Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH2:25][NH:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:26]([CH3:27])[CH2:25][C:17]1[N:16]([CH3:15])[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:10]
Reactant: O=C(O)c1ccccc1Br
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
Reaction time: 8 h
Yield: 60.9 %

Procedure:
EDC (660 mg, 3.44 mmole) was added to a solution of 2-bromobenzoic acid (693 mg, 3.45 mmole), 1-methyl-2-(methylaminomethyl)indole (600 mg, 3.45 mmole), and HOBt.H2O (466 mg, 3.45 mmole) in DMF at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (2% MeOH/CH2Cl2) gave the title compound (750 mg, 63%): MS (ES) m/e 357 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].CN(C)C1C=CC=CC=1.[O:22]1CC[CH2:24][CH2:23]1.ClCC(Cl)=O>C(OCC)(=O)C>[NH:1]1[C:23](=[O:22])[CH2:24][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]1=2)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1c(O)ccc2ccccc12
Reactant: C1CCOC1
Agent: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: O=C1COc2ccc3ccccc3c2N1
Reaction time: 1 h

Procedure:
To a mixture of 1-amino-2-naphthol (16.9 g), N,N-dimethylaniline (19.3 g) and tetrahydrofuran (200 ml) is added dropwise chloroacetyl chloride under ice cooling, and the mixture is stirred at the same temperature for one hour. To the reaction mixture is added ethyl acetate, and the ethyl acetate layer is washed, dried and distilled to remove the solvent. The resulting oil is dissolved in acetone (500 ml) and thereto is added potassium carbonate (75 g), and the mixture is refluxed for 2 hours, and acetone is distilled off. To the residue is added water, and the precipitate is separated by filtration, washed, dried and recrystallized from tetrahyrofuran to give 1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one (13.1 g). M.p. 219°-220.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([O:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:42])[CH2:38][C:39](O)=[O:40])([CH3:35])([CH3:34])[CH3:33].C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:42])[CH2:38][C:39]([O:29][C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:30][CH3:31])=[O:40]
Reactant: CC(C)(C)OC(=O)CC(=O)O
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.3 %

Procedure:
A suspension of 6-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxy-phenyl)-thieno[3,2-d]pyrimidin-4(3H)-one (100 mg; 0.219 mmol) (Example 82), 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol), diisopropylcarbodiimide (83 uL; 0.538 mmol) and 4-N,N-dimethylaminopyridine (27 mg; 0.219 mmol) in 1 mL of CH2Cl2 was stirred at rt for 17 h. Additional 3-tert-butoxy-3-oxopropanoic acid (83 uL; 0.538 mmol) and diisopropylcarbodiimide (83 uL; 0.538 mmol) were added and the suspension stirred at rt for 3 h. The suspension was diluted with CH2Cl2, filtered and the filtrate washed with 1N HCl, saturated aq. NaHCO3 and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 1:1 gradient) to afford 104 mg (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.64 (s, 6H), 3.23 (s, 2H), 3.87 (s, 3H), 4.20 (s, 2H), 6.91 (dd, J=8.24 Hz, 2.20 Hz, 1H), 6.95 (d, J=2.20 Hz, 1H), 7.02 (d, J=8.24 Hz, 1H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.80 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 23.37, 27.92, 44.04, 56.23, 74.44, 81.83, 82.01, 111.53, 114.75, 119.20, 120.87, 123.22, 127.65, 129.47, 130.51, 131.54, 135.67, 148.19, 149.30, 150.49, 151.63, 156.79, 157.40, 165.85, 166.20; HPLC (Method #1) 4.46 min retention time, (97%); MS (ES): m/z 599 [M+H]+.
Reaction SMILES: C1COCC1.[CH:6]1([C:12]([C:14]2[C:15]([NH:21][CH2:22][CH3:23])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl[CH:25]([CH2:31][CH2:32][C:33]([O-:35])=O)[C:26]([O:28]CC)=[O:27].N1C(C)=CC=CC=1C>O>[CH:6]1([C:12]2[C:14]3[C:15](=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:21]([CH2:22][CH3:23])[C:33](=[O:35])[C:32]=2[CH2:31][CH2:25][C:26]([OH:28])=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Reactant: CCNc1nc(C)ccc1C(=O)C1CCCCC1
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(C2CCCCC2)c2ccc(C)nc21
Temperature: 60 °C

