C. After distillation over a Vigreux column, 198.7 g (72% of theory) of methyl 3-pyrrolidinovalerate of boiling point 65° C./0.4 mbar, nD20 =1.4580, were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO>[Pd].ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(N)ccc1OC
Reaction time: 17 h

Procedure:
Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol. Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a pressure apparatus at 50 psi. After 17 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give a residue. Combine the residue and dichloromethane and extract with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-aminobenzoate. Rf=0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental Analysis calculated for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.