Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:4])=[O:3].[OH:18]O>CS(O)(=O)=O>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][OH:18])=[O:16])(=[O:3])=[O:4]
Reactant: OO
Reactant: CS(=O)(=O)CCCCCCCCCCC(=O)O
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)CCCCCCCCCCC(=O)OO
Temperature: 40 °C

Procedure:
A stirred mixture of 3 g of 11-(methylsulfonyl)undecanoic acid and 30 mL of methanesulfonic acid was heated to approximately 40° C. The solid dissolved only partially in the methanesulfonic acid at this temperature. Then 1.29 g of 90% hydrogen peroxide was added dropwise. The temperature of the reaction mixture was reduced to room temperature after twenty minutes of reaction time. For the remainder of the two hour reaction time, the reaction mixture was not heated and became homogeneous. The reaction mixture was then cooled in an ice bath forming a solid which was then filtered from solution. The filtrate was poured onto ice prepared from distilled water. A solid formed which was filtered from solution. The two solids collected were combined and washed several times with cold deionized water until the filtrate was no longer strongly acidic. The solid was dried overnight on a watchglass, weighed 2.91 g and had 4.8% by weight active oxygen (84.1% of theoretical).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) in DMF (3 mL) were added benzyl bromide (39 mg, 0.23 mmol) followed by DIPEA (40 μL, 0.23 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel prep TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 8 mg of the title compound, m/z 531.6 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:11]=1
Reactant: Oc1ccccc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-fluoro-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-Fluoro-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:31][CH2:30][CH2:29][NH2:32])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Reactant: NCCN
Solvent: O
Product: NCCNc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Temperature: 160 °C

Procedure:
A mixture of 56.3 mg (0.150 mmol) of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1.0 ml (15.0 mmol) of 1,2-ethylenediamine was heated at 160° C. for 30 min. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water 3 times, brine, dried over MgSO4 and concentrated. The residue was heated in a mixture of 4 M of hydrogen chloride in 6 ml of dioxane and 2 ml of conc. hydrochloric acid at 60° C. for 18 hours. The mixture was concentrated in high vacuum and triturated with ethyl ether. The solid material was filtered out and washed with ethyl ether to give 143. Yield 37.5 mg (56%) over two steps. ESI MS m/z 332.1 (M+1). 1H NMR (400 MHz, DMSO): 14.27 (s, 1H), 9.57 (s, 1H), 9.30 (s, 1H), 9.19 (d, J=8.0 Hz, 1H), 9.11 (s, 1H), 8.90 (d, J=4.8 Hz, 1H), 8.23 (s, 3H), 8.11 (dd, J=7.9, 5.6 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 3.75 (t, J=6.0 Hz, 2H), 3.17 (dd, J=11.4, 5.7 Hz, 2H)
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:26])[CH3:27])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc(N)cc3)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a solution of potassium thiocyanate (8.09 g, 83.2 mmol) in acetic acid (150 ml) was added a solution of N-[3-(4-aminophenoxy)phenyl]-3-(1-cyano-1-methylethyl)benzamide (7.34 g, 19.8 mmol) in acetic acid (150 ml), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (4.0 g, 25.0 mmol) in acetic acid (100 mL) at room temperature over 30 min or longer and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and ethyl acetate (200 mL), and basified with 2N aqueous sodium hydroxide solution. The aqueous layer was separated and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (7.4 g, 87%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12](OCC)(=O)[CH2:13]C.[O-]CC.[Na+]>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:12][CH3:13])=[O:9])[CH:3]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: CCOC(=O)CC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of ethyl nicotinate (15.1 g, 0.1 mole), ethyl propionate (15.3 g, 0.15 mole) and sodium ethoxide (10.2 g, 0.15 mole) was stirred and heated under nitrogen at 100° C. for five hours. After cooling, the mixture was diluted with water (150 ml) extracted with diethyl ether (50 ml) and the aqueous layer made acidic to pH 1 with concentrated hydrochloric acid (50 ml). The aqueous layer was heated at 90° C. for two hours, cooled, made alkaline with solid potassium carbonate and extracted with diethyl ether (3×75 ml). The dried (magnesium sulphate) organic layer was concentrated and distilled to give ethyl 3-pyridyl ketone (b.pt 97°-99°/14 mm Hg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([CH3:27])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Li+].Cl>C1COCC1.O>[F:29][C:2]([F:1])([F:28])[CH:3]([CH3:27])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(C(=O)O)c1ccc(CN2Cc3ccccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 270 mg (0.66 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-{4-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}butanoate were dissolved in 1 ml each of THF, methanol and water, and 69.9 mg (1.66 mmol) of lithium hydroxide were added. The mixture was stirred at RT overnight. The reaction mixture was diluted with water and acidified with 1 N hydrochloric acid, and the resulting precipitate was filtered off with suction. The solid was washed with water until the washings remained neutral. This gave 222 mg (88.3% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13](F)[C:12]=1[F:20])[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:5])[CH3:4].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[OH:37])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[O:37][C:13]1[C:12]([F:20])=[C:11]([N:2]([CH3:1])[C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:4])[CH3:5])[C:16]([F:17])=[C:15]([F:18])[N:14]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CCOC(=O)C(C)(C)N(C)c1c(F)c(F)nc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)N(C)c1c(F)c(F)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1F
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 4-[N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino]-2,3,5,6-tetrafluoropyridine (2.2 g, 6.6 mmol) in acetonitrile (60 mL) was added 2-benzyloxy-5-cyanophenol (1.5 g, 6.6 mmol) and cesium carbonate (2.8 g, 8.6 mmol). The resultant mixture was stirred at 40° C. for 2 days. The mixture was then cooled to ambient temperature and poured into 200 mL of 0.5 M aqueous KOH solution and 200 mL of ethyl acetate. The aqueous layer was separated and extracted with another 100 mL of ethyl acetate. The combined organic extracts were washed with 0.5 M aqueous KOH solution (200 mL) then brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil which solidified upon standing. Recrystallization from 30% ethyl acetate/hexanes afforded 2.4 g (68% yield) of 4-benzyloxy-3-[(4-(N-methyl-N-(1-ethoxycarbonyl-1-methylethyl)amino)-3,5,6-trifluoropyridin-2-yl)oxy]benzonitrile as a white, crystalline solid: NMR (CDCl3) 7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (q, 2), 3.1 (s, 3), 1.6 (s, 6), 1.3 (t, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1
Reactant: CI
Reactant: CC1(F)CN(C2CCCCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-9-cyclohexyl-7-fluoro-7-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (313 mg, 2.85 mmol) in 10 mL of DMA was added sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) at 0° C., followed by the dropwise addition of methyl iodide (0.07 mL, 1.1 mmol). The reaction mixture was warmed up to rt and stirred for 1 h. The whole was poured into ice-water, extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. The solution was concentrated in vacuo and used for next step reaction (330 mg). [M+H] calc'd for C15H20ClFN4O, 327. found 327.
Reaction SMILES: [CH:1]([Si:4]([SH:11])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[H-].[K+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1.C(OCC)(=O)C>O1CCCC1.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH:1]([Si:4]([S:11][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)([CH:5]([CH3:7])[CH3:6])[CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [Pd]
Agent: [H-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1ccc(CO)cc1)(C(C)C)C(C)C