Procedure:
To a 20 ml THF solution containing 2.34 g of 3-cyclohexanecarbonyl-2-ethylamino-6-methylpyridine were added 3 ml of monoethyl chloroglutarate and 2.8 ml of 2,6-lutidine, followed by stirring under heating at an oil bath temperature of 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with 3M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and 1.00 g of sodium methoxide was added to a 20 ml ethanol solution of the resulting residue, followed by heating under reflux for 1 hour. Then, 20 ml of a 1M sodium hydroxide aqueous solution was added to the reaction solution, followed by heating under reflex for another 1 hour. After the mixture was cooled to room temperature, water was added thereto, and the mixture was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol-water to obtain 764 mg of 3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid as colorless crystals.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].CON(C)[C:11](=[O:22])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[CH:14][C:13]=1[O:20][CH3:21].Cl[Si](C)(C)C.BrCC(Cl)CC>C1COCC1.Cl.O.C(OCC)(=O)C>[NH2:19][C:15]1[C:16]([Cl:18])=[CH:17][C:12]([C:11](=[O:22])[CH2:3][CH2:4][CH2:5][CH2:6][Cl:7])=[C:13]([O:20][CH3:21])[CH:14]=1
Reactant: ClCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Agent: CCC(Cl)CBr
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)CCCCCl
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
Magnesium (236 g, 9.71 mol) was suspended in 3.5 L of THF under nitrogen and 1-bromo-4-chlorobutane (1.11 L, 8.68M, 9.63 mol) was added at a rate such that the temperature of the mixture remained below 25° C. A solution of N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (400 g, 1.64 mol), prepared as in Example 2, under nitrogen in 4 L of THF was cooled to -20° C. and 410 mL of chlorotrimethylsilane was added. The mixture was allowed to warm to between -12 and 30° C. and then 2.5 L of the solution containing the magnesium and 1-bromo-2-chlorobutane was added over approximately 20 minutes. The mixture was cooled to 50° C. and then diluted with 420 mL of concentrated hydrochloric acid in 5 L of water. The mixture was heated to 32° C., stirred for 15 minutes and then diluted with approximately 2 L of ethyl acetate. The organic layer was separated and washed sequentially with 2 L of water and 2 L of 1:1 water/saturated sodium chloride solution and saturated sodium chloride solution. All aqueous layers were combined and extracted with ethyl acetate. All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was combined with hot hexane and allowed to stand at room temperature for approximately 12 hours giving a precipitate. The precipitate was isolated by filtration and washed with hexane. Drying in a vacuum oven at between 50 and 55° C. under a nitrogen gas bleed gave 1-(4-amino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one (365 g, 1.33 mol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O[CH:11]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[C:12]([OH:14])=[O:13].O>OS(O)(=O)=O>[C:16]([NH:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:12]([OH:14])=[O:13])(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(O)C(=O)O)c1ccccc1
Reactant: c1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)c1ccccc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
2,3-Dihydrobenzofuran (4.8 g, 40 mmole) is stirred with 9.0 g (40 mmole) of α-hydroxy-hippuric acid in 200 ml of 10% H2SO4 -90% acetic acid mixture. The reaction is run at room temperature for 0.5 hour. After the half-hour, the reaction mixture is poured into 500 ml of water. The aqueous solution is extracted with ethyl acetate (4×100 ml). The ethyl acetate extracts are dried over magnesium sulfate and then evaporated to give α-benzamido(2,3-dihydro-5-benzofuranyl)acetic acid. Recrystallization of the crude benzamido compound from hexanemethylene chloride gives 11.56 g (94% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([OH:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1=CC(c2ccccc2)Cc2c1ccc(O)c2O

Procedure:
Approximately 1 mmol of 1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene, from Example 2, was reacted with 1.2 mmol of acetic anhydride in the presence of 1.2 mmol of triethylamine in an excess of methylene chloride. The mixture was washed with 0.1N HCl, and dried. The product was precipitated by addition of ether, collected, and dried. mp 238° C. MS M/Z: 310. Anal. calc. for C19H19NO3.HBr C: 65.03; H, 5.72; N, 3.61; found: C, 73.46; H, 6.13; N, 4.49.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])OC(=O)[NH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[C:12]([NH:23][NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: NNc1ccccc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Solvent: CCO
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)NNc1ccccc1

