Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[I:26]C1C=C(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)C=CC=1>>[I:26][C:22]1[CH:21]=[C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CSc1ncnc2sc(-c3c(-c4cccc(I)c4)ncn3C)cc12
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(I)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(3-iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 54) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (220 mg, 68%);
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:24]=2)=[CH:16][CH:15]=1>>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[N:24]=4)=[CH:16][CH:15]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1oc(-c2ccc(-c3ccc4c(c3)OCO4)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3,4-Methylenedioxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 377.1 (M+1)
Reaction SMILES: [O:1]=[C:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7]/[C:8](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9]\[CH2:10]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[O:1]=[C:2]([CH3:6])[C:3]([O:5][CH2:10]/[CH:9]=[C:8](\[CH3:7])/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[O:4]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-oxopropanoic acid (3.40 g, 38.6 mmol), DMAP (0.48 g, 3.9 mmol) and (E)-3,7-dimethyl-2,6-octadienol (10.00 g, 64.8 mmol) in dichloromethane (90 ml) was cooled on an ice-bath before a solution of DCC (9.18 g, 44.5 mmol) in dichloromethane (45 ml) was added during 30 min. The reaction mixture was stirred for 10 min at 0° C., then at room temperature for ca. 5 h. The precipitate formed in the reaction was filtered off and the filtrate taken up in ether, washed with water (3×), HCl (10%, 3×), a saturated solution of NaHCO3 (3×) and water. The organic layer was dried (Na2SO4) and concentrated. Column chromatography (SiO2, heptane/ether 4:1) gave 4.68 g (53%) of a slightly yellow oil.
Reaction SMILES: C([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9](O)[CH:8]=2)(O)=O.Cl.C(N=C=NCCCN(C)C)C>>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:4][C:5]1=[O:15]
Reactant: O=C(O)c1cc2ccc(O)cc2oc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: O=c1ccc2ccccc2o1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
Antibody which binds specifically to atherosclerotic plaque (1 m mole) is dialyzed st 4° C. against a buffer solution of 0.01M PBS, pH 6.8 overnight. To this solution is added 50 nmole of 3-carboxy-7-hydroxycoumarin. The solution is added 50 mnole of 3-carboxy-7-hydroxycoumarin. The solution is cooled in an ice bath and added with 50 nmole of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. After addition the mixture was stirred at 4° C. for one hour and chromatographed on a 2.5 c 50 cm column of SEPHAEX® G-50. The absorbance of the conjugate is monitored at 345 nm to yield a solution of coumarin labeled antibody.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:23]([O-])=O)=[C:9]([CH:22]=1)[O:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14]CC)=O>C(O)C.[Ni]>[Cl:1][C:2]1[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:23][C:12](=[O:14])[CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:10][C:9]=2[CH:22]=1
Reactant: CCOC(=O)C(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Yield: 53.2 %

Procedure:
Diethyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrophenoxy]malonate (Reference compound IV-1) (2.0 g) was dissolved in ethanol (20 ml), and a hydrogenation was carried out, with addition of Raney nickel as the catalyst, at room temperature under normal pressure for 10 hours. The reaction mixture was filtered, the filtrate concentrated under a reduced pressure, and the residue obtained was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.9 g of the title compound (colorless crystals).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][N:19]([C@@H](C3C=CC=CC=3)C)[CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1)C1C=CC=CC=1.COC1C=CC=CC=1COCCCOC1C=CC([C@H]2CCNC[C@@H]2OCC2C=C3C(C=CC(OCCN4CCN(C)CC4)=C3)=CC=2)=CC=1.[H][H]>>[ClH:1].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]2[OH:30])=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: C[C@H](c1ccccc1)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@@H](O)C1
Agent: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3ccc(OCCN4CCN(C)CC4)cc3c2)cc1
Agent: Cl
Product: Oc1ccc([C@H]2CCNC[C@@H]2O)cc1

