Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH:7]([OH:9])[CH3:8])[CH3:2].C[O:23][C:24]([CH:26](C(CC(OC)=O)CC(OC)=O)CC([O-])=O)=O.C1OC2C=CC(CC(=O)C)=CC=2O1.C(OC(OCC)CI)C>C(OC=C)(=O)C.C(N(CC)CC)C>[C:24]([O:9][C@@H:7]([C@H:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:5][CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH3:8])(=[O:23])[CH3:26]
Reactant: COC(=O)CC(CC(=O)OC)C(CC(=O)[O-])C(=O)OC
Reactant: CCOC(CC(c1ccc2c(c1)OCO2)C(C)O)OCC
Agent: CC(=O)Cc1ccc2c(c1)OCO2
Agent: CCOC(CI)OCC
Solvent: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(C[C@@H](c1ccc2c(c1)OCO2)[C@@H](C)OC(C)=O)OCC
Temperature: 30 °C
Reaction time: 16 h

Procedure:
31.98 g of (2RS,3RS)-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentan-2-ol [synthesized by the same method as Reference Example 1(1) and (2) using 3,4-methylenedioxyphenylacetone and iodoacetaldehyde diethyl acetal as the starting materials] was dissolved in 320 ml of vinyl acetate, and 15.1 ml of triethylamine was added thereto. Then, 1.0 g of immobilized lipase (Toyothium LIP) was added thereto, followed by stirring at 30° C. for 16 hours. Further, 0.9 g of immobilized lipase was added thereto, followed by stirring at the same temperature for 46 hours. Then, insoluble matters were filtered off. The filtrate was diluted with ethyl acetate, then sequentially washed with 1N hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→1/1) to obtain 16.05 g of the above-identified compound, [α]D20 -31.8° (c 1.0, methanol) as colorless oily substance and 18.40 g of (2R,3S)-2-acetoxy-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentane as colorless oily substance. Further, the absolute configuration of the above-identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)=[C:5]([F:21])[CH:4]=1)[CH3:2].[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH2:30])[CH2:25][O:24]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH3:22][C:23]1([CH3:31])[O:28][CH2:27][CH:26]([O:29][NH:30][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:10]=2[NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[F:21])[CH2:25][O:24]1
Reactant: CC1(C)OCC(ON)CO1
Reactant: CCc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Nc2c(C(=O)NOC3COC(C)(C)OC3)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a stirring solution of the product of Example 1, Step D, 2-[(4-ethyl-2-fluorophenyl)amino]-3,4-difluorobenzoic acid (0.480 g, 1.626 mmol) in dichloromethane (15 mL) is added the product of Example 33, Step B, O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine (0.287 g, 1.951 mmol), triethylamine (0.41 mL, 2.927 mmol), and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.02 g, 1.951 mmol) and allowed to stir at ambient temperature for 75 minutes. The reaction mixture was concentrated in vacuo and the affording residue was partitioned between ethyl acetate and water. The organic layers were washed twice with saturated sodium carbonate solution and twice with brine. The organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo. N-(2,2-Dimethyl-[1,3]dioxan-5-yloxy)-2-(4-ethyl-2-fluoro-phenylamino)-3,4-difluoro-benzamide was isolated via silica column chromatography in 4:1 hexanes/ethyl acetate affording a white foam (0.423 g, 61.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH:23]([CH3:25])[CH3:24])[CH2:33][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CC(C)c1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2C(C)C)CC1
Yield: 77.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-isopropylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8](OCC)=[O:9])[N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1c[nH]cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of the ester from Step A (120 g, 71.4 mmol) in dry THF (230 mL) at 0° C. was added LAH (2.99 g, 78.6 mmol) portionwise over 30 min. The mixture was stirred for 2 h at room temperature then cooled back to 0° C. and H2O (4.2 mL) was added (care|) dropwise. This was followed by the dropwise addition of 10.6 mL of 1N NaOH then the resulting slurry was stirred at room temperature for 1 h. After filtration through celite washing with EtOAc, the solvent was removed to give the title compound as a clear oil (8.16 g). 1H NMR (CD3OD): δ 1.84 (2H, pentet), 2.68 (2H, t), 3.58 (2H, t), 6.88 (1H, s), 7.80 (1H, s).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:37][NH2:38].O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([NH:37][NH2:38])=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(C(=O)O)ccn2c1CC1CCCCC1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc2cc(C(=O)NN)ccn2c1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
2-tert-Butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carboxylic acid (500 mg, 1.59 mmol) was suspended in THF (5.0 mL), and the suspension was stirred at room temperature for 1 hour after adding carbonyldiimidazole (CDI) (280 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 1 hour after adding hydrazine monohydrate (0.240 mL, 4.80 mmol). Water was added to the reaction mixture. The precipitated solid was collected by filteration, and dried under reduced pressure to give 2-tert-butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carbohydrazide (331 mg, yield 79%).
Reaction SMILES: [N:1]1[N:2]2[CH:13]=[CH:12][N:11]=[C:3]2[N:4]=[C:5]([C:7]([OH:10])([CH3:9])[CH3:8])[CH:6]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:13]1[N:2]2[N:1]=[CH:6][C:5]([C:7]([OH:10])([CH3:9])[CH3:8])=[N:4][C:3]2=[N:11][CH:12]=1
Reactant: BrBr
Reactant: CC(C)(O)c1cnn2ccnc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(O)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
To a stirred solution of 2-(imidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (5.55 g, 31.1 mmol) in acetic acid (100 ml) was added sodium acetate (3.83 g, 46.7 mmol), then, dropwise over 5 min, a solution of bromine (1.77 ml, 34.4 mmol) in acetic acid (12 ml). The solution was stirred at room temperature for 25 min, then partitioned between saturated aqueous NaHCO3 (2 l) and ethyl acetate (1 l). The aqueous layer (pH 7) was further extracted with ethyl acetate (1 l), and the combined organic extracts were dried (Na2SO4) and evaporated iii, vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to afford 6.17 g (77%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 1.70 (6H, s), 3.12 (1H, br s), 7.95 (1H, s), 8.80 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.CO.O.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>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[CH:6][N:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: Nc1ncc(-c2cccc(F)c2)nc1C(=O)O
Yield: 82.3 %