Procedure:
Into a 1000-mL 3-necked round-bottom flask, was placed a solution of 7-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (56 g, 269.23 mmol, 1.00 equiv) in ethanol (500 mL), 1-phenylhydrazine (31.98 g, 296.11 mmol, 1.10 equiv). The resulting solution was heated to reflux for 5 min. The resulting mixture was then concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/petroleum ether (1:2˜1:0) and ethyl acetate/petroleum ether (1:1) to yield 2-amino-4-nitro-N′-phenylbenzohydrazide as a yellow solid. MS: 273 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][C:14]([CH3:24])=[CH:15][C:16]([O:17][CH:18]([CH2:21][O:22][CH3:23])[CH2:19][CH3:20])=[C:11]3[N:10]([CH3:25])[N:9]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[C:28]([C:30]1[NH:31][CH:32]=[CH:33][CH:34]=1)#[N:29]>[Cu]I>[CH3:27][O:26][C:4]1[CH:3]=[C:2]([N:31]2[CH:32]=[CH:33][CH:34]=[C:30]2[C:28]#[N:29])[CH:7]=[CH:6][C:5]=1[C:8]1[C:12]2=[N:13][C:14]([CH3:24])=[CH:15][C:16]([O:17][CH:18]([CH2:21][O:22][CH3:23])[CH2:19][CH3:20])=[C:11]2[N:10]([CH3:25])[N:9]=1
Reactant: CCC(COC)Oc1cc(C)nc2c(-c3ccc(Br)cc3OC)nn(C)c12
Reactant: N#Cc1ccc[nH]1
Agent: [Cu]I
Product: CCC(COC)Oc1cc(C)nc2c(-c3ccc(-n4cccc4C#N)cc3OC)nn(C)c12

Procedure:
Copper(I) iodide catalyzed Buchwald reaction of compound 18a with 2-cyanopyrrole, following the procedure of Example 10, Step 10B, afforded 1-{3-Methoxy-4-[7-(1-methoxymethyl-propoxy)-1,5-dimethyl-1H-pyrazolo[4,3-b]pyridin-3-yl]-phenyl}-1H-pyrrole-2-carbonitrile (compound 18-1).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:34](Cl)(=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 80 %

Procedure:
In a stream of nitrogen and under ice-cooling, 210 mg (1.67 mmol) of potassium tert-butoxide was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.78 mmol) of 2-(3-benzyloxybenzamido)benzenesulfonamide produced in Reference Example 1, and the mixture was stirred for 1 hour. This solution was mixed with 176 mg (1.19 mmol) of n-hexanoyl chloride and stirred at room temperature for 3 hours. After completion of the reaction, this was neutralized by adding an ammonium chloride aqueous solution and then the solvent was evaporated. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 300 mg (yield: 86%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][CH2:21][OH:22]>CC(O)C.[OH-].[Na+]>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][CH2:21][OH:22])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCBr
Reactant: COc1cc(O)ccc1CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cc(OCCO)ccc1CNC(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a stirred solution of (4-hydroxy-2-methoxy-benzyl)-carbamic acid tert-butyl ester (22.8 mg, 0.09 mmol) in 2-propanol (1 mL) and 2 N aq. NaOH (0.15 mL) is added 2-bromoethanol (22.5 mg, 0.18 mmol). The reaction mixture is heated to 85° C. and stirred for 8 h. The mixture is cooled to rt and subjected to prep. HPLC purification to give [4-(2-hydroxy-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (10.3 mg) as a colourless oil. LC-MS: tR=0.85 min, [M+1]+=298.07.
Reaction SMILES: N1C2C(=CC=CN=2)C(C(=O)C([O-])=O)=C1.[K+:15].[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O:32]CC)=[O:31])=[CH:21][NH:22]2>>[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O-:32])=[O:31])=[CH:21][NH:22]2.[K+:15]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(OC)ncc(OC)c12
Agent: O=C([O-])C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12

