Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][CH3:18])=[O:5].C(O[C:28](=[O:30])[CH3:29])(=O)C>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH3:18])[C:28](=[O:30])[CH3:29])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Product: CC(=O)N(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-(2,6-dichlorobenzoylamino)-4-methylaminoquinoline (130 mg) in acetic anhydride (2 ml) was heated at 120° C. for 3 hours. The solvent was removed in vacuo and the residue was dissolved in methanol (3 ml). To a solution was added 1N sodium hydroxide solution (0.5 ml) and the mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was washed with hot 50% ethanol (2 ml) and filtered. The residue was washed with hot 95% ethanol (1 ml) and the filtrate was allowed to stand to ambient temperature. The resulting precipitates were collected by filtration and dried to give 8-(2,6-dichlorobenzoylamino)-4-(N-methylacetamido)quinoline (90 mg).
Reaction SMILES: N1C=C[CH:4]=[CH:3][CH:2]=1.[NH2:7]/[C:8](=[C:14](\Cl)/[C:15]([O:17][CH2:18][CH3:19])=[O:16])/[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:21](O)(=[O:23])C>>[CH3:21][O:23][C:3]1[CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][CH:2]=1
Reactant: CC(=O)O
Reactant: c1ccncc1
Reactant: CCOC(=O)/C(N)=C(/Cl)C(=O)OCC
Product: CCOC(=O)c1cc(OC)cnc1C(=O)OCC

Procedure:
83 g (1.05 mol) of pyridine were added to 221.5 g (1.0 mol) of diethyl 2-amino-3-chloromaleate in 250 ml of glacial acetic acid at 80° C. while stirring. 90 g (1.05 mol) of mathoxyacrolein were then added at 120° C. in the course of 30 minutes, gentle refluxing being established without heating. The reaction mixture was stirred for 3 hours at 120° C. and then evaporated down under reduced pressure, water was added to the residue and the mixture was extracted with methylene chloride. After filtration of active carbon, drying, filtration over neutral alumina with suction and evaporating down under reduced pressure, 190 g (75% of theory) of the title compound were obtained as a pale yellow syrup.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20](C=O)OC2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH2:33]([OH:35])[CH3:34]>>[Cl:11][C:9]1[CH:8]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[CH:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:20](=[N:2][NH2:3])[O:35][C:33]2=[CH2:34])([CH3:15])[CH3:16])[CH:6]=[C:5]([Cl:4])[CH:10]=1
Reactant: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C=O)=C(c2ccccc2)C1=O
Reactant: CCO
Reactant: NN
Solvent: O
Product: C=C1OC(=NN)C(c2ccccc2)C(=O)N1C(C)(C)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
Hydrazine hydrate (0.06 ml) was added to a stirred solution of N-(3,5-dichlorophenyl)-2-(2,3-dihydro-6-formyl-4-oxo-5-phenyl-4H-1,3-oxazine-3-yl)-2-methylpropanamide (0.5 g) in ethanol at room temperature. After 0.5 hours the solvent was evaporated, the residue dissolved in ethyl acetate and washed with water and brine, dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with hexane/ethyl acetate to give N-(3,5-dichlorophenyl)-2-(6-aminoiminomethylene-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 119, 0.19 g) as a pale yellow solid, m.p. 153-155° C.
Reaction SMILES: [N:1]#[N:2].C([O:6][C@@H:7]1[C@@H:12]([O:13]C(=O)C)[C@@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:102]([OH:104])=[O:103])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:101])[CH2:76][CH2:77][C@@H]1O[C@H](COC(=O)C)[C@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1OC(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:102]([OH:104])=[O:103])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:101])[CH2:76][CH2:77][S:26][C@@H:8]2[O:9][C@H:10]([CH2:21][OH:22])[C@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]2[OH:6])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@H:53]([OH:54])[C@H:48]([OH:49])[C@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@H:11]([OH:17])[C@H:12]([OH:13])[C@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@@H](CCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)NC(=O)CCS[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)NC(=O)CCS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C(=O)O
Yield: 61 %