Procedure:
Another preferred aspect of the present invention is the transformation of (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride to 1-[2-[7-[(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-naphthalen-2-yloxy]-ethyl]-4-methyl-piperazine by the following procedure: a) reacting (3R,4R)-4-(4-benzyloxy-phenyl)-1-((R)-1-phenyl-ethyl)-piperidin-3-ol hydrochloride with hydrogen to yield (3R,4R)-4-(4-hydroxy-phenyl)-piperidin-3-ol hydrochloride;
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:21])[CH2:6][CH2:7][O:8][CH2:9][CH:10]([NH2:20])[CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:3].[C:22]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(N=C=NCCCN(C)C)C.CCN(CC)CC>C(Cl)Cl>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH:10]([NH:20][C:35](=[O:36])[CH2:34][CH2:33][NH:32][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:9][O:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:21])[CH3:19]
Reactant: CCOC(=O)CCOCC(N)COCCC(=O)OCC
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCOCC(COCCC(=O)OCC)NC(=O)CCNC(=O)OCc1ccccc1
Yield: 91.5 %

Procedure:
The compound 29 was prepared using General Procedure B with the ester hydrochloride salt (28) (1.53 g, 5.26 mmol), N-Cbz-β-alanine (1.41 g, 6.31 mmol), 1-hydrobenzotriazole (HOBt) (0.99 g, 7.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.41 g, 7.36 mmol) and Et3N (1.02 mL, 7.36 mmol) in CH2Cl2 (30 mL). Purification by flash column chromatography (on silica gel, EtOAc:n-hexane=3:1) afforded 2.39 g (92%) of the desired product (29) as a colorless liquid. 1H NMR (CDCl3): δ 7.33 (m, 5H, ArH), 6.33 (d, J=8.0 Hz, 1H, NH), 5.57 (s, 1H, NM, 5.08 (s, 2H, OCH2Ar), 4.18 (m, 1H, CH), 4.13 (q, J=7.2 Hz, 4H, CH2O), 3.70 (m, 4H, CH2O), 3.56 (m, 2H, CH2O), 3.48 (d, J=6.0, 12.0 Hz, 2H, CH2NHCO), 3.40 (m, 2H, CH2O), 2.53 (m, 4H, CH2CO), 2.42 (t, J=6.0 Hz, 2H, CH2CO), 1.25 (t, J=7.2 Hz, 6H, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]([OH:22])=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[C:25](=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:20]([O:22][CH3:25])=[O:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-carboxy-4-phenylpiperidine (1.53 g) in tetrahydrofuran (2 mL)-methanol (2 mL) was added dropwise 2N (trimethylsilyl)diazomehane-diethyl ether solution (8.8 mL) at room temperature and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=90/10 to 85/15) to obtain 1-tert-butoxycarbonyl-4-methoxycarbonyl-4-phenylpiperidine (1.31 g, yield: 82%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCOC(C)=O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH:37]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Yield: 93.8 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.397 g, 1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (0.464 g, 1.5 mmol), PdCl2(dppf) (56 mg), and 2 M Na2CO3 solution (8 mL) in dioxane (40 mL) was refluxed under nitrogen for 2 hrs. The dioxane was removed under vacuum and the residue was extracted into CH2Cl2. Chromatography on silica eluting with CH2Cl2/EtOAc (95:5) gave 0.51 g (94% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate: mp (MeOH) 223-225° C.; 1H NMR (CDCl3) δ 8.00 (dd, J=8.4, 0.6 Hz, 1H), 7.56 (t, JHF=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 7.38 (m, 1H), 6.85 (d, J=7.7 Hz, 1H), 4.23 (br d, J=3.0 Hz, 2H), 4.06 (s, 3H), 4.01 (m, 2H), 3.95 (m, 2H), 3.82 (m, 4H), 3.65 (t, J=5.7 Hz, 2H), 2.69 (m, 2H), 1.54-1.45 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C26H31F2N7O4: C, 57.45; H, 5.75; N, 18.0. Found: C, 57.4; H, 5.9; N, 18.15%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CO>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:17])[CH3:16]
Reactant: NCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-amino-1-pentanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 5-acetamido-1-pentanol. To a solution of 5-acetamido-1-pentanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-acetamido-1-pentyl triflate (30) which is used without further purification.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH3:11][O:12][N:13]=[CH:14][CH3:15].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:11][O:12][N:13]1[CH:14]([CH3:15])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CC=NOC
Reactant: C=C(C)C1CCCCC1=O
Agent: CON1C(=O)CCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCC=C(C)CC1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
An argon flushed three-necked flask which was cooled by an ice-water bath was charged with 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), acetaldehyde O-methyl oxime (0.56 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml). The mixture was stirred for 48 hours at room temperature. The completion of reaction was checked by GC analysis of reaction aliquots quenched with a solution of saturated NaHCO3 in water. The reaction mixture was quenched with sat. aqueous NaHCO3 solution (50 mL). The organic phase was separated and the aqueous layer was extracted with MTBE three times. The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated in vacuo. The crude product was purified by distillation under reduced pressure to yield the title product as a colorless liquid (1.13 g, 84%).
Reaction SMILES: [O:1]([CH2:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].C(N1CCN2CCN(C(C)C)P1N(C(C)C)CC2)(C)C.[N+:37]([CH2:40][CH3:41])([O-:39])=[O:38]>[N+](C)([O-])=O>[N+:37]([CH:40]([CH3:41])[CH:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:39])=[O:38]
Reactant: O=CCOc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: CC(C)N1CCN2CCN(C(C)C)P1N(C(C)C)CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Product: CC(C(O)COc1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 81 %

