Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>CN(C=O)C>[OH:3][C@@H:2]([CH3:4])[C:1]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:5]
Reactant: CC(O)C(=O)[O-]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 60 %

Procedure:
A mixture of sodium lactate (1.7 g, 15.0 mmole), diphenyl phosphorylazide (3.6 ml, 16.5 mmole) and dry DMF (30 ml) at 0° C. (ice bath) in an argon atmosphere was treated with triethyl amine (2.1 ml, 15.2 mmole) and L-proline, phenylmethyl ester, hydrochloride salt (3.6 g, 15.0 mmole). After 24 hours, the reaction mixture was partitioned between EtOAc and H2O. The aqueous phase was back extracted, the organic extracts combined, washed with 5% KHSO4, brine, and evaporated. The residue (5.0 g) was chromatographed on silica (130 g) eluting the EtOAc/Hexane (1:1) to give the title compound (2.5 g, 9.0 mmole, 60% yield) as a white crystalline solid after evaporation, m.p. 86°-88° C.
Reaction SMILES: C(#N)C.[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]2=[N:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:25]([F:28])([F:27])[F:26])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[CH:15][N:9]2[N:8]=1)[CH3:5].[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(N(CC)CC)C>[C:29]([NH:33][C:21](=[O:22])[C:20]1[CH:24]=[C:16]([C:14]2[N:13]=[C:10]3[N:9]([CH:15]=2)[N:8]=[C:7]([O:6][CH2:4][CH3:5])[CH:12]=[CH:11]3)[CH:17]=[CH:18][C:19]=1[C:25]([F:27])([F:28])[F:26])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C(=O)O)c3)cn2n1
Reactant: CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C(=O)NC(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 28 %

Procedure:
An 8 mL vial is charged with acetonitrile (0.5 mL), 5-(6-ethoxyimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)benzoic acid (0.035 g, 0.0001 mol), tert-butylamine (0.016 mL), triethylamine (0.055 mL), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.088 g). The mixture is stirred and heated at 80° C. for 16 hr, cooled, concentrated onto celite and purified by silica (0-100% EtOAc in Hexanes) to give the title compound (0.011 g, 28% yield). LCMS m/z=407.5 [M+H]+, tR=2.74 min. (compound same as Example 211)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C1C=CC(N2C(C)=CN=C2)=C(C=1)C#N>>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]([N:18]2[CH:19]=[C:15]([CH3:14])[N:16]=[CH:17]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Cc1c[nH]cn1
Agent: Cc1cncn1-c1ccc(C(F)(F)F)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-5-(trifluoromethyl)-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 16 h at 90° C. After aqueous workup and extraction with Ethyl acetate, the organic phase was dried (Na2SO4) and concentrated to furnish a 3.4:1 mixture of the title compound and its regioisomer [5-trifluoromethyl-2-(5-methyl-imidazol-1-yl)-benzonitrile] as a light brown oil (yield: 85%). MS: m/e=252.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Temperature: -75 °C
Reaction time: 4 h

