Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH2:7]([N:9]1[C:13]2[N:14]=[CH:15][C:16]([C:25]3[O:29][N:28]=[C:27]([CH2:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:26]=3)=[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:12]=2[CH:11]=[N:10]1)[CH3:8].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:7]([N:9]1[C:13]2[N:14]=[CH:15][C:16]([C:25]3[O:29][N:28]=[C:27]([CH2:30][CH:31]4[CH2:36][CH2:35][N:34]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:33][CH2:32]4)[N:26]=3)=[C:17]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:12]=2[CH:11]=[N:10]1)[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCNCC4)no3)cnc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCn1ncc2c(NC3CCOCC3)c(-c3nc(CC4CCN(S(C)(=O)=O)CC4)no3)cnc21
Temperature: 25 °C
Reaction time: 31 h

Procedure:
Methanesulphonyl chloride (1.16 mmol) was added to a stirred solution of Intermediate 125 (0.033 mmol) and pyridine (0.5 ml) in chloroform (1 ml) at room temperature. After stirring at room temperature for 31 h, the reaction mixture was applied to a SPE cartridge (aminopropyl, 5 g) and the cartridge was eluted sequentially with chloroform, ethyl acetate and methanol. Fractions containing the desired product were evaporated in vacuo. The resulting residue was further purified on a SPE cartridge (silica, 1 g) eluting with a gradient of 30-100% ethyl acetate in petroleum ether to afford Example 176. LCMS showed MH+=490, TRET=2.97 min.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][CH:13]=[C:12]2[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccnc2ccsc12
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccnc4ccsc34)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 2.6 %

Procedure:
Thieno[3,2-b]pyridin-7-ol (203 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 130° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (4 mg, yield 1%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CCOCC1.C(OCC)(=O)C=C.C1(N=C=NC2CCCCC2)CCCCC1.[F:40][C:41]1[CH:42]=[C:43]([N:53]2[CH2:57][C@H:56]([CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:55][C:54]2=[O:63])[CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl.C(O)C>[F:40][C:41]1[CH:42]=[C:43]([N:53]2[CH2:57][C@H:56]([CH2:58][NH:59][C:60](=[O:62])[CH3:61])[O:55][C:54]2=[O:63])[CH:44]=[CH:45][C:46]=1[N:47]1[CH2:52][CH2:51][N:50]([C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH2:49][CH2:48]1
Reactant: O=C(O)CCN1CCOCC1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=CC(=O)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCN1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CCN4CCOCC4)CC3)c(F)c2)C(=O)O1
Yield: 88.9 %

Procedure:
3-(4-Morpholinyl)propionic acid (0.600 g, 2.11 mmol), prepared by condensation of morpholine with ethyl acrylate (3 equivalents) in refluxing ethanol, followed by distillation, saponification (1N aqueous sodium hydroxide, tetrahydrofuran, reflux), neutralization (1N HCl) and lyophilization, was combined with 1,3-dicyclohexylcarbodiimide (0.434 g, 2.11 mmol), 4-(dimethylamino)pyridine (13 mg, 0.11 mmol), (S)-N-[[3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.354 g, 1.05 mmol), and 1:1 tetrahydrofuran/dichloromethane (50 mL) at room temperature. After 3 days the reaction mixture was filtered to remove the precipitated 1,3-dicyclohexylurea and the filtrate concentrated in vacuo. The crude product was chromatographed over silica gel (20 g), eluting with a gradient of 1-6% methanol/chloroform, to give 0.446 g (95%) of the title compound as a white solid with mp 209°-210° C. ##STR14##
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([OH:24])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].IC.[CH3:28]N1CCCN(C)C1=O>C1COCC1>[Si:3]([O:10][CH2:11][C:12]1[CH:23]=[C:22]([O:24][CH3:28])[C:21]([I:25])=[CH:20][C:13]=1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: COC(=O)CCc1cc(I)c(O)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CN1CCCN(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(I)c(OC)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
A suspension of 60% sodium hydride in mineral (1.2 g) in THF (56 ml) is cooled to -20° C. and of solution of methyl 2-tert-butyldimethylsilyloxymethyl-4-hydroxy-5-iodohydrocinnamate (12.6 g), iodomethane (5 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (8 ml) in THF (20 ml) is added. The cold bath is removed, the mixture stirred for about 2 hours, and diluted with ether. The ether solution is washed with 0.1M HCl, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% ether in hexanes, to give the desired product.
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:9]1[C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 1.10 g of 2-fluoro-3-(trifluoromethyl)benzaldehyde, 663 mg of methyl thioglycolate, 1.03 g of potassium carbonate and 15 ml of DMF was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 1.34 g of methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[OH:15])[C:11](O)=[O:12])=[CH:4][C:3]=2[O:2]1.Cl.[NH2:23][C@H:24]([C:35]([O:37][CH3:38])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:38][O:37][C:35](=[O:36])[C@H:24]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[NH:23][C:11](=[O:12])[CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15]
Reactant: O=C(O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(c1ccc2c(c1)OCO2)C(O)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (100 mg), HCl.H-L-Trp-OMe (136 mg) and HOBT (55 mg) in dimethylformamide (6 ml) was added WSCD (64 mg) under ice-bath cooling. After being stirred overnight at room temperature, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was washed with 5% hydrochloric acid solution, 1M aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo to afford N-[(2RS,3RS)-2-(3,4-methylenedioxyphenyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophane methyl ester (165 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 150 °C
Yield: 100.3 %

