Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([C:43]1[CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:47][C:48]=1OC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:60]([O-:63])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][C:23]=2[CH2:32][CH:33]([CH3:35])[CH3:34])[CH:11]=[CH:12][C:13]=1[C:47]1[CH:46]=[CH:45][C:44]([O:63][CH3:60])=[C:43]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:48]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2Cc2ccccc2)cc1Cc1ccccc1
Temperature: 80 °C
Yield: 91 %

Procedure:
167.7 mg (0.33 mmol) 4′-(2-Cyanoethyl)-3-benzyl-2′-isobutyl-1,1′-biphenyl-4-yl-trifluoromethanesulfonate (26), 158.7 mg (0.49 mmol, 1.5 eqv) 2-(3-Benzyl-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (23) and 58.8 mg (50.9 pmol, 0.15 eqv) Pd(Ph3P)4 were dissolved in 10 ml DME/EtOH (9+1). 0.33 ml (0.66 mmol, 2 eqv) of a 2 M aq. Na2CO3-solution was added to this yellow solution and the resulting mixture was heated at 80° C. for 8 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (3+1)) yielded 165.6 mg (0.30 mmol, 91%) (27) as a clear oil: Rf (Hexanes/EtOAc (3+1)) 0.30; 1H NMR (500 MHz, CDCl3) δ 0.69 (d, 6H, J=6.62 Hz), 1.63 (m, 1H), 2.43 (d, 2H, J=7.41 Hz), 2.61 (t, 2H, J=7.57 Hz), 2.93 (t, 2H, J=7.57 Hz), 3.82 (s, 3H), 3.93 (s, 4H), 6.85 (d, 1H, J=8.36 Hz), 6.94 (m, 2H), 7.02-7.22 (m, 16H); LRMS (EI) m/z 549 (3), 501 (2), 446 (11), 383 (5), 335 (6), 293 (9), 256 (14), 215 (16), 214 (100), 199 (16), 160 (49), 91 (47); HRMS (EI) Calcd. for C40H39NO: 549.303164. Found: 549.302298.
Reaction SMILES: [BrH:1].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8]O>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8][Br:1]
Reactant: Br
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (ice-water bath) mixture of 30% HBr in acetic acid (3 ml) was added 2.5 g 5-methyl-2-nitrobenzyl alcohol and the chilled solution stirred for 2 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with H2O, brine and the solvent removed under vacuum to give a mixture of product (50%) and starting material (50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16]>O1CCCC1.O>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22])([O-:17])=[O:16]
Reactant: Nc1cccnc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1cccc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 99.1 %

Procedure:
A solution of 3-aminopyridine (2 g, 20 mmol) in tetrahydrofuran (100 ml) was treated at 0° C. with triethylamine (3 ml, 2.2 g, 22 mmol) and then a solution of 3-nitrobenzoyl chloride (3.7 g, 20 mmol) in tetahydrofuran (50 ml). After 0.5 h the reaction mixture was diluted with water (400 ml) and set aside in the fridge for 3 days. Filtration and drying afforded the title compound as a purple crystalline solid (4.82 g, 99%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([O:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 100 mg (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.N1CCC[CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[CH2:6][CH2:7][CH2:28][CH2:4]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Reactant: C1CCNC1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCCC2)s1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (0.1 g, 0.2 mmol, Example 18B) and pyrrolidine (1.2 equivalents) in anhydrous acetonitrile (3 mL) was added Hunig's base (33 mg, 1.2 equivalents), and the resultant solution was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (25 mL) and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was chromatographed over silica using dichloromethane to give the title compound.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[Br-:15].[C:1]([C:5]1[S:9][C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[N+:7]([CH2:16][CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)/C=N/c1nnc(C(C)(C)C)s1
Reactant: CCCCBr
Solvent: Cc1ccccc1
Product: CCCC[n+]1nc(C(C)(C)C)sc1/N=C/N(C)C
Product: [Br-]
Temperature: 100 °C

Procedure:
To a suspension of Example 162A (1.00 g, 4.71 mmol) in toluene (10 mL) was added 1-bromobutane (0.56 mL, 5.18 mmol). The mixture was heated at 100° C. for 12 hours, then cooled to ambient temperature and diluted with hexanes. The solid was collected by filtration (heaxane wash) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.5 Hz, 3H), 1.23-1.36 (m, 2H), 1.39 (s, 9H), 1.70-1.84 (m, 2H), 3.22 (s, 6H), 4.29 (t, J=7.1 Hz, 2H), 8.54 (s, 1H).
Reaction SMILES: ON=[C:3]([C:8]1[CH:9]=[N:10][S:11][CH:12]=1)[C:4]([O:6]C)=[O:5].C=[O:14].Cl>O>[S:11]1[CH:12]=[C:8]([C:3](=[O:14])[C:4]([OH:6])=[O:5])[CH:9]=[N:10]1
Reactant: C=O
Reactant: COC(=O)C(=NO)c1cnsc1
Agent: Cl
Solvent: O
Product: O=C(O)C(=O)c1cnsc1
Reaction time: 7 h

