Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18](O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:32](=[O:43])[N:31]=2)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:14][CH2:13][N:12]4[CH2:15][CH2:20][CH2:19][CH2:18]4)=[CH:38][CH:37]=3)[C:32](=[O:43])[N:31]=2)=[CH:44][CH:45]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Reactant: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1
Product: O=c1nc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCCC2)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one was replaced with 4-(4-fluorobenzyloxy)-1-(4-hydroxyphenyl)-1H-pyrimidin-2-one, to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 28.7 %

Procedure:
The title compound (D22) (18 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (40 mg, 0.14 mmol) and 3-(trifluoromethyl)benzyl bromide (0.031 ml, 0.21 mmol). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:26][CH2:27][O:28][C:29]([CH3:31])=[O:30].N1(C(=O)CC2CCC(C(OCC)=O)CC2)C=CN=C1>C1COCC1>[CH2:27]([O:28][C:29](=[O:30])[CH2:31][C:13](=[O:15])[CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)[CH3:26]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Agent: CCOC(=O)C1CCC(CC(=O)n2ccnc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom vessel was charged 2-(4-(ethoxycarbonyl)cyclohexyl)acetic acid (Int-4c, 4.03 g, 18.79 mmol) and THF (20 mL). To this solution was added N,N′-carbonyldiimidazole (3.66 g, 22.55 mmol). The resulting solution was allowed to stir 18 hours at room temperature. After 18 hours, in a separate 250 mL round-bottom vessel, 80 mL THF was added and the flask was flushed with argon. This solution was cooled to −78° C. in dry ice/IPA bath. To this solution was added LiHMDS (1.0 M in THF, 39.46 mmol, 39.46 mL). To the resulting solution was added dropwise dry EtOAc (40.4 mmol, 3.95 mL). This solution was allowed to stir at −78° C. for one hour. After one hour, the solution of crude ethyl 4-(2-(1H-imidazol-1-yl)-2-oxoethyl)cyclohexanecarboxylate (Int-4d) in THF was added dropwise. This solution was allowed to gradually warm to room temperature and the reaction was stirred overnight. After 18 hours, the reaction was quenched with saturated NH4Cl(aq) and extracted with Et2O (x3). The combined organics were dried over Na2SO4 and the residue was purified via silica gel chromatography to yield the title compound as clear oil. Yield=2.33 g.
Reaction SMILES: C(O[C:6](=[O:41])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH2:23][CH2:22]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(C)(C)C.[C:42](O)([C:44](F)(F)F)=O.NC1C=CC=CC=1NC1N=C(N2CCN(C(NC3C=CC=C(C(F)(F)F)C=3)=O)CC2)C(Cl)=CN=1.C(Cl)(=O)C=C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)=[O:39])[CH2:25][CH2:26]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(=[O:41])[CH:42]=[CH2:44]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reactant: O=C(O)C(F)(F)F
Agent: C=CC(=O)Cl
Agent: Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(4-((3-(trifluoromethyl)phenyl)carbamoyl)piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (0.025 g, 0.043 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-(2-((2-aminophenyl)amino)-5-chloropyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide (0.043 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.004 mL, 0.052 mmol) and DIEA (0.018 mL, 0.11 mmol) and the mixture was stirred at 0° C. for 1 h. The crude reaction mixture was loaded onto silica gel and purified using 0-7% MeOH/DCM gradient to give the title compound (10 mg, 43%). MS (ES+) C25H23ClF3N7O2 requires: 545. Found: 546 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.Br[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21].O1CCCC1>[Cl-].[NH4+].[Zn]>[CH3:21][C:20]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)([CH3:22])[CH:19]=[CH2:18]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(C)(C)C1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.75 h

Procedure:
To a suspension of benzyl 3-oxopyrrolidine-1-carboxylate (4.50 g, 0.0205 mol) and 4-bromo-2-methyl-2-butene (4.75 mL, 0.0412 mol) in 25.0 mL of saturated ammonium chloride and tetrahydrofuran (4.75 mL, 0.0586 mol) was added zinc (2.70 g, 0.0412 mol) at rt. Soon after stirring was started, gas and heat were evolved. After 45 min., the resulting light grey mixture was filtered through celite. Layers of the filtrate were separated and the aqueous layer of the filtrate was extracted with EtOAc. The organic layers were combined, washed with brine, dried and evaporated in-vacuo. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na) 290.2.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]=[CH:17]N1CCCC1)[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[N:2][O:1][CH:17]=1)=[O:23])[CH3:13]
Reactant: CCOC(=O)C=CN1CCCC1
Reactant: Cc1ccccc1C(Cl)=NO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1conc1-c1ccccc1C
Yield: 47 %

