Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[CH2:6])[CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: C=Cc1cccc(N)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=Cc1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1
Temperature: 25 °C

Procedure:
3-Amino styrene (1.36 g, 11.4 mmol) was added to a solution of 2′,4′-difluorobiphenyl-4-sulphonyl chloride (3.0 g, 10.3 mmol) in DCM (25 mL) at 0° C. Pyridine (6.0 mL, 74 mmol) was then added and the mixture was allowed to stir and warm to room temperature overnight. The reaction was partitioned between further DCM (100 mL) and 2 M HCl (30 mL), stirred and separated. The DCM layer was washed with water (20 mL) and brine (20 mL) and dried over MgSO4. The solvent was evaporated and the title compound obtained as an orange gum (3.46 g) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4 g (0.0017 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 13 ml of methanol is treated with 4.7 ml of methyl thioglycolate and 7.1 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent the residue is worked-up with water and methylene chloride. The organic phase is dried and freed from solvent. The residue is chromatographed on silica gel with ether. There is obtained methyl [[(6E,10Z)-12-hydroxy-2,6,10-trimethyl-3-oxo-6,10-dodecadienyl]thio]acetate which has the following bands in the IR spectrum: 1736 cm-1, 1711 cm-1, 1437 cm-1, 1408 cm-1, 1281 cm-1, 1137 cm-1, 1007 cm-1.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-]>CO.O>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([O:23][CH3:1])=[O:22])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20% aqueous solution of cesium carbonate was slowly added to a mixture of 14.2 g of 10 in 230 ml of methanol and 23 ml of water, until the mixture was neutral (about 50 ml of the carbonate solution). The solvent was evaporated under reduced pressure. The residue was placed in 50 ml of dimethylformamide and stripped twice. The residue was placed in 150 ml of dimethylformamide and 50 ml of methyl iodide was added to the mixture, which then was stirred overnight at room temperature. The mixture was filtered, and a large volume of methylene chloride was added to the filtrate. The filtrate was washed with a large volume of water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane, the mixture was filtered, and the solvent was evaporated from the filtrate to give 13, as a tan solid, m.p.: 46°-48° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(CN2CC[C@H](N3CCOCC3)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of 1-benzyl-3-phenyl-piperidin-4-one (2.07 g, 7.78 mmol) and morpholine (678 mg, 7.78 mmol) was added tetraisopropyl-orthotitanate (2.97 mL, 9.73 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (8.0 mL) and sodium cyanoborohydride (369 mg, 5.37 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with toluene/ethyl acetate 6:1 to give rac-cis-4-(1-benzyl-3-phenyl-piperidin-4-yl)-morpholine (1.42 g, 54%) as a yellow solid, MS: m/e=337.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH:26]=[CH:25]1>O>[C:24]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(OC(=O)/C=C\C(=O)O)cc(C(C)(C)C)c1O