Procedure:
A mixture of methyl 2-hydroxyimino-2-(isothiazol-4-yl)-acetate (anti isomer) (3.41 g.), 36% aqueous solution of formaldehyde (24 ml.), conc. hydrochloric acid (12 ml.) and water (24 ml.) was stirred for 7 hours at 90° to 100° C. The reaction mixture was allowed to stand overnight in a refrigerator to precipitate crystals. The crystals were collected by filtration, washed with a small amount of ice-water and then dried to give 2-(isothiazol-4-yl)glyoxylic acid (2.09 g.). The mother liquor was extracted with ethyl acetate to give the same compound (0.34 g.), mp 145° to 148° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C:3]2([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C=C1CCC(CO)(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C1CCC(CO)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound 100b (0.25 g, 1.6 mmol) and pyridine (0.40 mL) in dichloromethane was added at 0° C. a solution of para-toluenesulphonyl chloride (0.336 g, 1.76 mmol) in 1 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 30 min., then at r.t. for 3.5 h. Dilution with dichloromethane, washing with 1M aqueous NaHSO4 and brine, drying with Na2SO4, afforded, after evaporation, a crude which was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Dichloromethane-Methanol from 1:0 to 95:5) to give the title
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1.[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1>[N:19]1([CH2:18][CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=5)=[CH:3][C:4]4=[O:24])=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1cc(O)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 65 °C
Yield: 13.5 %

Procedure:
To a solution of 4-hydroxy-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (100 mg, 0.308 mmol) in THF was added NaH (25 mg, 0.62 mmol) followed by 4-(trifluoromethyl)benzyl bromide (88 mg, 0.37 mmol). After heating at 65° C. overnight, the reaction mixture was cooled down, filtered through a thin layer of Celite, washed with CH2Cl2, and the filtrate was concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 90:10) gave 1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridine-2(1H)-one (20 mg, 13%) as a white solid. According to the procedure of Example 1, the HCl salt was made to give the title compound as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.12 (m, 1H), 7.80-7.67 (m, 6H), 7.62 (d, J=7.5 Hz, 1H), 7.34 (m, 1H), 6.13 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.27 (s, 2H), 4.58-4.54 (m, 2H), 2.89 (m, 2H), 2.52-2.42 (m, 4H), 1.73-1.64 (m, 4H); ESI MS m/z 483 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:8](CC2C=CC(OC)=CC=2OC)[C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P(O)([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:1][O:2][C:3]([C@H:5]1[NH:8][C:7](=[O:20])[C@H:6]1[NH:21][C:22](=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1

Procedure:
A mixture of 412 mg of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, 810 mg of potassium persulfate and 261 mg of dipotassium phosphate in 20 ml of acetonitrile and 20 ml of water is heated under reflux for one hour. The reaction mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate, and washed successively with an aqueous 5% sodium hydrogen carbonate solution and an aqueous sodium chloride solution, and dried over magnesium sulfate, and the solvent is then distilled off in vacuo. Ethyl acetate is added to the residue and the precipitated crystals are collected by filtration to give cis-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 176°-180° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30]Br)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][O:10][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=Cc1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(I)cc2C=O)CC1
Temperature: 60 °C
Yield: 63 %

Procedure:
To a solution of 5-iodosalicylaldehyde (2 g, 8.2 mmol) (Aldrich) in N,N-dimethylformamide (20 mL) was added anhydrous K2CO3 (1.15 g, 8.2 mmol), and 4-bromomethyl-piperidine -1-carboxylic acid tert-butyl ester (2.3 g, 8.2 mmol, Pharmacore). The reaction mixture was heated at 60° C. for 18 h. The crude was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, concentrated to give 4-(2-formyl-4-iodo-phenoxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (Yield 2.3 g, 63%).
Reaction SMILES: [CH2:1]([Sn:11](Cl)([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[S-:33][C:34]#[N:35].[K+].C1C=CC=CC=1>O>[CH2:1]([Sn:11]([N:35]=[C:34]=[S:33])([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C[Sn](Cl)(CC(C)(C)c1ccccc1)c1ccccc1C(F)(F)F)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(N=C=S)c1ccccc1C(F)(F)F)c1ccccc1
Yield: 96.2 %

Procedure:
Dineophyl-orthotrifluoromethylphenyltin chloride (6 g, 10.6 mmol) prepared in Example 5, potassium thiocyanate (1.5 g, 15.9 mmol), benzene (40 g) and water (10 g) were charged into a flask and the mixture was refluxed for 2 hours. The aqueous layer was removed and the organic layer was washed with water and filtered. Evaporation of the benzene under reduced pressure gave 6.0 g of dineophyl-orthotrifluoromethylphenyltin isothiocyanate as a colorless viscous liquid.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CCN=C=NCCCN(C)C.[C:19]([OH:31])(=O)[CH2:20][NH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].C(OC([N:39]1[CH2:42][CH:41]([NH2:43])[CH2:40]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:39]1[CH2:42][CH:41]([NH:43][C:19]([CH2:20][NH:21][C:22](=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:31])[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccccc1)NC1CNC1