Procedure:
A solution of (4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.[Cu]>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1Oc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (0.8 g) and anhydrous potassium carbonate (0.21 g) were stirred together in DMF under nitrogen at 70° C. After 20 minutes benzyl bromide (1.06 g) was added together with copper bronze (cat.) and the reaction mixture heated to 100° C. for 3 hours. GC analysis indicated 50% reaction. A second equivalent of both potassium carbonate and benzyl bromide was added and heating continued at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water and extracted with ether (×3). The ether extracts were combined, dried, filtered and evaporated to give a brown oil. Chromatography on silica gel (eluent petroleum ether - ether, 50:50) afforded methyl 2-(3-benzyloxyphenoxy)-3-pyridinylacetate as a light yellow solid (0.5 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH2:18](I)[CH3:19].O>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([N:9]1[C:8]2[CH:14]=[CH:15][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13])[CH3:19]
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)COc2cc(C(=O)OC)ccc21
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a solution of 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 4(1)] (1.0 g) in dimethylformamide (80 ml) were added 60% sodium hydride (in oil) (0.25 g) and ethyl iodide (1.0 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from ethyl acetate/hexane to give 4-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.3 g).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:26]=[CH:25][C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[C:4]([F:27])[CH:3]=1.C(I)(I)[I:29].N(OC(C)(C)C)=O>O1CCCC1>[F:27][C:4]1[CH:3]=[C:2]([I:29])[CH:7]=[CH:6][C:5]=1[O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: IC(I)I
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(N)cc3F)cc2CC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(I)cc3F)cc2CC1

Procedure:
To a solution of 1,1-dimethylethyl 7-[(4-amino-2-fluorophenyl)oxy]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (E274, Step 2) (0.5 g, 1.34 mmol) and iodoform (1 g, 2.69 mmol) in tetrahydrofuran (10 ml) was added dropwise tert-butyl nitrite (0.32 ml, 2.69 mmol). The reaction was then heated at reflux for 1 hour, cooled and concentrated in vacuo and resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 384 [M-COOtBu]+.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14](O)=[O:15])=[CH:10][N:9]=[C:8]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:29]1(=[O:36])[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C.OC(C)(C)C#N>ClCCl.CN(C)C=O>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([CH:30]3[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:29]3=[O:36])=[O:15])=[CH:10][N:9]=[C:8]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)C1C(=O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-cyclohexyl-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylic acid (i.e. the product from Example 11, Step B) (0.58 g, 1.5 mmol) in 10 mL of dichloromethane was added oxalyl chloride (0.490 g, 3.9 mmol) and one drop of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 h and then concentrated under reduced pressure. The crude oil was then redissolved in 10 mL of dichloromethane and then treated with 1,3-cyclohexanedione (0.24 g, 2.1 mmol) and triethylamine (0.39 g, 3.8 mmol) stirred for 30 min, then treated with a catalytic amount of 2-hydroxy-2-methyl-propanenitrile (0.015 g, 0.15 mmol) and triethylamine (0.393 g, 3.8 mmol) and stirred at ambient temperature for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 10% methanol in chloroform to provide 0.570 g of the title compound, a compound of the invention, as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH3:27])[CH:34]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: COc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc(Cn3nc(C(C)C)c(O)c(C(=O)NCC(=O)O)c3=O)cc2)ccn1
Yield: 42.5 %

