Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]2[C:15]=1[CH3:16])=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:15]([CH3:16])=[C:6]([NH2:5])[N:7]=2)[CH:10]=1
Reactant: Cc1c(NC(=O)C(F)(F)F)nc2ccc(F)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(N)nc2ccc(F)cn12
Temperature: 100 °C

Procedure:
2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide (0.188 g, 0.00072 mol) was dissolved in methanol (4.0 mL) and water (0.5 mL). Potassium carbonate (0.40 g, 0.0029 mol) was added and heated in the microwave for 45 min at 100° C. The solvent concentrated and residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried (magnesium sulfate) then chromatographed on silica (55:40:5, DCM:acetonitrle:MeOH) to give 6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine Rf 0.47, (55:40:5, DCM:acetonitrle:MeOH); MS m/z 166 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:44]1([CH:54]([NH2:56])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.CN1CCOCC1>CC(N(C)C)=O>[C:44]1([CH:54]([NH:56][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH3:55])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC(NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (40.0 mg, 0.156 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (89 mg, 0.23 mmol) were combined in a 20 mL vial and dimethylacetamide (DMA) (1 mL) was added. The yellow solution was stirred at room temperature for 10 minutes and then a solution of 1-(1-napthyl)ethylamine (40.1 mg, 0.234 mmol) and N-methylmorpholine (NMM) (0.086 mL, 0.78 mmol) in DMA (0.20 mL) was added. The mixture was shaken at room temperature for 16 hours then the solution was evaporated in vacuo. The crude product was purified by preparative reversed-phase HPLC to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C(O)C>[CH:19]([NH:23][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([Cl:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCC(C)N
Solvent: CCO
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]

Procedure:
To a stirred mixture of 20 g. (0.0655 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 150 ml. of absolute ethanol was added 9.58 g. (0.131 mole) of sec-butylamine, dropwise, over a period of about 15 minutes. The resultant solution was refluxed for 2 hours and the ethanol then removed by distillation under reduced pressure. The solid yellow residue was triturated with 300 ml. water to dissolve the sec-butylamine hydrochloride. The water insoluble product was isolated by filtration, washed with water, and then dissolved in 600 ml. of refluxing 95% ethanol. Upon cooling, the product crystallized. Filtration gave 20.4 g. of a yellow crystalline solid, melting at 90.5°-91.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.12 mol) in DMF (100 mL) was added K2CO3 (26.3 g, 0.19 mol). The reaction mass was stirred at 80° C. for 1 h followed by addition of methyl iodide (12.3 mL, 0.19 mol). The reaction mass was further stirred at 80° C. for 5-6 h. The reaction mass was filtered and the obtained filtrate was concentrated. The residue was further diluted with water and obtained solid was filtered off to afford 20.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.83 (s, 3H), 3.97 (s, 3H), 7.38 (d, J=9.3 Hz, 1H), 8.41 (dd, J=2.4 Hz & 2.4 Hz, 1H), 8.47 (s, 1H); MS (m/z): 212.44 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCOCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 35.9 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.0 g of 4-(2-propoxyethoxy)-benzyl bromide, and then 2.0 g of anhydrous potassium carbonate was added thereto. The mixture was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, procedures similar to those in Preparation Example 2 were carried out to obtain 1.4 g of the aimed product as an oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:34](OC)=[O:35])[CH2:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:38][OH:39]>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:15][CH:16]([CH2:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:34]([NH:38][OH:39])=[O:35])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)NC(=O)CNC(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CNC(=O)OCc1ccccc1)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.2 %