Procedure:
A solution of 19 (50 mg) in methanol-water-triethylamine 5:4:1 (v/v/v, 2 ml) was kept for 18 hours at room temperature, and evaporated in vacuo to dryness. The residue was put on a column of silica gel and eluted with chloroform-methanol-water 60:40:10 (v/v/v). The title compound was isolated in 61% yield (20 mg): RF 0.15 (CHCl3 -MeOH-H2O, 60:40:10); NMR (D2O)δ: 4.51 (d, J1,2 =9.5 Hz, 2H, H-1), 4.52 (d, J1,2 =9.5 Hz, 1H, H-1), 4.34, 4.18 (q, q, α-CH), 3.99 (d, J4,3 =3.0 Hz, 3H, H-4), 3.22 (m, εCH2), 3.02 (m, SCH2), 2.70 (t, J=6.5 Hz, 2H, SCH2CH2), 2.62 (t, J=6.5 Hz, 4H, SCH2CH2); [α]D27 -17.3° (c 1.5, H2O).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1[Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].O.[CH3:34][C:35]#[N:36]>>[C:1]([O:5][C:6]([C:7]1[C:35]([C:34]2[CH:11]=[CH:10][CH:8]=[CH:7][CH:6]=2)=[N:36][O:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1[Cl:21])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#N
Reactant: COC(=O)Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 25 °C

Procedure:
Intermediate 56 (115 mg, 0.35 mmol) is dissolved in MeCN (3 mL). Potassium bis(trimethylsilyl)amide (106 mg, 0.53 mmol) is added slowly while stirring at room temperature. Then the mixture is cooled to 0° C., and a solution of intermediate 58 (55 mg, 0.35 mmol) in CH3CN (1 mL) is added. The mixture is stirred at room temperature overnight, then H2O (5 mL) is added and the mixture is extracted with DCM (3×10 mL). After concentration the crude product is purified on reverse phase HPLC (H2O/MeCN gradient) to afford 5-(2-chloro-4-methoxycarbonylmethyl-phenyl)-3-phenyl-isoxazole-4-carboxylic acid tert-butyl ester 59 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.73 (m, 2H), 7.47 (m, 5H), 7.33 (m, 1H), 3.72 (s, 3H), 3.68 (s, 2H), 1.23 (s, 9H). MS calculated for C23H23ClNO5 (M+H+) 428.1, found 428.1.
Reaction SMILES: [CH2:1]1[NH:13][CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]1[C:3]=2[C:4]=34.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].NC(C)(C)C(N1CC2NC3C=CC=C4C(=O)NN=C(C=2C=34)C1)=O>>[C:18]([O:22][C:23](=[O:24])[NH:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](=[O:28])[N:13]1[CH2:12][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:14](=[O:17])[NH:15][N:16]=[C:2]([C:3]=2[C:4]=34)[CH2:1]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C1NN=C2CNCc3[nH]c4cccc1c4c32
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 63 was prepared from 2,3,4,9-tetrahydro-2,4,9,10-tetraazacyclohepta[def]fluoren-8(1H)-one and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid to the procedure similar to that for Compound 62. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.0 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.05-7.47 (m, 7H), 4.96-5.02 (m, 1H), 4.25-4.81 (m, 4H), 2.62-2.88 (m, 2H), 1.27 (s, 6H), and 1.16 (s, 3H). MS (ESI) m/e [M+1]+ 474.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C(O[C:18]([O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)(C)(C)C.[OH-].C[N+](C)(C)C>>[C:24]([O:23][C:21]([O:20][C:18]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
To a single neck 250 ml round bottom were added 10.0 g (0.617 moles) of 4-acetoxystyrene, 13.46 g (0.617 moles) of di-t-butyldicarbonate and 52 ml (15% mole excess) of a 25 weight % solution of tetramethylammonium hydroxide and the resulting reaction mixture was stirred under nitrogen at room temperature for about 18 hours. The reaction mixture was extracted twice with ether (50 ml) and washed once with a 25 weight % solution of tetramethylammonium hydroxide (50 ml) and then twice with water (50 ml). The organic products were dried over magnesium sulfate and evaporated to dryness leaving a clear colorless oil (12.16 g, 90% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[NH:24]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[NH:24]1[C:32]2[C:27](=[C:28]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]5[CH2:20][O:21][CH2:22][CH2:23][N:5]5[C:4]=4[N:3]=3)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(Cl)ncc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CN1C[C@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 90.7 %

