Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4].[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:46]3[CH:47]=[CH:48][C:43]([S:40]([CH3:39])(=[O:42])=[O:41])=[CH:44][CH:45]=3)=[CH:15][CH:16]([CH3:18])[CH3:17])[N:11]([S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC(C)C)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC(C)C)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 72.5 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[3-methyl-1-(toluene-4-sulfonyloxy)-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.2 g, 2.1 mmol), 4-(methanesulfonyl)phenylboronic acid (1.0 g, 5.2 mmol), dichlorobis(triphenylphosphine)palladium (II) (150 mg, 0.21 mmol) in dioxane (10 mL) was added an aqueous sodium carbonate solution (2 M, 5.2 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (820 mg, 73%) as a light yellow solid: LC/MS m/e calcd for C27H26N2O6S2 [M+H]+ 539.65, observed 539.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (d, J=6.6 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 2.68 (m, 1H), 3.08 (s, 3H), 3.99 (s, 3H), 6.27 (d, J=10.2 Hz, 1H), 6.67 (s, 1H), 7.28 (m, 2H), 7.36 (m, 2H), 7.49 (m, 1H), 7.67 (m, 2H), 7.78 (m, 2H), 8.55 (d, J=2.0 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH2:17][CH2:18][Cl:19]
Reactant: ClCCBr
Reactant: Oc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution comprising 2,6-dibromophenol (3.90 g, 15.00 mmol), potassium carbonate (2.48 g, 17.94 mmol) and DMF (40 ml) was added with 1-bromo-2-chloro ethane (4.30 g, 29.98 mmol) and stirred at room temperature for 16 hours. The reaction solution was concentrated and liquid separation was carried out with ethyl acetate-water. The organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (n-hexane) to obtain the target compound (4.75 g, quant.) as a colorless oily substance.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1([F:34])[CH2:5][CH2:6][N:7]([C:20]([C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:24][C:23]=2[CH3:33])=[O:21])[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2/[C:10]/1=[CH:11]/[C:12]([O:14]C)=[O:13]>CO>[F:34][C:4]1([F:3])[CH2:5][CH2:6][N:7]([C:20]([C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:33])=[O:21])[C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2/[C:10]/1=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2sc(-c3ccccc3)nc2C)CCC1(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A 1N aqueous solution of sodium hydroxide (5 ml) was added to a solution of 1,080 mg of methyl (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetate in 30 ml of methanol, followed by stirring at room temperature for 18 hours. After evaporating the reaction solution, 20 ml of water and 10 ml of 1N hydrochloric acid were added to the residue, and the resulting precipitate was collected by filtration and washed with water to give 1,000 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetic acid as a colorless powder.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3cncnc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cncnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyrimidin-5-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.15 mmol), β-alanine (706 mg, 7.9 mmol) and NaOMe solution (12 mL, 6.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 4. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 44 mg of the title compound. MS: (+) m/z 446.27 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH2:34]([N:37]=[C:38]=[O:39])[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH2:34][CH2:35][CH3:36])[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: CCCN=C=O
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone was reacted with sodium iodide and n-propylisocyanate to give (S)-1-(2-chloro-benzenesulfonyl)-3-propyl-4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-imidazolidin-2-one as a colorless foam. MS: 559.6 ([M+H]+)
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[C:17](=[O:33])[N:18]([C:29]([CH3:32])([CH3:31])[CH3:30])[S:19](=[O:28])(=[O:27])[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)=CC=1.O[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([OH:40])=[O:39]>>[C:29]([N:18]1[C:17](=[O:33])[C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:35]2[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=2)[C:38]([OH:40])=[O:39])=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:19]1(=[O:28])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(C(=O)O)c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate and 3-hydroxybenzoic acid in a similar manner as described for Example 12. 1H NMR (500 MHz, d8-THF): δ 7.62-7.58 (d, 1H), 7.57-7.51 (m, 2H), 7.49 (s, 1H), 7.46-7.42 (m, 3H), 7.31 (t, 1H), 7.30 (t, 1H), 6.51 (t, 1H), 3.82 (t, 2H), 3.14-3.08 (m, 2H), 1.83-1.78 (m, 2H), 1.70 (s, 9H); 13C NMR (125 MHz, d8-THF): δ 166.7, 159.8, 158.9, 135.5, 132.5, 131.9, 129.2, 129.1, 128.4, 126.4, 122.1, 119.1, 114.9, 106.9, 65.6, 60.4, 41.3, 29.0, 26.9; Mass Spectrum: M+H+ 459.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18](Cl)=O.[OH-].[K+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:13][C:18]([C:17]3[CH:21]=[CH:22][C:23]([F:24])=[C:15]([F:14])[CH:16]=3)=[CH:11][C:10](=[O:12])[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cccc(C(C)=O)c1O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])O
Solvent: c1ccccc1
Solvent: O
Product: C=CCc1cccc2c(=O)cc(-c3ccc(F)c(F)c3)oc12
Temperature: 60 °C
Yield: 57.8 %