Procedure:
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5 g) in THF (75 ml) was cooled to 0° C. and sodium hydride (60%, 1.23 g) added portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) added over 25 minutes maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added to the reaction over 10 minutes and the reaction stirred at −70° C. for 4 hours. The reaction was quenched with water (20 ml) and the mixture allowed to warm to 5° C. The reaction was concentrated under vacuum and the residue partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in DCM/ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate/DCM gradient (5-100% ethyl acetate) and then methanol. The product fractions were combined and the solvent evaporated under vacuum to give {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid. LCMS MH+ 238, retention time 2.19 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:16]
Reactant: COc1ccc(N)c(CO)c1
Reactant: CNC1CCCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and N-methyl-cyclohexylamine analogous to Example 1. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride): 3240 cm-1NH2 ; 3400 cm-1NH2 ; 2780 cm-1N-methyl; 2830 cm-1OCH3 ; 2850 cm-1 aliphatic hydrocarbon; 2930 cm-1 aliphatic hydrocarbon; 1500 cm-1C=C; 1510 cm-1C=C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:30][C:31]1[N:32]=[CH:33][O:34][C:35]=1[C:36](Cl)=[O:37]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([C:35]3[O:34][CH:33]=[N:32][C:31]=3[CH3:30])=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ncoc1C(=O)Cl
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ncoc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.90 g, 5.9 mmol) in CH3CN (25 ml), were added triethyl amine (2.05 mL, 14.7 mmol) and 4-methyl-oxazole-5-carbonyl-chloride (0.85 g, 5.9 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH3CN (20 mL), water (2×20 mL) and EtOAc (20 mL) to afford 4-methyl-oxazole-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (1.82 g, 78%): mp, 308-310° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.49 (98%); 1H NMR (DMSO-d6): δ 2.06-2.10 (m, 1H), 2.38 (s, 3H), 2.59-2.64 (m, 2H), 2.85-2.97 (m, 1H), 4.88 (d, J=5.9 Hz, 2H), 5.17 (dd, J=6, 12 Hz, 1H), 7.70-8.47 (m, 4H), 9.05 (t, J=5.9 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 12.52, 21.96, 30.92, 37.57, 48.86, 121.91, 127.09, 131.51, 133.01, 134.81, 138.86, 138.89, 140.67, 151.42, 157.96, 166.94, 167.51, 169.82, 172.74. Anal Calcd for C19H16N4O6: C, 57.58; H, 4.07; N, 14.14. Found: C, 57.48; H, 4.04; N, 14.33.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([S:12][C:13]#N)[CH:11]=1)=[O:6].BrC[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)(C)C>[CH2:13]([S:12][C:10]1[CH:11]=[C:7]([C:5]([O:4][CH3:3])=[O:6])[NH:8][CH:9]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(SC#N)c[nH]1
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cc(SCCc2ccccc2)c[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (88.0 mg, 2.20 mmol) in degassed H2O (0.500 mL) was added to a mixture of 2-methoxycarbonyl-4-thiocyanopyrrole (0.200 g, 1.10 mmol), prepared according to the procedure described in J. Chem. Soc. Perkin Trans. 2 1990, 699, and (2-bromoethyl)benzene (0.165 mL, 1.21 mmol) in degassed t-BuOH (2.0 mL). The reaction mixture was stirred at 60° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×25 mL), dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel with MeOH and CH2Cl2 (0-10% gradient) as the mobile phases to afford 0.247 g of the title compound as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 2.83-2.88 (m, 2H), 2.89-2.95 (m, 2H), 3.87 (s, 3H), 6.94-6.97 (m, 1H), 7.00 (dd, J=2.7, 1.6 Hz, 1H), 7.14-7.22 (m, 3H), 7.26-7.30 (m, 2H), 9.30 (br. s., 1H); HPLC a) column: Phenomenex Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.561 min retention time, (>95%); HPLC b) column: Phenomenex Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.535 min retention time; MS (ES) 262 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>COC1C=CC([Mg]Br)=CC=1C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:6]3[CH:15]=[CH:14][C:30]([O:29][CH3:28])=[C:26]([CH3:27])[CH:4]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Agent: COc1ccc([Mg]Br)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 1.3 mL 0.5M 4-methoxy-3-methylphenylmagnesium bromide. Yield: 102 mg of a white solid. LC-MSD, m/z for C24H19BrN2O3 [M+H]+=463.0, 465.0; HPLC retention time: 2.5 min.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2O)[N:31]=1>>[CH3:29][C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:16][CH2:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)=[CH:37][CH:36]=2)[N:31]=1
Reactant: Cc1nc(-c2ccccc2O)no1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: Cc1nc(-c2ccc(OCCCc3c[nH]cn3)cc2)no1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (5-methyl-1,2,4-oxadiazol-3-yl)phenol (prepared according to Swain, C. J. et al. J. Med. Chem. 1991, 34, 140) are treated as described in Example 56, but isolated in the form of the free base.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:21]O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:21])=[S:12])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: OC(=S)c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=S)c1ccc(-c2ccccc2)cc1
Reaction time: 10 h

Procedure:
A mixture of 4-phenylthiobenzoic acid (26.29 g), conc. sulfuric acid (5 ml) and methanol (400 ml) is refluxed with stirring for 10 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, and to the residue is added ethyl acetate (400 ml). The mixture is washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 4-phenylthiobenzoate (27.44 g).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH2:20].C(Cl)(Cl)Cl.Cl>C(O)C.C(OCC)C>[ClH:1].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH:20][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: COc1ccccc1C(O)CCl
Reactant: COc1ccc(CCN)cc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNCC(O)c2ccccc2OC)cc1OC
Yield: 41.1 %