Procedure:
A mixture of (S)-tert-butyl 2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate (PREPARATION x80, 100 mg, 0.293 mmol), indole-4-boronic acid (70.8 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and sodium carbonate (62.2 mg, 0.587 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was heated to 120° C. for 1 hour in a microwave. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through Celite, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (silica-NH, gradient 10-80% EtOAc/hexane) to afford the title compound as an off-white solid (112 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38-1.48 (m, 9 H), 2.98-3.09 (m, 1 H), 3.15-3.40 (m, 3 H), 3.52-3.64 (m, 2 H), 3.87-4.11 (m, 3 H), 4.28 (d, J=17.94 Hz, 1 H), 4.52-4.60 (m, 1 H), 7.12 (t, J=7.71 Hz, 1 H), 7.29-7.44 (m, 3 H), 7.51-7.68 (m, 1 H), 7.93 (dd, J=7.45, 0.88 Hz, 1 H), 11.12 (br s, 1 H); ESI-MS m/z [M+H]+ calc'd for C23H27N5O3, 422.22; found 422.3.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.Br[CH2:23]CCCC(C)(C1C=CC(C)=CC=1)CO.O1C=CCCC1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:21])([C:15]1[CH:16]=[CH:17][C:18]([CH3:23])=[CH:19][CH:20]=1)[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Reactant: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(C)(CCCCBr)COC2CCCCO2)cc1
Yield: 93 %

Procedure:
According to the method described for the synthesis of 207d, 206e (18.2 g, 63.8 mmol) was reacted with 3,4-dihydro-2H-pyran (6.4 g, 76.0 mmol) and p-toluenesulfonic acid hydrate (0.43 g, 2.3 mmol) in CH2Cl2 (300 mL) to give 207e (22.0 g, 93%) as an oil, which was used without further purification. 1H NMR (CDCl3): δ 7.25-7.05 (m, 4 H), 4.60-4.48 (m, 1 H), 3.82 (m, 2 H), 3.48-3.37 (m, 2 H), 3.35-3.26 (m, 2 H), 2.30 (s, 3 H), 1.90-1.40 (m, 11 H), 1.34 (s, 3 H), 1.40-1.08 (m, 1 H). 13C NMR (CDCl3): δ 142.78, 135.22, 128.81, 126.39, 99.09, 99.01, 61.93, 61.85, 41.67, 41.56, 38.12, 37.87, 33.68, 33.64, 30.62, 25.96, 22.89, 20.97, 19.41, 19.37. HRMS (LSIMS, nba): Calcd for C19H30O2Br (MH+): 369.1429, found: 369.1451.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine prepared in the previous step (about 0.125 mmol) in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (31 mg).
Reaction SMILES: [N+]([O-])([N+]([O-])=O)=O.N[C:8]1[CH:9]=[CH:10][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:12]([CH:15]=1)[C:13]#[N:14].[I-:22].[Na+].O>C(#N)C>[I:22][C:8]1[CH:9]=[CH:10][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:12]([CH:15]=1)[C:13]#[N:14]
Reactant: N#Cc1cc(N)ccc1-c1ccccn1
Reactant: [I-]
Agent: O=[N+]([O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(I)ccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dinitrogen tetroxide (2.2 equiv.) was added to a suspension of 5-amino-2-pyridin-2-ylbenzonitrile (0.85 mmol) in acetonitrile (8.5 mL) at −30° C. After 5 min, sodium iodide (1.28 mmol, 1.5 equiv.), and the mixture was stirred for 10 minutes. Water (10 mL) was added and the reaction was allowed to warm to room temperature over 30 min. The product was extracted with methylene chloride and the extracts were washed with saturated sodium thiosulfate solution and brine, dried over sodium sulfate and concentrated. The resulting residue was passed through a silica gel plug, rinsing with 2% methanol in methylene chloride to provide 5-iodo-2-pyridin-2-ylbenzonitrile, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4](O)[CH:3]=1.P(Br)(Br)([Br:12])=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:12][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Cc1cc(O)cc(O)n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(O)n1
Temperature: 110 °C
Yield: 46.2 %