Procedure:
To a solution of the title compound of Example 16b (440 mg, 0.81 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added NH2OH (50% aqueous solution, 0.74 mL, 12 mmol). After stirring for 20 hours at room temperature, the solution was concentrated. Purification by flash chromatography (5:95 MeOH/CHCl3) yielded the title compound as a white solid (80 mg, 18%): Anal. Calcd. for C25H25N3O7S2.0.25 H2O: C, 54.78; H, 4.69; N, 7.67; S, 11.70. Found: C, 54.78; H, 4.72; N, 7.46; S, 11.53.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[O:23][CH3:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10]C=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]([B:26]([OH:31])[OH:27])=[CH:18][C:17]=1[O:23][CH3:24])=[O:25])[C:7]1[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 8.5 ml, 13.54 mmol) was added slowly to a solution of N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 5.41 mmol) in tetrahydrofuran (40 mL) at −78° C. After 30 minutes, triisopropyl borate (1.87 mL, 8.12 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 3 hours. Hydrochloric acid (2.5N, 40 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile to give 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (0.916 g, 56%). 1H NMR (DMSO-d6) δ 2.85 (m, 2H), 3.53 (m, 2H) 3.88 (s, 3H), 7.31 (m, 7H), 7.70 (d, J=7.61 Hz, 1H), 8.19 (m, 2H), 9.10 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cncc(N)c1N
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cncc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 120 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A mixture containing 4,5-diamino-nicotinic acid ethyl ester (79; 1.81 g, 10 mmol), 2-trifluoromethylbenzaldehyde (1.9 g, 11 mmol), Na2S2O5 (9.5 g, 50 mmol) in 50 mL of DMF was stirred at 120° C. for 18 h. Upon cooling to room temperature, the reaction mixture was poured into 100 mL of cold water. The resulting solids were collected by filtration, washed with water, and dried to provide 2-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 80 (2.35 g, 70%)
Reaction SMILES: O.Cl.[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][CH2:24]OC3C=CC(CNCC)=CC=3)[N:22]=2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].C(C1C=C(C2OC=C(CCOC3C=CC(CNCC)=CC=3)N=2)C=C(C(C)(C)C)C=1O)(C)(C)C.Cl.[CH:70]([C:72]1[CH:73]=[C:74]([CH:77]=[CH:78][C:79]=1[OH:80])[CH:75]=[O:76])=[O:71].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]([C:11]1[CH:10]=[C:9]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][CH2:24][O:80][C:79]3[CH:78]=[CH:77][C:74]([CH:75]=[O:76])=[CH:73][C:72]=3[CH:70]=[O:71])[N:22]=2)[CH:8]=[C:7]([C:3]([CH3:4])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCNCc1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Reactant: O=Cc1ccc(O)c(C=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(-c2nc(CCOc3ccc(C=O)cc3C=O)co2)cc(C(C)(C)C)c1O
Yield: 48.9 %

Procedure:
In a flask, 4.75 g (15 mmole) of the compound of Example 1 C, 2.36 g (15.75 mmole) of 3-formyl-4-hydroxybenzaldehyde, and 3.93 g (15 mmole) of triphenylphosphine were dissolved in 45 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −10° and a solution of 2.36 ml (15 mmole) diethyl azodicarboxylate in 15 ml. Tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +1° C. The bath was removed and the reaction stirred under nitrogen for 18 hours. The reaction was then stripped, dissolved in a minimum amount of methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed, Prep 500, two columns, eluting with 0 to 20% ethyl acetate/toluene gradient over 30 minutes. The appropriate fractions were bulked and stripped to give 3.3 g (49%) product which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].I[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)CCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5 mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir at room temperatue for 30 minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to room temperature and stir overnight at room temperature. Cool to 5° C., quench by addition of ice and saturated ammonium chloride solution (5 mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve the residue in ethyl acetate (150 mL), wash the organic phase with water (3×40 mL), dry (Na2SO4), filter and concentrate to afford a yellow oil. Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60% ethyl acetate in hexane. Concentrate the appropriate fractions in vacuo and dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:13]=[N:12]2)[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Sc2ccccc2)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Sc3ccccc3)cc2=O)n1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionic acid (Intermediate 95) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenylsulfanyl-6H-pyridazin-1-yl)-propionamide was obtained as an off-white solid (83.5 mg, 61%); ES+-HRMS m/e calcd for C25H31N5O3S [M+H+] 482.2221 found 482.2221. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H), 1.05 (br. s., 3H), 1.19-1.78 (m, 9H), 1.78-2.00 (m, 1H), 2.10-2.32 (m, 1H), 3.88 (s, 2H), 4.67 (s, 1H), 5.42 (dd, J=10.9, 4.2 Hz, 1H), 5.95 (d, J=2.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.56-7.70 (m, 5H), 7.94 (d, J=2.4 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: CC1C=C(C)C=C(C)C=1[Mg]Br.C1([Mg]Br)C=CC=CC=1.[C:20]1([CH3:32])[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[C:28](O)([CH3:30])[CH3:29]>COC1CCCC1.C1COCC1>[CH3:30][C:28]([C:21]1[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[CH3:32])=[CH2:29]
Reactant: Cc1cc(C)c(C(C)(C)O)c(C)c1
Agent: Br[Mg]c1ccccc1
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Solvent: COC1CCCC1
Product: C=C(C)c1c(C)cc(C)cc1C
Yield: 81.9 %

