Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:21])[CH3:20].C(O)(=O)C.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[C:44]([O:46][CH3:47])[CH:45]=1)[NH2:42]>CO.O>[CH3:47][O:46][C:44]1[CH:43]=[C:41]([NH:42][C:2]2[C:11]([NH:32][S:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[CH:28][CH:27]=3)(=[O:30])=[O:31])=[N:10][C:9]3[C:4]([N:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:40]=[C:39]([O:38][CH3:37])[CH:45]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(OC(C)C)cc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A solution of 2,3-dichloroquinoxaline (2.0 mL, 0.38 M) was combined with K2CO3 (105 mg, 0.76 mmol) in a glass vial. A solution of 4-isopropoxybenzene sulfonamide (1.75 mL, 0.43 M) was added and the solution was stirred overnight at 125° C. After cooling, acetic acid (45 mL, 0.79 mmol) and 3,5-dimethoxyaniline (230 mg, 1.5 mmol) were added. The reaction mixture was stirred again at 125° C. overnight. Upon cooling, the reaction mixture was diluted with 8 mL of methanol and then 8 mL of water. The precipitate was collected by filtration and recrystallized from N,N-dimethylacetamide/water to give N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)-4-isopropoxy-benzenesulfonamide (45 mg, 12%). 1H-NMR (400 MHz, d6-DMSO): 12.16 (bs, 1H), 8.93 (s, 1H), 8.03 (d, 2H), 7.92 (bs, 1H), 7.56 (d, 1H), 7.36 (m, 4H), 7.07 (d, 2H), 6.24 (s, 1H), 4.72 (m, 1H), 3.76 (s, 6H), 1.27 (d, 6H); MS (EI) m/z C25H26N4O5S: 495 (MH+).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Br[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]>CN(C)C=O.O>[CH3:19][C:18]([CH3:20])=[CH:17][CH2:16][CH2:15][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)=CCCBr
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 2-nitroimidazole (3.0 g, 27 mmol) in dry dimethylformamide (25 mL), was added anhydrous sodium bicarbonate (4.2 g, 50 mmol) followed by 5-bromo-2-methyl-2-pentene (5.0 g, 30.67 mmol). The reaction mixture was heated at 60-70° C. with stirring under nitrogen for 16 hours. Solvent dimethylformamide and the unreacted bromide were removed under reduced pressure (<1 mm) at 50-60° C. to yield a paste which was dissolved in water (50 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried and concentrated to give a brown oil which was recrystallized from petroleum ether (b.p. 40-60° C.) to yield a yellow solid. Yield: 4.8 g, m.p. 51-52° C. 1H NMR (CDCl3) δ 1.55 (s, 3H, CH3), 1.75 (s, 3H, CH3), 2.7 (q, 2H, olefinic CH2), 4.5 (t, 2H, N—CH2), 5.2 (t, 1H, olefinic H), 7.1 (s, 1H, imidazole H), 7.2 (s, 1H, imidazole H). M.S. [M+H]+ 196, [M+NH4]+ 213.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([OH:9])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](Cl)(Cl)=[O:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl>C1(C)C=CC=CC=1.CN(C)C=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:9][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:12])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(O)CC(C)C
Reactant: O=C(Cl)Cl
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)OC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-hydroxy-4-methylpentanoic acid methyl ester was added 150 ml of 12.5% phosgene in toluene and 25 drops of dimethylformamide. After stirring for 16 h at room temperature, the solvent was evaporated and the residue chased several times with benzene. The resulting product was dissolved in methylene chloride (50 ml), cooled to 0° C. and treated by dropwise addition with 3.86 g (0.044 mol) of morpholine. The reaction mixture was stirred for 2 h at 0°-5° C. and then distributed between 0.5N HCl and methylene chloride. The organic phase was washed with aqueous NaHCO3 and brine and evaporated to a residue. Flash chromatography on silica gel gave the desired compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.COS(OC)(=O)=O>CN(C=O)C>[CH3:5][NH3+:6].[CH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: C[NH3+]
Product: c1ccc2cnccc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-8-nitroisoquinoline (0.99 g, 3.91 mmol) and dimethylsulfate (0.41 mL) in anhydrous DMF (20 mL) was heated at 80° C. for 24 hours. After removing the DMF in vacuo, the isoquinoiine methylammonium salt was obtained (used without further purification).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C@H:25]([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1.CI.[NH4+].[Cl-]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([C:25]([CH3:1])([O:27][C:28]3[N:29]([CH3:39])[C:30]([C:33]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)=[N:31][N:32]=3)[CH3:26])[N:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@@H](Oc1nnc(-c2ccncc2)n1C)c1noc(-c2cccc(Cl)c2)n1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(OC(C)(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccncc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of diisopropylamine (55.0 ml, 0.39 mmol) in THF (3 ml) at 0° C. was added nBuLi (2.5M, hex., 135 ml) slowly. After 20 minutes the mixture was cooled to −78° C. and (−)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine (107 mg, 0.28 mmol) in THF (2 ml) was added. The resulting mixture was stirred for 45 minutes before CH3I (22 ml, 0.34 mmol) was added and the reaction mixture was stirred for 1 h at r.t. Sat. NH4Cl solution was added and the mixture was extracted with EA. The organic phase was washed with H2O and brine, dried and evaporated. Purification of the residue by silica gel chromatography using CHCl3:MeOH 50:1 followed by prep. HPLC gave the title compound (22 mg, 20%). 1H-NMR: 2.11 (s, 6 H) 3.63 (s, 3 H) 7.45 (d, 1 H) 7.52-7.57 (m, 1 H) 7.59 (d, 2 H) 7.98 (d, 1 H) 8.09 (s, 1 H) 8.72 (d, 2 H)
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:19]=3)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].CO.O>C1COCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2[N:19]=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][CH2:8]4)[C:23]([CH3:24])=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(OC)cc4)ccc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(C)c(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1