Procedure:
Compound 3ao (Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate) was prepared (as a yellow solid), by the same method used to prepare compound 3a except Ethyl (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was employed as the starting material. MS m/z: (M+H)+ of the corresponding acid of compound 3ao (M−K+H)+ calcd for C11H11N2O5: 251.07. found 251.09. HPLC retention time: 0.69 minutes (column B).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[C:23]([O:27][C:28]([NH:30][CH:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH:21][C:32](=[O:33])[CH:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:35]2[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=2)[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: CSc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(SC)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
A solution of 2-((2S,3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (75 mg, 0.24 mmol) and tert-butoxycarbonylamino-(4-methylsulfanyl-phenyl)-acetic acid (77 mg, 0.26 mmol) in dichloromethane (10 mL) at 0° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol). The reaction was allowed to slowly warm to room temperature and stirred for 60 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel gradient eluted up to 7:3 ethyl acetate/hexane. The material obtained after chromatography was further treated by precipitation of dichloromethane solution with excess of hexanes to give 2-{(2S,3S)-2-[2-tert-butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white amorphous solid (115 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[C:3]1=[O:18].[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][CH2:32][OH:33])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C.O>[OH:33][CH2:32][CH2:31][C@@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])[C:28]([N:14]1[CH2:15][CH2:16][CH2:17][C@:4]2([C:3](=[O:18])[N:2]([CH3:1])[CH2:6][C@H:5]2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)O
Reactant: CN1CC(c2ccccc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCO)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (100 mg; 0.409 mmol) was solubilised in acetonitrile (1.4 ml). (R)-2-(Tert-butoxycarbonylamino)-4-hydroxybutanoic acid (90 mg; 0.409 mmol) was added followed by diisopropylethylamine (0.286 ml; 1.637 mmol). ®T3P (50% solution in ethyl acetate) (0.478 ml; 0.819 mmol) was added and the mixture stirred at RT for 2 hr. The reaction was diluted with water and extracted with EtOAc; the organics were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 0-10% MeOH in DCM with ammonia to afford tert-butyl (R)-4-hydroxy-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxobutan-2-ylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>ClCCCl.ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)CCCCCl
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCCl)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of 4-chloroquinolin-3-amine (4.00 g, 22.39 mmol) and 5-chlorovaleryl chloride (1.30 mL, 33.6 mmol) dissolved in 150 mL of 1,2-dichloroethane was heated to reflux. After 2.8 days more 5-chlorovaleryl chloride (1.0 mL, 7.7 mmol) was added. After 16 hours more the reaction was cooled to room temperature, diluted with dichloromethane, washed with saturated aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 3.78 g of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide as a tan solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[K].CC(C)([O-])C.Cl.[NH:21]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1>CS(C)=O>[N:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C1CCNN1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(=O)N2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirred together with 1.35 g (12.0 mmol) potassium-tert.-butoxide in 4 ml DMSO at ambient temperature under an argon atmosphere for 35 min and then 1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at ambient temperature for 68 h the reaction mixture is poured into semisat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[F:17][C:18]1[CH:23]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[CH:20][C:19]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)C.CCCCC>[CH2:1]([O:3][C:4]([C:6]1[S:14][C:13]2[C:12]([F:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:19]1[CH:20]=[CH:21][C:22]([Si:24]([CH3:26])([CH3:25])[CH3:27])=[CH:23][C:18]=1[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2c(F)cncc2c1N
Reactant: C[Si](C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1sc2c(F)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Yield: 64 %

Procedure:
A mixture of 3-amino-7-fluoro-thieno[3,2-c]pyridine-2-carboxylic acid ethyl ester (360 mg, 1.5 mmol), trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (411 mg, 1.3 mmol), Pd2 dba3 (69 mg, 0.075 mmol), Xantphos (86 mg, 0.15 mmol) and Cs2CO3 (685 mg, 2.1 mmol) in toluene (6 ml) was subjected to microwave irradiation at 160° C. for 20 minutes. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give a residue which was subjected to flash chromatography (Si-SPE, pentane:diethyl ether, gradient 100:0 to 90:10) to give the title compound as a yellow solid (338 mg, 55%). LCMS (method B): RT=5.20 min, M+H+=407.