Procedure:
2-Phenoxyacetaldehyde (1.36 g, 10 mmol) was added to a suspension of anhydrous magnesium sulfate (2.65 g, 22 mmol) in nitroethane (7.0 mL) under an argon atmosphere. After 5 min a solution of 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (0.30 g, 1.0 mmol) in nitromethane (3.0 mL) was added. The mixture was vigorously stirred for 5 days at r.t., filtered through celite and concentrated. Purification by column chromatography (SiO2, dichloromethane/t-butyl methyl ether) gave the subtitle compound as an oil (1.7 g, 81%).
Reaction SMILES: [CH2:1]([NH2:8])C1C=CC=CC=1.Cl.CN.[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=O)[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]>>[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([NH:8][CH3:1])=[O:31])[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]
Reactant: NCc1ccccc1
Reactant: CC(=O)c1sc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)nc1C
Agent: CN
Agent: Cl
Product: CNC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Yield: 85 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with methylamine monohydrochloride to react with 3-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.73-7.62 (m, 2H), 7.42-7.34 (m, 2H), 6.32 (br s, 1H), 4.51 (s, 2H), 4.13-4.04 (m, 2H), 3.49-3.41 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.45 (s, 3H): MS (ES+) m/z 373.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5](C)[CH2:6][CH:7]([C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)C.C(N(CC)CC)C.[OH-:37].[NH4+].[Cl-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5](=[O:37])/[CH:6]=[CH:7]/[C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: [OH-]
Reactant: COC(=O)C=C(C)CC(C)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 2 liter round-bottomed flask equipped with a magnetic stirrer and nitrogen delivery line, 30.5 g of crude 5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylhex-2-enoic acid methyl ester are dissolved in 250 ml of THF, 13.49 g (133.3 mmol) of triethylamine are added and the yellow solution is heated under reflux for 2 hours. The reaction mixture is then cooled to room temperature, 53 ml (212 mmol) of 4N ammonium hydroxide solution are added and the mixture is stirred vigorously for 3 hours. The reaction mixture is then poured into 1 liter of saturated sodium chloride solution and extracted three times with 250 ml of ethyl acetate. The combined organic phases are washed once with 100 ml of 1N hydrochloric acid and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product (22.78 g of an orange resin) is purified by means of flash chromatography (hexane/ethyl acetate=9:1). A resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:29]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C=C(Br)Br)cc1OC
Yield: 96.9 %

Procedure:
According to the General Procedure F, carbon tetrabromide (4.00 g, 12.05 mmol), triphenylphosphine (6.30 g, 24.10 mmol) and 3,4-Dimethoxybenzaldehyde (2.00 g, 12.05 mmol) are converted to give after workup and chromatography (SiO2, CH2Cl2, Rf=0.48) the title compound (3.76 g, 11.68 mmol, 97%) as a yellow oil.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(O)C>CCCCCC>[C:5]([C:4](=[C:3]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[S:9][CH3:10])[C:7]#[N:8])#[N:6]
Reactant: COc1ccc(CN)cc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(CNC(SC)=C(C#N)C#N)cc1
Temperature: 25 °C