Procedure:
Methyl 3-amino-6-bromopyrazine-2-carboxylate (0.116 g, 0.5 mmol), 3-fluorophenylboronic acid (0.14 g, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.018 g, 0.02 mmol), and K2CO3 (0.14 g, 1.0 mmol) were combined in 3 mL of 4:1 CH3CN:H2O and heated to 150° C. for 10 minutes in the SmithSynthesizer microwave. Upon cooling, the reaction mixture was diluted with MeOH and H2O to dissolve all but the catalyst. The mixture was filtered and the pH was adjusted to 6 with 2N HCl. The solution was concentrated in vacuo, and the solids were collected to afford 3-amino-6-(3-fluorophenyl)pyrazine-2-carboxylic acid (96 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:4][O:25]2)=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(COC1CCCCO1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(C2(COC3CCCCO3)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
6.3 g (0.21 mol) of sodium hydride (80% strength) are added to a mixture of 42 g (0.19 mol) of trimethylsulphoxonium iodide and 200 ml of dimethylsulphoxide at 15° C. The reaction mixture is stirred at room temperature for 1 hour and a solution of 39 g (0.153 mol) of 1-(4-chlorophenyl)-2-[(tetrahydro-2H-pyran-2-yl)-oxy]-ethan-1-one in 50 ml of dimethylsulphoxide is then added dropwise. The reaction mixture is stirred at 50° C. for 12 hours and then poured into water. The mixture formed is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. 37 g (90% of theory) of 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy-methyl)-oxirane are obtained in this manner in the form of a pale yellow oil which is used for the subsequent synthesis without additional purification.
Reaction SMILES: [C:1]([CH:3]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[F:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])#[CH:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[F:16][C:12]1[C:11]([F:17])=[C:10]2[C:15]([CH:2]=[CH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:9]2)=[CH:14][CH:13]=1
Reactant: C#CC(CCCCC)Oc1cccc(F)c1F
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: CCCCCC1C=Cc2ccc(F)c(F)c2O1