Procedure:
To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride (2.07 g, 12.2 mmol, 1.0 equiv) in diethyl ether (15 mL) was added a solution of 3-pyrrolidin-1-yl-acrylic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 4,187,099) (2.06 g, 12.2 mmol, 1.0 equiv) and triethylamine (1.48 g, 12.2 mmol, 1.0 equiv) in diethyl ether (30 mL) dropwise over 15 minutes. The resultant mixture was stirred at ambient temperature for 16 hours, partitioned between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×), and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane) gave 1.32 g (47%) of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 3H), 4.19 (q, 2H), 2.23 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.CO.[ClH:45]>O1CCOCC1>[ClH:45].[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:18]([C:27]([NH:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)NC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@H](N)Cc1cc(F)ccc1F)CC2

Procedure:
A solution of the product (25 mg) from Step A above, 0.5 mL of methanol and 2.5 mL of 4.0M hydrogen chloride in 1,4-dioxane was kept at room temperature for 18 h. The volatiles were removed under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a white powder. LC/MS: 499.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1C(C#N)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:12][CH2:13][CH3:14])C.Cl.[CH2:16]1COCC1>>[C:13]([C:14]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:12])[CH3:16]
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: N#Cc1ncccc1Cl
Agent: Cl
Product: CC(=O)c1ncccc1Cl
Reaction time: 2 h

Procedure:
Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33:565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgl in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3×100 mL) and dry over anhydrous MgSO4. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate/hexane as eluent. Removal of solvent under reduced pressure gives pure 2-acetyl-3-chloropyridine as oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Na+].O.C(OCC)C>O1CCCC1>[CH2:2]([C:14]1[CH2:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: c1cc[cH-]c1
Reactant: CCCCCCCCBr
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC1=CC=CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Under a high purity nitrogen atmosphere, 5.8 ml(30mmol) of 1-bromooctane was introduced into a Schlenck flask and 50 ml of tetrahydrofuran (THF) was added thereto. To the resulting mixture, 18 ml of 2N sodium cyclopentadienide in THF was added at 0° C. The resultant was stirred for 5 hours at room temperature, 100 ml of water and 100 ml of diethyl ether were added thereto, followed by agitation. The diethyl ether layer was separated and dried over anhydrous magnesium sulfate. After removing magnesium sulfate, the organic solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: hexane) to obtain 4.21 g of n-octylcyclopentadiene (yield: 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15]C(C#N)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-:24].[Na+].[CH2:26]([OH:28])[CH3:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:27]([C:26]([OH:24])=[O:28])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Temperature: 70 °C
Yield: 79 %