Procedure:
A solution of 6-methylpyridine-2,4-diol (1.75 g, 14.0 mmol) in dry DMF (6.0 mL) is stirred under N2 and phosphorus oxybromide (3.05 g, 10.6 mmol) is added in one portion. The mixture is heated at 110° C. for 45 min and then cooled and diluted with water (7 mL). Na2CO3 (s) is added to bring the pH to 7 and the resulting suspension is cooled to 0° C. The product is collected by suction filtration, rinsing with cold water and diethyl ether, and dried overnight in a vacuum desiccator to afford the title compound as a light brown solid (920 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H-].[Na+].I[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(OCC)(=O)C>O1CCCC1.O>[C:2]([CH:3]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:1])[CH3:11]
Reactant: CCOC(=O)CCCCI
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCCC(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran (200 mL) was added 60% sodium hydride in oil (5.56 g) portionwise over 20 minutes in an ice-water bath under N2. After 40 minutes, to the mixture was added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15 minutes, the mixture was stirred at ambient temperature. After 1 hour, the reaction mixture was heated at 50° C. for 24 hours. The cooled mixture was partitined between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash silica gel chromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1, 20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate (27.3 g, 75.4%) as colorless oil.
Reaction SMILES: Cl[C:2](=[Ti:4]([CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)Cl.[CH3:15][Al:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.CCCCCC>C1(C)C=CC=CC=1>[CH2:2]=[Ti:4]([CH:5]1[CH:6]=[CH:7][CH:8]=[CH:9]1)[CH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH3:15][Al:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: ClC(Cl)=[Ti](C1C=CC=C1)C1C=CC=C1
Agent: C[Al]1CCCCO1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=[Ti](C1C=CC=C1)C1C=CC=C1
Temperature: -78 °C
Yield: 71 %

Procedure:
97.2 mg (0.372 mmol) of dichloromethylenebis(cyclopentadienyl)titanium was weighed out. Thereto 20 ml of dry toluene was added, and the mixture was cooled to a temperature of -78° C. 2.98 mmol of methylalumoxane (16-mer ) in toluene was added thereto dropwise with stirring, and the mixture was allowed to react at 50° C. for 6 hours. Then 20 ml of hexane was added to deposit a reddish brown solid. The solid was collected by filtration, recrystallized from toluene/hexane, and dried. The intended product was obtained in a yield of 71%.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:18]1[CH:17]=[C:16]2[C:21]([N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C@@H:13]([CH2:24][CH3:25])[C:14](=[O:23])[N:15]2[CH2:31][CH3:32])=[CH:20][CH:19]=1
Reactant: CCI
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccc(Br)cc3NC(=O)[C@@H]2CC)cc1
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CC[C@H]1C(=O)N(CC)c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-6-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-7-bromo-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−780 (c=0.005 G/ML, DMSO); MS (ESI) m/z 439/441 ([M+H]+); MS (ESI) m/z 437/439 ([M−H]−).
Reaction SMILES: C[O-].[Na+].Cl.[F:5][CH2:6][C:7]([NH2:9])=[NH:8].[C:10](OCC)(=[O:17])[CH2:11][C:12](OCC)=[O:13]>CO>[F:5][CH2:6][C:7]1[N:9]=[C:12]([OH:13])[CH:11]=[C:10]([OH:17])[N:8]=1
Reactant: N=C(N)CF
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cc(O)nc(CF)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of fluoroacetonitrile (11 g) in ethanol (10.9 mL)-diethyl ether (186 mL) was bubbled with hydrogen chloride under ice-cooling until the solution was saturated with hydrogen chloride with stirring, and the mixture was stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give ethyl 2-fluoroacetimidate hydrochloride (24.9 g). This material was suspended in ethanol (50 mL). To the suspension was added ethanol (130 mL) containing ammonia (about 5 g), and the mixture was stirred at room temperature overnight. The crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give 2-fluoroacetamidine hydrochloride (16.3 g). To a mixture of sodium methoxide (28% methanol solution, 83.6 mL) and methanol (145 mL) was added 2-fluoroacetamidine hydrochloride (16.3 g), followed by adding diethyl malonate (22.0 mL), and the mixture was heated at reflux for 11 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water (145 mL). The mixture was acidified by adding concentrated hydrochloric acid (18 mL), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g). To a mixture of fuming nitric acid (36 mL) and acetic acid (18 mL) was added 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g) slowly under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in ice. To the mixture was added cold water, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (16.8 g).