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl hydrogen maleate was prepared by stirring a mixture of 15.5 grams of 2,6-di tert.butyl hydroquinone, 10 grams of trifluoroacetic acid and 8.6 grams maleic anhydride for 12 hours at 35° C. to 40° C. Addition of 100 milliliters of water resulted in the precipitation of a light brown paste which crystallized when mixed with petroleum ether. The solid was filtered off and washed twice with petroleum ether yielding 10.5 grams of product melting at 120° C. to 125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]1[CH:18]2[CH:13]([CH2:14]CCC2)[CH2:12][CH2:11][CH2:10]1.C1(C(Cl)(Cl)Cl)C=CC=CC=1>>[C:13]1([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCC2CCCCC2C1
Reactant: Nc1ccccc1O
Solvent: ClC(Cl)(Cl)c1ccccc1
Product: c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
16.4 g (0.15 mol) of 2-aminophenol (A) was refluxed together with 75 ml of decaline in the apparatus described under (a). 29.3 g (0.15 mol) of benzotrichloride (B) was added drop by drop over a period of 15 minutes, and the mixture was heated for another 3 hours with gentle refluxing. Then it was suction filtered while hot and concentrated by evaporation under dry. One half was chromatographed through Al2O3 : 7 g of Compound I, melting point 99°-100° C (41% of the theory). Of the remaining half, one gram was sublimed at 140° C and 0.2 mm Hg; 0.8 g of Compound I, melting point 100°-103° C (44% of the theory).
Reaction SMILES: [O:1]=[C:2]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)=[CH:12][CH:11]=1)[CH3:9])[CH2:3][C:4](OC)=[O:5].[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[F:23][C:22]([F:24])([F:25])[C:20]1[N:21]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C@H:8]([C:2]3[O:1][N:29]=[C:4]([OH:5])[CH:3]=3)[CH3:9])=[CH:15][CH:14]=2)[S:18][CH:19]=1
Reactant: NO
Reactant: COC(=O)CC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cc(O)no1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a cooled (−30° C.) solution of the intermediate 7a, methyl (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanoate, (372 mg, 1 mmol) in CH3OH (0.5 ml), a solution of NaOH (42 mg, 1.05 mmol) in CH3OH (4 ml) was added by dripping. The resulting mixture was stirred for 10 min, then a mixture of hydroxylamine hydrochloride (133 mg, 2 mmol) and NaOH (83 mg, 2 mmol) in CH3OH/water (4 ml/0.5 ml) was added at the same temperature. After stirring for 2 h at −30° C., the reaction mixture was poured into 37% HCl (1.5 ml) and the resulting mixture was heated at 80° C. for 2 h. After cooling at room temperature and solvents evaporation, the crude was diluted with water and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over anhydrous Na2SO4, evaporated and purified by flash chromatography (n-hexane/EtOAc 8:2; 1% AcOH) to afford pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isoxazol-3-ol (10) (202 mg, 0.57 mmol) as a pale yellow solid (57%). [α]D=−40 (c=1.4; CH3OH); 1H-NMR (CDCl3): δ 10.70 (bs, 1H, OH), 9.15 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 5.70 (s, 1H), 3.80 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-[2-(4-bromo-phenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methyl-pyrrolidine (product of Example 3C, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound 1H NMR (300 MHz, CD3OD) 1.08 (m, 1H), 1.19 (m, 1H), 1.32 (d, J=6 Hz, 3H), 1.42 (m, 1H), 1.63 (m, 1H), 1.99 (m, 3H), 2.20 (m, 1H), 2.65 (m, 1H), 2.94 (m, 1H), 3.07 (m, 1H), 3.34 (dd, J=9 Hz, J=6 Hz, 1H), 3.51 (m, 1H), 7.24 (d, J=9 Hz, 2H), 7.60 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: [C:1]1(=[O:36])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15](=[O:30])[C:16](=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:17]([CH3:19])=O)[C:4](=[O:31])[C:3]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:2]12.[CH3:37][O:38][C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42]>C(O)(C)C>[CH3:42][C:41]1[NH:43][C:17]([CH3:19])=[C:16]([C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]2[C:1](=[O:36])[C:2]3=[CH:35][CH:34]=[CH:33][CH:32]=[C:3]3[C:4]2=[O:31])=[O:30])[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:40]=1[C:39]([O:38][CH3:37])=[O:44]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCCCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 84.2 %

Procedure:
6.68 g (13.6 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid-(8-phthalimidooctyl)ester and 1.57 g (13.6 mmol) of 3-amino-crotonic acid methyl ester are boiled under reflux in 70 ml of isopropanol for 5 hours. The oil obtained after removal of the solvent by evaporation under vacuum is chromatographed on silica gel with dichloromethane/methanol (97:3) as solvent. 6.75 g (85%) of a yellow oil are obtained.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1.C(Cl)CCl>>[C:22]1([CH2:21][O:28][NH:29][C:7]([C:5]2[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=2)=[O:9])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)NOCc2ccccc2)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
To a solution of diethyl 1,3,5-benzenetricarboxylate (3.192 g, 20 mol) and O-benzylhydroxyamine hydrochloride (4.789 g, 19 mmol) in 40 mL were added N-methylmorpholine (2.2 mL, 20 mmol) and EDC (3.834 g, 20 mmol) at 0° C., and the mixture was stirred at room temperature for 20 hours. The solvent was removed by evaporator and the residue was dissolved in EtOAc (150 mL). The organic solution was washed with 1 N HCL (150 mL), washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4, and concentrated to give white solid. This material was recrystallized from EtOAc to give 4.154 g of white powder (59% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])[CH2:40][CH2:39]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:30])[CH3:29].[ClH:53].C(N=C=NCCCN(C)C)C>CN(C)C=O>[ClH:53].[C:28]([C:32]1[N:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:42][CH2:43]2)[CH:35]=[C:34]([CH:49]2[CH2:52][CH2:51][CH2:50]2)[N:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccc(F)cc3)CC2)n1
Reaction time: 68 h
Yield: 74.2 %