Procedure:
A mixture of 3.7 g of α-chloromethyl-2-methoxybenzylalcohol (crude oil) and 10.9 g of 3,4-dimethoxyphenethylamine is heated at 130° to 140° C. for 2 hours. After cooling, chloroform is added to the reaction mixture, and said mixture is washed with water. The mixture is dried and evaporated to remove solvent. 30 ml of ethanol are added to the residue obtained. Then, hydrochloric acid-containing diethylether is added to the ethanol mixture, and crystalline precipitates are collected by filtration. 3.0 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-methoxybenzylalcohol hydrochloride are obtained as crystals. M.p. 142°-143° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.C1(=[O:15])CCCCC1.OOS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+]>O.C1COCC1>[Cl:1][C:2]1[N+:7]([O-:15])=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cl)[n+]1[O-]
Reaction time: 24 h

Procedure:
To a solution of 6-chloro-2-methylpyridine (49.04 g; 384 mmol) in 500 mL pH 8 buffer and 300 mL THF was added cyclohexanone (3.77 g; 38.4 mmol) and Oxone® (potassium peroxymonosulfate) (236.3 g; 384 mmol). After stirring for three days an additional portion of Oxone® (236.3 g; 384 mmol) was added and the reaction was stirred for 24 hours. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated. The 6-chloro-2-methylpyridine-N-oxide was used with no further purification.
Reaction SMILES: [ClH:1].Cl.[NH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.[F:19][C:20]([F:53])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=O)[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]>ClCCl>[ClH:1].[ClH:1].[F:53][C:20]([F:19])([F:52])[C:21]1[CH:22]=[C:23]([CH:45]=[C:46]([C:48]([F:49])([F:50])[F:51])[CH:47]=1)[C:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH:34]=[N:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]2([CH3:11])[CH3:10])[CH2:28][C@H:27]1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([CH3:44])[CH:38]=1)=[O:25]
Reactant: Cc1ccc(C[C@@H]2CN(CCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC1(C)COCCN1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CCC=NN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
To a stirred mixture of 4-amino-3,3-dimethylmorpholine dihydrochloride (122 mg) in dichloromethane (5 ml) was added triethylamine (61 mg) at ice bath temperature. A solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethyl benzyl)-4-(2-formylethyl)piperazine (150 mg) in dichloromethane (2 ml) was added and the resulting mixture was stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent and the desired product was treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(3,3-dimethylmorpholino-imino)propyl]piperazine dihydrochloride (122 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:16]C1C=CC=CC=1CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[Br:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCc1ccccc1Br
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1Br
Yield: 80 %

Procedure:
The title compound was prepared as described for (B4) using 2-bromobenzyl bromide (1.250 g, 5.00 mmol), magnesium (0.134 g, 5.50 mmol) and diethyl oxalate (1.462 g, 10.00 mmol). The product was isolated in the form of colorless oil in 80% yield and used instantly in next step.
Reaction SMILES: C1C=CC2N([OH:10])N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.[F:22][C:23]([F:39])([F:38])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:27]1)=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH4+:7].[OH-:10].[F:39][C:23]([F:22])([F:38])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([CH2:32][N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:27]1)=[O:25]
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C(N1CCNC(CN2CCCC2)C1)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: [NH4+]
Product: [OH-]
Temperature: 0 °C
Yield: 28 %