Procedure:
To a 20 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), [2-(methyloxy)-4-pyridinyl]boronic acid (11.18 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with 1N HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-2-({4-[2-(methyloxy)-4-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (15 mg, 0.031 mmol, 43.1% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 12.96 (br. s., 1H), 10.18 (t, J=5.56 Hz, 1H), 8.22 (d, J=5.31 Hz, 1H), 7.76 (d, J=8.34 Hz, 2H), 7.42 (d, J=8.34 Hz, 2H), 7.30 (dd, J=5.43, 1.39 Hz, 1H), 7.10 (s, 1H), 5.31 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.89 (s, 3H), 3.19 (sept, J=6.78 Hz, 1H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 453 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.NC(N)=O.[N+:14]([O-])([O-:16])=[O:15].[K+].[OH-].[Na+]>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(N)cc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a stirred solution of 30.0 g (244 mmol) p-anisidine in 105 ml concentrated sulfuric acid at 0° C. was added 17.6 g (292 mmol) urea. After stirring for 1 h, a solution of 27.1 g (268 mmol) potassium nitrate in 47 ml concentrated sulfuric acid was then added dropwise over 1 h while the reaction mixture was maintained at 5-10° C. The mixture was then poured onto ice, and sodium hydroxide pellets added portionwise with stirring until the pH was 14. Ethyl acetate was then added and the phases were separated. The organic phase was washed with water and then with brine, dried over sodium sulfate, and concentrated in vacuo to afford 31.4 g (77%) 4-methoxy-3-nitro-phenylamine as an orange solid. EI-MS m/e (%): 169 (M+, 100), 153 ([M-CH3]+, 10), 92 (21).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:25]2[CH2:26][CH2:27][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Reactant: c1ccc(C2CCNCC2)cc1
Product: CC(=O)N1CC(CCN2CCC(c3ccccc3)CC2)c2ccccc21

Procedure:
In the manner described in Example 1, reaction of 1-acetyl-3-(2-bromoethyl)indoline with 4-phenylpiperidine gives a solid that is recrystallized from dilute ethanol to give white crystals, m.p. 92°-93°C.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:21](CC)CC)[CH3:20].C(N)C.C(O)(=O)C>CO.CC(O)C.O>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:21][CH2:19][CH3:20])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Agent: CCN
Solvent: CC(=O)CC(C)=O
Solvent: CO
Solvent: CC(C)O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
First, 20.0 g (0.124 mol) of L-glutamic acid-γ-methyl ester was suspended in 20 g of methanol. To this, 13.7 g (0.137 mol) of acetylacetone and 12.5 g (0.124 mol) of triethylamine were added. The mixture was stirred at 60° C. for one hour. Subsequently, 80 g (1.24 mol) of 70% ethylamine was added to the mixture. After the mixture was allowed to react for 6 hours, excessive ethylamine was distilled away under reduced pressure. To this, 29.8 g (0.496 mol) of acetic acid, 30 mL of water and 120 mL of IPA were added. The mixture was heated for one hour and cooled on ice. The crystal precipitated was filtrated by suction and washed with 20 mL of IPA to obtain wet matter. The wet matter was dried under reduced pressure to obtain 13.1 g of theanine as a white crystal substance (yield: 61%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1[C:19]2[C:14](=[C:15]([B:20]3[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]3)[CH:16]=[CH:17][CH:18]=2)CCC1)=O.BrC1C=CC=C2C=1CCCN2C(=O)CCCOC1C=CC=C(C)C=1C.BrC1C=C(C=CC=1)[CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66]>>[CH3:26][C:23]1([CH3:25])[C:22]([CH3:27])([CH3:28])[O:21][B:20]([C:15]2[CH:14]=[C:19]([CH:18]=[CH:17][CH:16]=2)[CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[O:66])[O:24]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(Br)c1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Product: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one was replaced with tert-butyl 3-((3-bromobenzyloxy)carbonylamino)propanoate. LCMS, [M+Na]+=428.2.