Procedure:
A mixture of 1.7 g (9.4 mmol) of 3'-allyl-2'-hydroxyacetophenone, 2.0 g (11 mmol) of 3,4-difluorobenzoyl chloride, 1.6 g (4.7 mmol) of tetra-n-butylammonium bisulfate, 60 ml of 10% aqueous potassium hydroxide and 60 ml of benzene was heated at 60° C. for 4 hours, cooled and the phases separated. The organic phase was washed with three 60 ml portions of water, treated with 5.6 g (28 mmol) of p-toluenesulfonic acid monohydrate and an additional 60 ml of benzene and refluxed for 3 hours, using a Dean-Stark trap to remove the water in the reaction. The resulting mixture was washed with 150 ml of 8% aqueous sodium bicarbonate and then with three 60 ml portions of water. The organic phase was then concentrated in vacuo; treated with 25 ml of methanol and cooled to -20° C. After four hours the resulting solid was filtered, washed with three 5 ml portions of methanol and dried to give 1.62 g (56%) of 8-allyl-2-(3,4-difluorophenyl)-4H-benzopyran-4-one as a solid: m.p. 127°-130° C.; TLC Rf 0.48 in 3:1 toluene-methyl isobutyl ketone.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[CH2:10][CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[N:15][N:14]=2)C(=O)C2=CC=CC=C12.O.NN.[Br:56][C:57]1[CH:62]=[CH:61][C:60]([N:63]=[C:64]=[O:65])=[CH:59][CH:58]=1>CCO>[Br:56][C:57]1[CH:62]=[CH:61][C:60]([NH:63][C:64](=[O:65])[NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[CH2:10][CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[N:15][N:14]=2)=[CH:59][CH:58]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(CCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCCc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C(NCCCN(CCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCCc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 3-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[1-(triphenylmethyl)tetrazol-5-yl]propane (50 mg, 0.073 mmol) in EtOH (1 ml) was added hydrazine monohydrate (17 μl, 0.36 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under vacuum, and then water was added. The mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. To the filtrate was added 4-bromophenyl isocyanate (17 mg, 0.088 mmol), and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 3% methanol/chloroform to afford 3-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[1-(triphenylmethyl)tetrazol-5-yl]propane (Compound 217, 33 mg, 60%): MS(ES+) m/e 756 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 1H), 7.53 (br, 1H), 7.34 (m, 10H), 7.09 (m, 12H), 5.79 (br, 1H), 4.05 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.17 (m, 1H), 2.74 (m, 4H), 2.55 (m, 1H), 2.44 (m, 2H), 1.96 (m, 3H), 1.86 (m, 1H), 1.72 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[Cl:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][SH:19].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:18]([S:19][CH:18](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[Cl:15])[C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[Cl:15]
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Reactant: COc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(OC(C)=O)c(OC)c2)SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-acetoxystyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2N(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
In an argon gas stream, 2.0 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine was added gradually to 0.4 g of 60% sodium hydride in oil in 40 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hour and 2.68 g of phenacyl bromide was added. The mixture was stirred at room temperature for 1 hour, after which the solvent was distilled off under reduced pressure. The residue was diluted with 50 ml of water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and elution was carried out with methylene chloride-ethyl acetate. Recrystallization from ethyl acetate-ether gave 2.04 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-4-phenacyl-2H-1,4-benzoxazine.
Reaction SMILES: [NH2:1][C@@H:2]([CH:11]([CH3:13])[CH3:12])[C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].S=[C:15]1[CH2:19][S:18][C:17](=[O:20])[NH:16]1>C(O)C>[CH3:12][CH:11]([CH3:13])[C@H:2]([NH:1][C:15]1[CH2:19][S:18][C:17](=[O:20])[N:16]=1)[C:3]([N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CC(C)[C@H](N)C(=O)N1CCOCC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of (2S)-2-amino-3-methyl-1-(morpholin-4-yl)butan-1-one (850 mg) in ethanol (10 mL) was added 4-thioxothiazolidin-2-one (608 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (583 mg).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.BrC1SC=CC=1.[C:13]1([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[S:4]1[CH:5]=[CH:6][C:2]([N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccsc1
Agent: [Pd+2]
Agent: Brc1cccs1
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 50.4 %