Procedure:
62.0 g (0.26 mol) of 1-(1-ethynylhexyloxy)-2,3-difluorobenzene are heated at 195° C. for 2 h in 390 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with 1 N HCl. The organic phase is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-pentane:1-chlorobutane=5:1), giving 7,8-difluoro-2-pentyl-2H-chromene as a brown oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([F:16])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:20]1>>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([N:21]1[CH2:22][CH2:23][N:24]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Br:1])[N:3]=[CH:4][C:5]=3[F:16])[NH:9][CH:8]=2)=[O:15])[C@H:19]([CH3:18])[CH2:20]1)=[O:32]
Reactant: C[C@@H]1CN(C(=O)c2ccccn2)CCN1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Br)ncc(F)c12
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccn2)CCN1C(=O)C(=O)c1c[nH]c2c(Br)ncc(F)c12

Procedure:
Precursor 5o, (R)-1-picolinoyl-3-methyl-4-[(7-bromo-4-fluoro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (7-bromo-4-fluoro-6-azaindol-3-yl)oxoacetate, Precursor 4h, and (R)-3-methyl-1-picolinoyl-piperazine. 1H NMR (500 MHz, CD3OD) δ8.68-7.52 (m, 6H), 4.94-2.69 (m, 7H), 1.48-1.24 (m, 3H). MS m/z: (M+H)+ Calc'd for C20H18BrFN5O3: 474.06; Found 474.23. HPLC retention time: 1.20 minutes (column A).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Mg]Br.[CH2:8](OCC)C.[CH3:13][C@H:14]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(OCC)(=O)C>C1COCC1>[OH:19][C@@:18]1([CH3:8])[CH2:17][CH2:16][N:15]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@H:14]1[CH3:13]
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1N(C(=O)OCc2ccccc2)CC[C@]1(C)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A suspension (300 mL) of cerium chloride (47 g) in THF was cooled to −78° C., and 3 mol/L methylmagnesium bromide-diethyl ether solution (56 mL) was added dropwise while adjusting the temperature of the solution to not higher than −70° C. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min, and a solution (60 mL) of benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (18 g) in THF was added dropwise while adjusting the temperature of the solution to not higher than −70° C. The reaction mixture was warmed to 0° C. over 2 hr, ethyl acetate (1 L) was added, and the insoluble material was filtered off. Water was added to the filtrate and then the mixture was partitioned. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→1/1) to give the title compound as a colorless oil (yield: 16.2 g, yield: 84%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(O)C>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[N:16]=[CH:15][S:14][C:12]3=2)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Solvent: CCO
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NCc2ccncc2)cc1
Temperature: 78 °C
Yield: 22.4 %