Procedure:
0.45 g of 4-fluorobenzoic acid (3.21 mmol) and 0.98 g of triethylamine (9.7 mmol) were dissolved in 30 ml of dimethylformamide. At room temperature, 0.5 g of hydroxybenzotriazole (HOBt, 3.7 mmol), 1.2 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.47 mmol), and 0.7 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.65 mmol) were added and the mixture was stirred for 68 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). The oily residue was re-dissolved in isopropanol and 1 N hydrochloric acid in diisopropyl ether was added. The resulting precipitate was filtered and dried to yield 1.2 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23].C(O)(=O)C>CN(C=O)C>[NH2:24][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17])=[O:23]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: NC(=O)c1ccccc1N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccccc3C(N)=O)c2cc1OC
Temperature: 100 °C
Yield: 41.7 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 2-aminobenzamide (0.029 g, 0.21 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 6 h. After cooling the reaction mixture was evaporated. The residue was dissolved in a mixture of MeCN and water (1:3) containing 0.1% trifluoroacetic acid and the turbid solution was filtered through a plug of glass wool. Preparative HPLC using a gradient (containing 0.1% trifluoroacetic acid) of 10→40% MeCN in water as eluent gave, after evaporation, the title compound as the trifluoroacetic acid salt. The product was suspended in saturated aqueous NaHCO3 an absorbed on a short SPE column [ISOLUTE™ C18 (EC)] pre-conditioned subsequently with methanol and then water. The column was washed extensively with water until the pH of the eluent was neutral. The product was then eluted with methanol. After evaporation, the residue was crystallized from ethanol to give the title compound (26 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][NH2:32])[CH:20]=[N:19][N:18]=[N:17]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:32][CH2:31][C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=1[N:16]1[CH:20]=[N:19][N:18]=[N:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(C(F)(F)F)ccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-L-proline (39 mg, 0.18 mmol), 1-[2-(1H-tetraazol-1-yl)-5-(trifluoromethyl)phenyl]methanamine (42 mg, 0.17 mmol), EDC (49 mg, 0.26 mmol) and HOAt (12 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. The crude product was purified by reverse phase HPLC followed by neutralization of an aqueous slurry of the compound with saturated aqueous K2CO3 and repeated extraction of the resulting aqueous mixture with EtOAc (the aqueous layer was saturated with NaCl before each extraction). The combined organic extracts were dried (anhydrous Na2SO4) and concentrated to afford the title compound as an oil which was carried on directly to the deprotection step (Step D below). LCMS (M+H): 441.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6](I)[CH:5]=1.[CH2:16]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:17][C:18]#[CH:19]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([C:19]#[C:18][CH2:17][CH2:16][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:5]=1
Reactant: COC(=O)c1ccc(NC(C)=O)c(I)c1
Reactant: C#CCCOC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(C)=O)c(C#CCCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 148.8 %

Procedure:
To a degassed solution of 4-acetylamino-3-iodo-benzoic acid methyl ester (41.4 g, 130 mmol) in DMF (200 mL) and triethylamine (40 mL) were added PdCl2(PPh3)2 (3.99 g, 5.68 mmol) and copper (I) iodide (7.43 g, 39.0 mmol). A degassed solution of 2-but-3-ynyloxy-tetrahydro-pyran (30.1 g, 195 mmol) in DMF (100 mL) and triethylamine (20 mL) was added at 80° C. over a period of 1 hour under nitrogen. After the addition, the reaction mixture was stirred at 80° C. for 2 hours and then cooled to room temperature. Solvent was evaporated under reduced pressure. Ethyl acetate (200 mL) was added. The solid was filtered, and washed with ethyl acetate. The ethyl acetate solution was washed with brine, and dried over anhydrous Na2SO4. The organic phase was concentrated to dryness, to afford 66.8 g crude 4-acetylamino-3-[4-(tetrahydro-pyran-2-yloxy)-but-1-ynyl]-benzoic acid methyl ester. This was used in next step without further purification.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:9](=[O:16])([O-])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1)#[N:25]>O1CCCC1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C@H:32]2[CH2:37][N:36]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16])[CH2:35][CH2:34][N:33]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1ccc([C@H]2CNCCN2)cc1
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(C#N)cc2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-Chloroethyl chloroformate (2.7 g, 18.9 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 3.81 mmol) in dichloroethane (30 ml). The reaction mixture was vigorously stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure and methanol (40 ml) was added to the residue. The mixture was heated at 80° C. for one hour and the solvent was evaporated under reduced pressure to afford (2S)-2-(4-cyanophenyl)piperazine as white crystals. Di-tert-butyl di-carbonate (1.9 g, 8.71 mmol) was added to a solution of triethylamine (1.2 g, 11.9 mmol) and (2S)-2-(4-cyanophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred at 50° C. for one hour. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([CH3:37])[C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([O:27]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:14]2)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].O>CN1CCCC1=O>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]([CH3:38])[C:10]([N:12]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:25]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:27])[CH2:14]2)[CH3:37])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(Cl)cc(Cl)c1
Yield: 49.4 %

Procedure:
A solution of the compound (0.31 g) obtained in Example 419 and 1-(methylsulfonyl)piperazine (0.14 g) in 1-methyl-2-pyrrolidone (5 mL) was stirred at 110° C. for 24 hr and at 135° C. for 14 hr. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 75→100% ethyl acetate/hexane) to give the title compound (0.16 g, 48%) as a pale-yellow powder.