Procedure:
Into a reactor were introduced 0.358 g (2.20 mmol) of 3-bromothiophene and 4 mL of toluene under a nitrogen atmosphere. The bromothiophene was dissolved in the solvent. To this solution were added 0.343 g (2.03 mmol) of diphenylamine, 0.229 g (2.39 mmol) of sodium t-butoxide, 4.4 mg (1 mol % based on the amine) of palladium acetate, and 30.6 mg (2 mmol % based on the amine) of the 1,1-diphenyl-2-(dicyclohexylphosphino)propene obtained in Example 2. The resultant reaction mixture was stirred at 100° C. for 10 hours and then cooled. Saturated aqueous ammonium chloride solution was added thereto, and this mixture was extracted with toluene. The extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography to obtain 0.257 g (50%) of N-(3-thiophenyl)-N,N-diphenylamine. The results obtained are shown in Table 20.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.[Br:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[C:12]=1N.[ClH:20]>C(O)(=O)C>[Cl:20][C:12]1[C:14]([Cl:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=1[Br:10]
Reactant: Cl
Reactant: Nc1c(Cl)cc(Cl)cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc(Cl)c(Cl)c(Br)c1

Procedure:
Sodium nitrite (3.88 g, 0.056 mole) was added in portions to concentrated sulphuric acid (28.16 ml) stirred below 10° C. A solution of 2-bromo-4,6-dichloroaniline (12 g, 0.05 mole, Lancaster) in glacial acetic acid (126 ml) was added maintaining the temperature below 10° C. The mixture was stirred below 10° C. for 1 hr and then slowly added to a stirred solution of cuprous chloride (10.11 g, 0.10 mole) in concentrated hydrochloric acid (101.05 ml) at room temperature. The mixture was then stirred at room temperature for 17 hrs. The product was filtered, washed with water (3×50 ml), dissolved in chloroform (150 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give the desired product. Yield 10 g (77%), M.p. 55-57° C.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[CH2:56][O:55][CH2:54][C@H:53]2[OH:57])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:57][C@@H:53]1[CH2:54][O:55][CH2:56][C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O
Product: CCO[C@@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting trans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3354, 2973, 2958, 2938, 1484, 1462, 1446, 1396, 1300, 1239, 1172, 1072, 1050, 1043, 885 cm−1; OAMS supporting ions at: ESI+ 386.1; MS (EI) m/z 385 (M+); HRMS (FAB) calcd for C22H31N3O3+H1 386.2443, found 386.2438. Anal. Calcd for C22H31N3O3: C, 68.54; H, 8.11; N, 10.90. Found: C, 68.38; H, 7.99; N, 10.85.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>>[CH2:29]([NH:32][CH2:28][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1)[CH:30]=[CH2:31]
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: C=CCN
Product: C=CCNCC(O)COc1ccc2c(=O)c(-c3ccccc3)c(-c3ccccc3)oc2c1

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)-2,3-diphenychromone and allylamine afforded the desired amine as white needles, m.p. 119- (iPrOH); yield, 82%. Its hydrochloride salt had m.p. 140°-142° (iPrOH/PhCH3); containing water).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][NH:7][C:8](=[O:29])[C@@H:9]([O:17][P:18]([OH:28])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[Ca]>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][NH:7][C:8](=[O:29])[C@@H:9]([O:17][P:18]([O:28][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)[C@H](Cc1ccccc1)OP(=O)(O)OCc1ccccc1
Agent: [Ca]
Product: CCOC(=O)CCNC(=O)[C@H](Cc1ccccc1)OP(=O)(OCc1ccccc1)OCc1ccccc1

Procedure:
N-[(S)2-[[hydroxy(phenylmethoxy)phosphinyl]oxy]-1-oxo-3-phenylpropyl]β-alanine ethyl ester, calcium salt thereof;
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]3[O:8][C:9]([NH:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)=[N:10][C:6]=3[CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1cc(Nc2nc3ccnc(Br)c3o2)cc(OC)c1OC
Reactant: Nc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2nc3ccnc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 83 h

Procedure:
0.082 g (0.209 mmol) (4-bromo-oxazolo[5,4-c]pyridin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine and 0.04 g (0.22 mmol) (4-aminophenyl) boronic acid are dissolved in 3 ml 1,2-dimethoxy-ethane, a solution of 0.044 g (0.425 mmol) Na2CO3 (in 0.6 ml water) is added and a stream of argon is bubbled through the mixture in order to exclude oxygen from the reaction mixture. Tetrakis (triphenylphosphine) palladium (0.0259 g, 0.021 mmol) is added and the reaction mixture is stirred at 100° C. or 83 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane=>EtOAc) and recrystallisation from dichloromethane/diethyl ether to afford the title compound. Rt=1.70 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 393 (M+1)+; m.p. 148-151° C.