Procedure:
To a test tube (20 mm by 150 mm) was added a magnetic stir bar, 8-[ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one (0.123 gram, 0.5 mmol), 4-amino-N-(4-pyridinylmethyl)benzenesulfonamide (0.132 gram, 0.5 mmol) and 95% ethanol (5 milliliters). The reaction mixture was sealed with a rubber septum (14/22) and vented with a 3-inch 18-gauge hypodermic needle. The reaction vessel was placed in an oil bath at room temperature with stirring, and the temperature of the oil bath was then raised to 78° C. and maintained at that temperature for approximately 24 hours. The reaction vessel was removed from the oil bath and allowed to cool until warm to the touch. The resulting precipitate was collected by suction filtration. The solid was washed with excess 95% ethanol and collected by suction filtration. The resultant solid was dried under vacuum for two hours at 40° C. The solid was allowed to cool to yield 52 mg (11%) of the title compound. MS (M+H)=464.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:45](O)=[O:46])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C@H:37]([C:45]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:46])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3(1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-phenylalanine N-hydroxysuccinimmide ester (500 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:21])([F:20])[CH2:16][C:17](=[O:19])[CH3:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([OH:19])([CH2:16][C:15]([F:21])([F:20])[F:14])[CH3:18])=[CH:3][CH:4]=1
Reactant: CC(=O)CC(F)(F)F
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(CC(F)(F)F)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,4-dibromobenzene (2.5 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.5 mL, 10.4 mmol; 1.6 M in hexanes) and the mixture was stirred at −78° C. for 15 min. 4,4,4-Trifluoro-2-butanone (1.3 g, 10.3 mmol) was then added. After further stirring for 15 min., the mixture was quenched with aqueous NH4Cl and extracted with Ethyl acetate. Purification by combi-flash chromatography (40 g column; eluted with hexanes—Ethyl acetate (10% -20%) in 20 min.; flow rate: 35 mL/min and collected 18 mL/fraction) yielded the title compound as a light brown liquid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH3:29]>CO.CN(C=O)C>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([O:8][C:9]2[C:14]([NH:15][C:16]3[C:17]4[C:24]([CH3:25])=[C:23]([C:26]([NH2:29])=[O:27])[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:7]1
Reactant: N
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCC(O)CC3)c12
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@@H](O)CC3)c12

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[2-(4-hydroxy-cyclohexyloxy)-pyridin-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia in methanol (7M) in DMF. Separated from trans isomer by chromatography.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14])([O-:10])=[O:9].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][C:17]1[CH:16]=[CH:15][C:13]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 1237.4 %

Procedure:
Triethylamine (23 ml) was added to a suspension of 3-nitro-4-methylaniline (0.8 g), 4-cyanobenzoyl chloride (13.1 g), 4-dimethylaminopyridine (0.8 g) in methylene chloride (200 ml) which had been cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The mixture was partitioned between methylene chloride and 0.5M hydrochloric acid solution. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness. The residue was triturated under isohexane and the resulting solid was isolated and dried under vacuum at 55° C. to yield N-(4-methyl-3-nitrophenyl)-4-cyanobenzamide (18.3 g); NMR: 2.5 (s, 3H), 7.49 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 8.12 (d, 2H), 8.51 (d, 1H), 10.77 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccs2)CC1
Yield: 10.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound, potassium carbonate (3.0 g) and 6-bromo-1-(2-thienyl)-1-hexanone (1.6 g) were reacted and treated in the same manner as in Example 172 to give 0.27 g of 4-amino-5-chloro-N-((1-(6-oxo-6-(2-thienyl)hexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([NH:24][N:25]2[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]2)=[O:23])=[N:10]1.[C:33]([CH2:35][CH2:36][C:37]#[CH:38])#[N:34].[Cl-].[NH4+]>N1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]([CH2:35][CH2:36][C:37]#[C:38][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]([C:22]([NH:24][N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:23])[C:12]=2[CH3:21])=[CH:15][CH:16]=1)#[N:34]
Reactant: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Reactant: C#CCCC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#CCCC#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
To a stirred solution of amide obtained from step E (2 g, 3.3 mmol) in pyrrolidine (40 ml), under an argon atmosphere, tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.3 mmol) was added. The reaction mixture was stirred for 5 min at room temperature, and subsequently 4-cyano-1-butyne (0.78 g, 9.9 mmol) in pyrrolidine (1.5 ml) was added over 5 minutes. The resulting mixture was heated at 80-85° C. for 10 h. The reaction was hydrolyzed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic extract was dried over MgSO4 and the solvent was removed in vacuo. Purification by flash column chromatography on silica gel (eluant ethylacetate) gave compound 15 as a white solid (0.8 g, 43.7%)