Procedure:
A solution of triisopropylsilyl thiol (1.904 g, 10.0 mmol) in tetrahydrofuran (10 mL) was added to a stirred suspension of potassium hydride in tetrahydrofuran (10 mL). The resulting suspension was then added to a stirred solution of 4-bromobenzyl alcohol (1.87 g, 10 mmol) and tetrakis[triphenylphosphine]palladium(0) (0.350 g, 0.30 mmol) in benzene (25 mL). The reaction mixture was stirred at reflux for 2 h under a nitrogen atmosphere. Ethyl acetate (200 mL) was added and the solution washed with water. The organic phase was dried with magnesium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel chromatography using a gradient of 0% to 2% ethyl acetate in dichloromethane to yield (4-triisopropylsilanylsulfanyl-phenyl)-methanol as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[NH2:10][C@H](C(O)=O)CC(=O)N>>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:10].[NH4+:1]
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: N[C@@H](CC(=O)[O-])C(=O)[O-]
Product: [NH4+]
Temperature: 180 °C

Procedure:
The IR spectrum of the product obtained after heating at 180° C. for three hours showed the peaks associated with polymers of aspartate, e.g. at 1391 (carboxylate), 1533 and 1589 (primary amide doublet), and 3300 cm−1 (carboxylate), as well as signals characteristic of asparagine residues, at 1648 cm−1 and 3072 cm−1 (side chain of the —CONH2 R-group) (3300 s, 3072 m, 1648 s, 1589 s, 1533 s, 1391. s, 1196 w). After heating at 220° C. for 4.5 hours, the imide signal at 1704 cm−1 began to emerge, as a result of ammonium aspartate residues being converted to succinimides (3292 s, 3057 w, 2933 w, 1704 sh, 1651 s, 1585 s, 1392 m, 1290 w, 1197 w). After heating at 220° C. for 10 hours, the imide signal at 1704 cm−1. became prominent (FIG. 6) (3300 s, 1704 s, 1664 m, 1530 s, 1383 m, 1355 m, 1296 w, 1194 m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([N:7]1[CH2:9][CH2:8]1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CO.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>CC(=O)C.C1C=CC=CC=1>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[O:29]=[C:21]1[N:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:8][CH2:9][NH:7][C:5](=[O:6])[C:4]3[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=3[O:2][CH3:1])[CH2:19][CH2:18]2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22]1
Reactant: COc1ccccc1C(=O)N1CC1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Solvent: c1ccccc1
Product: COc1ccccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 1.75 parts of 1-(2-methoxy-benzoyl)aziridine, 2.18 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 1.6 parts of methanol and 10.8 parts of benzene is stirred and refluxed for 1.50 hours. The reaction mixture is cooled. After the addition of 2-propanone, the whole is acidified with ethanedioic acid. The formed ethanedioate salt is filtered off and crystallized from ethanol 70%, yielding 2.9 parts of N-{2-[4-(2,3-dihydro-2-oxo-1 H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-methoxybenzamide ethanedioate; mp. 217.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:32][CH2:31][C:28]2[CH:27]=[C:26]([C:25]([F:34])([F:33])[F:24])[O:30][N:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)on1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN 1018782-82-5) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BF) as starting materials; MS: 478.0 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH:43][CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)=[O:33])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:18])=[O:19])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1OC
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)cc1OC
Yield: 74 %