Procedure:
To a solution of trans-3-furanacyrlic acid (0.10 g, 0.74 mmol) in 5 mL of dry CH2Cl2 under a nitrogen atmosphere was added HOBt (0.10 g., 0.74 mmol). The reaction mixture is stirred at 0° C. and added solid EDCI (0.143 g, 0.75 mmol). Then, stirred for 30 minutes at 0° C. A solution of compound e (0.18 g, 0.67 mmol) in 5 mL of dry CH2Cl2 was added followed by DIEA (0.177 mL, 1.01 mmol). The reaction mixture was stirred for 24 h while warming to room temperature. The reaction mixture was then poured into water (50 mL) and stirred for 30 minutes. After dilution with CH2Cl2, the organic layer was separated, washed with saturated NaHCO3, salt solution, and water. Then, dried over Mg2SO4. The compound was purified by flash column chromatography on silica gel, eluting with CH2Cl2:CH3OH:28% NH4OH (99:1:2) to give the desired product as a free base (m.p. 144-145° C.; 0.25 g, 95% yield). The hydrochloride salt was prepared from 1 M etheral HCl. (0.1 g) 1H NMR (free base 200 MHz, CDCl3) δ1.74 (m, 4H), 2.57 (m, 5H), 3.11 (m, 2H), 3.31 (m, 2H), 4.05 (m, 1H), 4.25 (m, 1H), 4.65 (m,1H), 6.58 (d, J=3.3, 7.8 Hz, 2H), 7.44 (m, 1H), 7.64 (d, J=3.3 Hz, 2H); MS (FAB) m/z 3.86 Anal. Calcd. For C18H22N3F3O3.HCl: C, 51.25; H, 5.50; N, 9.96. Found: C, 51.44; H, 5.57; N, 9.86.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[CH3:28][O-:29].[Na+]>CO>[CH3:28][O:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:13])[S:11][CH:12]=2)=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15]
Reactant: C[O-]
Reactant: COc1cc(C(=O)c2cc(-c3csc(C)n3)ccc2F)cc(OC)c1OC
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2csc(C)n2)cc1C(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
(2-Fluoro-5-(2-methylthiazol-4-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (50 mg, 0.13 mmol) as a synthetic intermediate of Compound 596 was dissolved in NaOMe (2 ml) and methanol (5 ml). The solution was heat refluxed for 3 hours. After completion of the reaction, the reaction solution was extracted with water and dichloromethane, and the organic layer was vacuum concentrated.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C[Si]([N:14]=[C:15]=[O:16])(C)C.[OH:17][CH:18]([CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][NH:40][CH2:39][C:38]=2[C:37]([C:44]2[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=2)=[N:36]1)[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]#[N:29])[CH2:22][CH2:21]1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl>[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH:18]([OH:17])[CH2:34][N:35]2[C:43]3[CH2:42][CH2:41][N:40]([C:15]([NH2:14])=[O:16])[CH2:39][C:38]=3[C:37]([C:44]3[CH:49]=[CH:48][C:47]([I:50])=[CH:46][CH:45]=3)=[N:36]2)[CH2:25][CH2:24]1)#[N:29]
Reactant: C[Si](C)(C)N=C=O
Reactant: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCNC3)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(CC(O)Cn2nc(-c3ccc(I)cc3)c3c2CCN(C(N)=O)C3)CC1
Reaction time: 20 h
Yield: 78 %

Procedure:
Diisopropylethylamine (0.531 mL, 3.05 mmol), DMAP (5 mg), and trimethylsilyl isocyanate (0.413 mL, 3.05 mmol) were added to a solution of 2-(4-{2-hydroxy-3-[3-(4-iodo-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-benzonitrile in pyridine (3 mL) and CH2Cl2(6 mL). The reaction mixture was stirred for 20 h, then partitioned between aqueous NaHCO3 and CH2Cl2. The CH2Cl2 layer was washed with brine, dried (Na2SO4), and concentrated. The resulting product was dissolved in CH2Cl2 (5 mL) and treated with 21 wt % sodium ethoxide in EtOH (0.5 mL) for 3 h. The reaction mixture was washed with brine, dried (Na2SO4), and concentrated. Purification by column chromatography (silica, 0-10% MeOH/CH2Cl2) afforded 290 mg (78%) of the title compound. HPLC (reverse phase conditions), tR=4.21 min. MS (electrospray): m/z 612.2 (612.5, calculated for C27H30IN7O2, M++H). 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.6 Hz, 2H), 7.57 (dd, J=7.6, 1.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.05 (t, J=7.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 4.64 (br s, 2H), 4.57 (br s, 2H), 4.30 (br s, 1H), 4.20 (dd, J=14.1, 3.3 Hz, 1H), 4.06 (dd, J=14.1, 6.3 Hz, 1H), 3.82-3.65 (m, 2H), 3.29-3.20 (m, 4H), 3.04-2.80 (m, 6H), 2.68 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2C=O.C[O:14][C:15]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:16].[CH3:23]C(C)([O-])C.[K+]>C(O)(C)(C)C>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:23][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][N:8]=[CH:7]2)[CH2:17][C:15]([OH:14])=[O:16]
Reactant: Cc1cccc2c(C=O)n[nH]c12
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)OC
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=Cc1cc(C)c2[nH]ncc2c1)CC(=O)O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of 7-methyl indazole aldehyde (0.2619 g, 1.64 mmol) and DBE-4 dibasic ester (dimethyl succinate) (0.32 mL, 2.45 mmol) in t-butanol (20 mL) was added potassium t-butoxide (0.4036 g, 3.60 mmol). The reaction mixture was heated at 50° C. for 2 h under nitrogen. After a further 16 h at room temperature, the solvent was removed in vacuo and the residue was taken up in water (100 mL) and extracted with ethyl acetate (3×50 mL). The aqueous layer was acidified with 1N hydrochloric acid to pH 3˜4 and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solution was dried and concentrated in vacuo to give the crude product as a yellow solid (99%, cis/trans isomer approximately 40:60). The crude mixture was carried to next step without further purification. Mass spec.: 275 (MH)+.