Procedure:
The same experiment as in Example 2 was carried out, except for using 45 ml (0.045 mol) of a 1 M 2,4,6-trimethylphenylmagnesium bromide solution in CPME instead of 45 ml of the 1 M phenylmagnesium bromide solution in THF. The resulting reaction mixture was analyzed by gas chromatography to confirm that 2-mesityl-2-propanol and α-methyl-2,4,6-trimethylstyrene were obtained in a yield of 81.9% and 1.6%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([CH3:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.06 g, 3.9 mmol) in methanol (100 mL) and sodium hydroxide (0.31 g, 7.8 mmol) in water (2 mL) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was poured into 2 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, concentrated, and dried under high vacuum to give N-[2-chloro-4-[[[(3-hydroxyphenyl) methyl]amino]carbonyl]-6-methylbenzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (1.50 g, 75%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14](O)=[O:15])=[CH:5][CH:4]=1)#[N:2].B.C1COCC1.O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][CH2:14][OH:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(CCO)CC(=O)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.9 %

Procedure:
To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (1.00 g, 4.06 mmol) in THF (15 mL) was added borane-THF complex (1.2M, THF solution 6.77 mL, 8.12 mmol) under ice-cooling. The mixture was stirred at room temperature for 14 hr, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give N-(4-cyanophenyl)-5-hydroxy-3-methylpentanamide (0.442 g, 1.904 mmol, 46.9%) as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].C(N(CC)CC)C.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]([N:7]1[CH:6]([CH3:8])[CH2:5][NH:4][C:3](=[O:9])[C@@H:2]1[CH3:1])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CNC(=O)[C@H](C)N1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of (3S, 5RS)-3,5-dimethyl-piperazin-2-one (24.3 mmol) in 100 mL of methylenechloride is added triethylamine (8.45 mL, 60.75 mmol) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol). After stirring overnight, the CH2Cl2 is removed, and the crude mixture is chromatographed (50% EtOAc/Hexane). (2S, 6RS)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (3.3 g, 52% yield over three steps) is isolated as a white powder. MS C14H18N2O3 MS m/z: 263.
Reaction SMILES: [OH-].[Na+].C[Si](C)(C)[C:5]#[C:6][C:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10]>O.C(O)C>[CH2:15]([O:14][C:7]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])[C:6]#[CH:5])[CH3:16]
Reactant: CCOC(C#C[Si](C)(C)C)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CC(OCC)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
A solution of sodium hydroxide (0.14 g, 3.60 mmol) in water (50 mL) was added to a solution of trimethyl-triethoxyprop-1-ynyl-silane (50.0 g, 208 mmol) in ethanol (250 mL). After stirring for 1 hour at room temperature, water was added and the mixture was extracted with ethyl acetate. The organic extracts were dried with magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (20.0 g, 52% yield) as yellow oil. 1H NMR (CDCl3) δ 3.70 (q, 6H, J=8.0 Hz), 2.56 (s, 1H) 1.24 (t, 9H, J=8.0 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.[Cl:35]CCl.Cl>C(OCC)C>[ClH:35].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(O)C[C@@H](Cc1c[nH]c2ccccc12)NCCNCCc1ccccc1
Reaction time: 1 h

Procedure:
Combine 2-[(R)-2-(1H-Indol-3-yl)-1-carboxymethyl-ethylamino]-N-(t-butoxycarbonyl)-N-(2-phenyl-ethyl)-ethylamine (1.64 g, 3.53 mmol) and dichloromethane (30 mL). Slowly pass hydrogen chloride gas through the solution for 20 minutes. Stir for 1 hour. Add diethyl ether (150 mL) to form a solid. Filter and dry under vacuum to give the title compound. Elem. Anal. calculated for C22H27N3O2.0.75 H2O: C, 58.70; H, 6.98; N, 9.14. Found: C, 58.71; H, 6.98; N, 9.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 42 %

Procedure:
The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 42% of theory; LC (method 4): tR=1.98 min; Mass spectrum (ESI+): m/z=342/344 (Cl) [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH2:32])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[N:18]=[C:17]([CH3:29])[N:16]=2.N1C=CC=CC=1>ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:14]([CH2:30][CH2:31][NH:32][C:2](=[O:3])[O:4][CH3:5])[C:15]2[C:20]([N:21]=1)=[C:19]([N:22]1[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]1)[N:18]=[C:17]([CH3:29])[N:16]=2
Reactant: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(CCN)c2n1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NCCn1c(-c2ccccc2Cl)nc2c(N3CCN(C)CC3)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Add methyl chloroformate (0.25 g, 0.0027 mol) to a solution of 2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethanamine (0.39 g, 0.0010 mol) and pyridine (4.0 mL) in dry dichloromethane (4 mL) at 0° C. Allow to warm to room temperature and stir for 2 hour. Quench the reaction mixture with saturated aqueous sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column using dichloromethane:methanol (97:3) as eluent to afford methyl N-[2-[8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)purin-9-yl]ethyl]carbamate (0.3 g). ES/MS m/z 444 (M+1).