Procedure:
The title compound was prepared as a TFA salt from the EDCI coupling of hippuric acid (Fluka) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharm) followed by the de-protection of N-Boc by TFA using the procedures described in Example 1, steps D and E.
Reaction SMILES: [OH-:1].[Na+].[NH2:3]O.Cl.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O>O.C(O)C>[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1/[CH:11]=[N:3]/[OH:1]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C/c1ccccc1OC(F)(F)F

Procedure:
To a solution of sodium hydroxide (7 g, 175.00 mmol, 1.19 equiv) in water (120 mL) was added a stirred solution of NH2OH.HCl (11.8 g, 169.78 mmol, 1.15 equiv) in water (120 mL) at 0°C. The resulting solution was stirred fo(10 min at 0°C. Then a solution of 2-(trifluoromethoxy)benzaldehyde (28 g, 147.29 mmol, 1.00 equiv) in ethanol (120 mL) was added. The resulting solution was allowed to stir for an additional 1 h at room temperature. The resulting solution was diluted with 500 ml of H2O, extracted with 2×700 mL of ethyl acetate and the organic layers were combined, washed with 2×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give (E)-2-(trifluoromethoxy)benzaldehyde oxime as an off-white crystalline solid.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1)[CH:9]=O.[C:20]([CH2:22]P(=O)(OCC)OCC)#[N:21].C(OCC)(=O)C>C1COCC1.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:22]/[C:20]#[N:21])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C/C#N)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A lithium hydroxide monohydrate powder (2.23 g) was added to a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (10 g) and diethyl cyanomethylphosphonate (8.2 g) in THF (50 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for one hour. Ethyl acetate (200 mL) and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered through a silica gel pad (carrier: Chromatorex™ NH). The filtrate was concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate and hexane, and the crystals were collected by filtration. The resulting crystals were dried under reduced pressure to obtain 7.49 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH2:19][C:20]1[C:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])=[CH:24][CH:23]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]2)[N:21]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:19][C:20]1[N:21]=[C:22]([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:34]2)[CH:23]=[CH:24][C:25]=1[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
29.5 mg (0.1 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 30 mg (0.1 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.09 ml (0.52 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 35 mg (63% of theory) of the product were obtained in solid form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=1)=[O:20].C(=O)(O)[O-].[K+].[I-].[K+]>C(O)CCC.C(OCC)(=O)C>[ClH:16].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:25][CH:26]=3)=[O:20])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CCCl)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)CCN2CCC(C(=O)c3ccc(F)cc3)CC2)cc1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of 4-fluorophenyl-4-piperidinyl methanone (3.30 g, 15.9 mmol) and N-[4-(3-chloro-1-oxopropyl)phenyl]methanesulfonamide was prepared in n-butanol (100 mL), treated with potassium bicarbonate (1.60 g, 1.6.0 mmol) and a catalytic amount of potassium iodide and refluxed for 18 hours. The mixture was cooled to room temperature and evaporated at reduced pressure onto neutral alumina. The resulting solid was put on top of a column of silica gel and eluted with acetone. The appropriate fractions were combined and evaporated to afford an orange oil. The oil was dissolved in ethyl acetate, dried (MgSO4), filtered, and treated with a slight excess of HCl in EtOAc. The resulting solid was filtered and recrystallized from methanol to yield the desired product as tan crystals: mp 230°-236° C. (decomp.).
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)=[CH:25]1)[CH2:10][C:9]([OH:41])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(C)(C)C
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(C)(C)C
Yield: 32 %

Procedure:
According to the procedure described in Example 1(a), N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed in MeOH after 20 hours. Purification via flash column chromatography with 1% HOAc/10% MeOH/CHCl3 as eluant and azeotrope with n-heptane furnished 24 mg (32%) of N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamic acid as yellow crystals. 1H NMR (CD3OD): δ 8.54 (d, 2H, J=5.6 Hz), 7.99 (bd, 1H, J=4.4 Hz), 7.80-7.59 (m, 6H), 7.34 (t, 1H, J=1.9 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.55 (dd, 1H, J=1.9, 2.8 Hz), 5.28 (t, 1H, J=7.2 Hz), 4.17 (s, 1H), 3.23 (dd, 1H, J=7.5, 16.7 Hz), 3.01 (dd, 1H, J=7.2, 16.7 Hz), 2.66 (d, 3H, J=3.5 Hz), 0.95 (s, 9H). IR(KBr): 3422, 1654, 1598, 1562, 1535 cm−1. HRFABMS: Calculated for C26H31N4O4(M+H+): 463.2345. Found: 463.2356. Anal. Calculated for C26H30N4O4•1.15 H2O•0.1 CHCl3: C, 63.30; H, 6.59; N, I 1.31. Found: C, 63.28; H, 6.58; N, 11.08.