Procedure:
6-[N-(5-Bromo-2-propoxybenzyl)-N-ethylamino]-3-cyanopyridazine (reference example 18) (1.5 g, 4 mmol) in ethanol (100 ml) was treated with aqueous sodium hydroxide (20 ml, 2M, 40 mmol) and was heated to 70° C. for 16 hours. The solvents were evaporated at reduced pressure, the residue dissolved in water, acidified with acetic acid and extracted with ethyl acetate (×4). The combined organic phases were washed with water and brine dried over MgSO4 and concentrated in vacuo. The resulting gum was triturated with ether to give the title compound as a solid (1.24 g, 79%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([C:24]1[CH:25]=[C:26]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29](OC)=[O:30])([CH3:23])([CH3:22])[CH3:21]>>[C:37]([C:34]1[CH:33]=[C:26]([CH:25]=[C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:35]=1[OH:36])[CH2:27][CH2:28][C:29]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])([CH3:39])([CH3:40])[CH3:38]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
The general procedure of Example 1 is repeated, but using 382.9 g (1.416 mole) of octadecyl alcohol and 471.3 g (1.612 mole) of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and employing 2 ounces (30.1 g) of PROPAK® and 2.5 ounces (69.4 g) of TiS catalyst. The system is brought to reflux at a pressure of 6-8 mm Hg and a temperature of between 190 and 202° C. After 2.5 hours, analysis of the contents of the reaction flask using Gas Chromatography shows a mixture of 51.7 wt % of the title compound, 26.2 wt % of methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and 20.8 wt % octadecyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c(ccn2-c2nnn[nH]2)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:27][C:26]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][C@H:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 78.9 g of (S)-5-oxo-pyrrolidine-2-carboxylic acid benzyl ester in 400 mL of dichloromethane is added 2.20 g of dimethylaminopyridine and 78.54 g of di-tert-butyl carbonate at room temperature. The mixture is stirred for 4 hours at room temperature. The reaction mixture is then washed twice with 400 mL of 0.5 M sulphuric acid. The organic phase is separated and the solvent removed to give (S)-5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a semi-crystalline solid.
Reaction SMILES: [NH:1]([C:3](=[O:30])[CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH:7]=1)[NH2:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].CN(C)C(=O)C>O>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][C:6]([CH2:5][CH2:4][C:3]3[O:30][C:31](=[O:32])[NH:2][N:1]=3)=[CH:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)NN)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCc4n[nH]c(=O)o4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of N-{2-[5-(3-hydrazino-3-oxopropyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.29 g), 1,1′-carbonylbis-1H-imidazole (0.22 g) and N,N-dimethylacetamide (15 mL) was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.20 g, yield 65%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 255-256° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[O:9][C:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[NH:13][C:12](=[O:24])[C:11]=1[CH:25]([CH3:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[CH:25]([C:11]1[C:12](=[O:24])[NH:13][C:14](=[O:23])[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[C:10]=1[O:9][C:8]1[CH:7]=[C:6]([CH:30]=[C:29]([CH3:31])[CH:28]=1)[CH:2]=[O:1])([CH3:27])[CH3:26]
Reactant: Cc1cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccncc2)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C=O)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1-pyridin-4-ylmethyl-1H-pyrimidine-2,4-dione (1.2 g, 2.83 mmol), p-toluenesulfonic acid monohydrate (538 mg, 2.83 mmol), and water (15 drops) in acetone (20 ml) was heated under reflux for 3 hr. After cooling to room temperature, excess sodium bicarbonate was added and the mixture was stirred for 1 hr. Then the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (9:1)) to afford 978 mg (91%) of 3-(5-Isopropyl-2,6-dioxo-3-pyridin-4-ylmethyl-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzaldehyde as a white solid. 1H NMR (200 MHz, CDCl3) δ 1.12 (6H, d, J=7.0 Hz), 2.40 (3H, s), 2.70 (1H, m), 4.92 (2H, s), 6.90 (1H, s), 7.08 (1H, s), 7.11 (1H, s), 7.14 (1H, s), 7.43 (1H, s), 8.50 (2H, d, J=6.2 Hz), 9.73 (1H, s), 9.91 (1H, s). 6.85-6.89 (3H, m), 7.09 (1H, s), 7.21-7.27 (2H, m), 7.40 (1H, s), 8.98 (1H, s), 9.89 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[C:33]1([CH2:39][CH2:40][SH:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]3[CH2:12][S:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1cccc(B(O)O)c1
Reactant: SCCc1ccccc1
Product: COc1cccc(-c2ccc3c(c2)C(CSCCc2ccccc2)=CC(C)(C)N3)c1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 3-methoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 21 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([O:20][CH3:21])=[C:11]([C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:12]([OH:14])=O.S(Cl)([Cl:24])=O.C([C@H]([C@@H](C(O)=O)O)O)(O)=O.[NH2:36][CH2:37][CH:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH2:43][CH3:44]>O>[ClH:24].[CH2:43]([N:39]1[CH2:40][CH2:41][CH2:42][CH:38]1[CH2:37][NH:36][C:12](=[O:14])[C:11]1[C:15]([O:18][CH3:19])=[CH:16][CH:17]=[C:9]([Br:8])[C:10]=1[O:20][CH3:21])[CH3:44]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: O=S(Cl)Cl
Reactant: CCN1CCCC1CN
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CCCC1CNC(=O)c1c(OC)ccc(Br)c1OC
Product: Cl

Procedure:
Using the same method as for compound in Example 14, except of the addition of triethylamine, this compound was prepared from 8.4 g (0.032 mol) of 3-bromo-2,6-dimethoxybenzoic acid, 20 ml of thionyl chloride and 9.0 g (0.032 mol) of (+)-2-(aminomethyl)-1-ethylpyrrolidine d-tartrate. Yield: 7.5 g, m.p. 166°-68° C., [α]D20° =10.7° (0.5% in water).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10](=[S:12])[NH2:11])=O)(C)(C)C.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[CH3:21]>>[C:15]1([C:20]2[N:11]3[CH:6]=[N:8][CH:9]=[C:10]3[S:12][CH:21]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCC(N)=S
Reactant: CC(=O)c1ccccc1Br
Product: c1ccc(-c2csc3cncn23)cc1
Yield: 66 %

Procedure:
The same procedure as in Preparation 10 was repeated except that 1.9 g of (N-t-butoxycarbonylamino) acetothioamide and 2.49 g of 2'-bromoacetophenone were used, thereby obtaining 1.32 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:3]=12.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C:3]=23)[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2c(oc3ccccc32)c1Cl
Reactant: Nc1cccc(Br)c1
Solvent: CCOCCO
Product: N#Cc1cnc2c(oc3ccccc32)c1Nc1cccc(Br)c1
Yield: 63.4 %

Procedure:
A solution of 300 mg (1.30 mmol) of 4-chlorobenzo[4,5]furo[3,2-b]pyridine-3-carbonitrile and 0.160 mL (1.43 mmol) of 3-bromoaniline in 8 mL of 2-ethoxyethanol is heated at reflux temperature for 24 hours. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is washed with saturated sodium bicarbonate, followed by brine, then dried over sodium sulfate, filtered through a pad of diatomaceous earth and concentrated in vacuo. The resultant solid is collected by filtration to give 300 mg (42%) of a beige solid, mp 242-245° C.
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]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].C(OC(O)C)C>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1OC
Yield: 65.3 %

Procedure:
A mixture of 1.0 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.22 g of 3,4-dimethoxyaniline, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 5 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystalized from ethyl acetate to give 0.96 g of 4-[(3,4-dimethoxyphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 230-240° C.