Procedure:
Method E. Reaction of oxalyl chloride (92 λL, 1.06 mmol) and benzoic acid 41 (294 mg, 0.70 mmol) with subsequent coupling to 3-pyridinylmethylamine (78 λL, 0.77 mmol) gave benzamide 42 (263 mg, 74%) as a white powder: mp (EtOAc) 104-108° C.; 1H NMR δ 9.23 (t, J=5.9 Hz, 1 H, CONH), 8.57 (d, J=1.6Hz, 1 H, H-2′), 8.46 (dd, J=4.7, 1.5Hz, 1 H, H-6′), 8.01 (d, J=8.5Hz, 2 H, H-2, H-6), 7.92 (d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.5Hz, 1 H, H-4′), 7.37 (dd, J=7.5, 4.8Hz, 1 H, H-5′), 7.33 (dd, J=8.5, 2.1Hz, 1 H, H-6″), 7.25 (d, J=2.1Hz, 1 H, H-2″), 7.14 (d, J=8.5Hz, 1 H, H-5″), 4.63 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 3.84 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 2.15 (s, 3 H, CH3); 13C NMR δ 165.5, 157.9, 153.1, 149.9, 148.8, 148.6, 148.0, 135.3, 135.1, 134.8, 129.7, 128.8, 128.0 (2), 126.2, 125.3 (2), 123.4, 122.2, 111.2, 110.6, 55.9, 55.7, 52.9, 40.4, 9.6; MS m/z 508.7 (MH+, 100%). Anal. calcd for C26H25N3O6S.¾CH3OH: C, 60.44, 5.31; N, 7.90. Found: C, 60.58; H, 5.17; N, 7.63%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[C:8]([O:12][C:13](=[O:20])[NH:14][C:15]([CH3:19])([CH3:18])[CH:16]=O)([CH3:11])([CH3:10])[CH3:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCN(CC)CC>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][CH2:19][C:15]([NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:20])([CH3:16])[CH3:18]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNCC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
Amino-acetic acid methyl ester hydrochloride (80.6 g) and Et3N (160 mL) were dissolved in DCM (1000 mL) and stirred for 15 min to liberate the amine from the salt. Then a solution of 1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (compound M; 29.0 g) in DCM (600 mL) was added. The resulting mixture was stirred for 0.5 hour at ambient temperature before NaBH(OAc)3 (102 g) was added and the mixture was stirred at ambient temperature overnight. Sat. aqueous NaHCO3 was added. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford (2-tert-butoxycarbonylamino-2-methyl-propylamino)-acetic acid methyl ester (compound N; 26.5 g) as white solid which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:37])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC(NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of (1R,2S,SR)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate (460 mg, 1.0 mol) (from Example 12b, Step 6 above) in CH2Cl2 was treated with a solution of 37% aq formaldehyde (1 ml) and NaBH(OAc)3 (436 mg, 2.0 mol) and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 330 mg (70%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate. MS found: (M+H)+=460.49
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[N:27]=[C:28]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][N:45]([CH:48]5[CH2:51][O:50][CH2:49]5)[CH2:44][CH2:43]4)=[CH:38][N:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)[C:5]([CH2:22]C(=O)C)=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.[OH2:52].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2[N:27]=[C:28]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][N:45]([CH:48]5[CH2:49][O:50][CH2:51]5)[CH2:44][CH2:43]4)=[CH:38][N:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)[C:5]([CH2:22][OH:52])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: O
Reactant: CC(=O)Cc1c(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cn4ccnc4c(Nc4ccc(N5CCN(C6COC6)CC5)cn4)n2)c1CO)CCCC3
Yield: 52 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 107a (150 mg, 0.21 mol) in THF/iPA/H2O (5 mL/5 mL/2 mL) and LiOH (85 mg, 3.5 mmol) while stirring. This mixture was stirred at 50° C. for 0.5 h. Then 20 mL H2O was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 107 as a white solid (74 mg, 52% yield). LCMS: [M+H]+ 664.3. 1H NMR (500 MHz, DMSO) δ 9.06 (s, 1H), 8.41 (s, 1H), 8.13-8.10 (m, 2H), 7.98 (d, J=2.5, 1H), 7.71 (s, 1H), 7.48-7.44 (m, 2H), 7.39-7.36 (m, 1H), 6.54 (s, 1H), 5.38 (m, 1H), 4.57-4.35 (m, 6H), 4.18-4.13 (m, 4H), 3.44-3.42 (m, 1H), 3.15 (s, 4H), 2.59 (d, J=3.0, 2H), 2.47-2.40 (m, 6H), 1.79-1.69 (m, 4H)