Procedure:
A mixture of 17.03 g (0.1 mol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 12.98 ml (0.1 mol) of 4-methoxy-benzylamine and 60 ml of ethanol is heated under reflux for 2 hours. Approx. 90 ml of hexane are then added dropwise to the hot solution which is then allowed to cool to RT. The title compound which has precipitated in the form of colorless crystals is filtered off, washed with diethyl ether and dried under a HV; m.p. 100-101° C.
Reaction SMILES: [OH:1][C:2]1([CH2:21][C:22](=[O:32])[CH2:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=O)[CH2:7][CH2:6][N:5]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH3:19])[CH:10]=2)[CH2:4][CH2:3]1.C(O)(=O)C>>[CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:5]2[CH2:6][CH2:7][C:2]3([O:1][C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:23][C:22](=[O:32])[CH2:21]3)[CH2:3][CH2:4]2)=[O:20])=[CH:10][C:11]=1[CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(C(=O)N2CCC(O)(CC(=O)CC(=O)c3cccnc3)CC2)ccc1OC(C)C
Solvent: CC(=O)O
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cccnc2)O3)ccc1OC(C)C
Yield: 86.6 %

Procedure:
4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (4.5 g, 10.3 mmol) was dissolved in glacial acetic acid (45 mL, 791 mmol) and stirred at reflux for 2 hours. Acetic acid was removed under reduced pressure. The crude residue was purified by column chromatography (40 gram silica gel column, 40-80% ethyl acetate/hexane) to provide 3-(4-isopropoxy-3-methyl-benzoyl)-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (3.75 g) as a yellow sticky foam. 1H NMR (400 MHz, CDCl3) δ=9.04 (d, J=1.9, 1H), 8.74 (dd, J=4.8, 1.5, 1H), 8.08-8.02 (m, 1H), 7.44 (dd, J=8.0, 4.9, 1H), 7.26-7.21 (m, 2H), 6.82 (d, J=8.6, 1H), 6.07 (s, 1H), 4.57 (dt, J=12.1, 6.0, 1H), 4.5-3.75 (m, 2H), 3.44 (br s, 2H), 2.65 (s, 2H), 2.23 (br s, 2H), 2.22 (s, 3H), 1.74 (br s, 2H), 1.35 (d, J=6.0, 6H). ESI-MS m/z calc. 420.20, found 420.8 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH2:8][C:9]#[CH:10])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:39])([F:38])[CH:31]([S:36][CH3:37])[CH2:32][C:33](O)=[O:34]>CN(C)C1C=CN=CC=1.ClCCCl>[Cl:1][C:2]1[C:6]([N:7]([CH2:8][C:9]#[CH:10])[C:33](=[O:34])[CH2:32][CH:31]([S:36][CH3:37])[C:30]([F:39])([F:38])[F:29])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: C#CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CSC(CC(=O)O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: C#CCN(C(=O)CC(SC)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a 7 mL vial was added 3-chloro-N-(prop-2-yn-1-yl)-1-(pyridin-3-yl)-1H-pyrazol-4-amine (140 mg, 0.6 mmol), N,N-dimethylpyridin-4-amine (249 mg, 2.040 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (276 mg, 1.440 mmol) followed by 4,4,4-trifluoro-3-(methylthio)butanoic acid (158 mg, 0.840 mmol) and DCE (1.2 mL). The solution was stirred at 25° C. for 18 hours, the crude reaction mixture was concentrated and purified with silica gel chromatography (0-100% EtOAc/hexane) to give the title compound as a brown oil (237 mg, 0.588 mmol, 98%): (IR thin film) 1674 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.6 Hz, 1H), 8.64 (dd, J=4.7, 1.3 Hz, 1H), 8.13 (s, 1H), 8.07 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.48 (ddd, J=8.3, 4.8, 0.5 Hz, 1H), 4.39 (s, 2H), 3.76 (dqd, J=17.2, 8.6, 3.6 Hz, 1H), 2.67 (dd, J=16.6, 3.6 Hz, 1H), 2.46 (dd, J=16.5, 9.9 Hz, 1H), 2.29 (d, J=2.5 Hz, 4H); ESIMS m/z 403 ([M+H]+).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.C(N(CC)CC)C.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of glycine tert butyl ester hydrochloride salt (compound of formula XIV, 50 g, 300 mmol) and dimethylformamide (400 ml) at about 0° C. was added triethylamine (127 ml, 885 mmol) and 4-benzyloxybenzenesulfonyl chloride (102 g, 357 mmol). After stirring for about 1 hour, the mixture was warmed to a temperature of about 20° C. to about 25° C., and stirred for about an additional 12 hours. The mixture was diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 91 g of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV) as a colorless solid.