Procedure:
Following the procedure described above (Example 472, step 2) and starting with ethyl((1S)-5-{2-[6-(4-methoxyphenyl)-3-methyl-2-pyridinyl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 481, 90 mg, 0.190 mmol) and LiOH (50 mg, 1.91 mmol) in a mixture of THF (4 mL), MeOH (5 mL), and water (2 mL), the title compound was obtained (0.052 g, 65%). 1H NMR (400 MHz, CD2Cl2) δ 7.96 (d, 2H), 7.52-7.45 (m, 2H), 7.09 (d, 1H), 6.96 (d, 2H), 6.83 (d, 1H), 6.74 (dd, 1H), 4.49 (t, 2H), 3.86 (s, 3H), 3.50 (qt, 1H), 3.31 (t, 2H), 2.96-2.75 (m, 3H), 2.52-2.35 (m, 5H), 1.82-1.73 (m, 1H); LC-MS: RT=2.48 min, (M+H)+ 418.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([O:20][CH3:21])=[N:16][NH:17][C:18]=2[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCC[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]([O:20][CH3:21])=[N:16][N:17]([CH2:23][CH3:24])[C:18]=2[CH3:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1n[nH]c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCNCC1
Product: CCn1nc(OC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C

Procedure:
The title compound was prepared from 1-tert-butoxycarbonyl-4-(3-methoxy-5-methyl-(1H)-pyrazol-4-yl)piperidine (Step D) using a procedure analogous to that described for Piperidine 15, Step E. RF: 0.29 (9:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.31 (t, J=7.3, 3H), 1.47 (s, 9H), 1.54–1.56 (m, 2H), 1.79–1.87 (m, 2H), 2.13 (s, 3H), 2.38–2.45 (m, 1H), 2.70 (m, 2H), 3.84 (s, 3H), 3.91 (q, J=7.3, 2H), 4.25 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-:8])=[N:6][CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.C([Br:15])(=O)C.[OH-].[Na+]>C(O)(=O)C>[Br:15][C:4]1[CH:3]=[C:2]([CH3:1])[N+:7]([O-:8])=[N:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cn[n+]1[O-]
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(Br)cn[n+]1[O-]

Procedure:
6-Methyl-4-nitro-pyridazine-1-oxide (270 mg, 1.74 mmol) was dissolved in 2 mL acetic acid, acetyl bromide (650 mL, 8.7 mmol) was added and the reaction mixture was heated at reflux for 1 h. The reaction mixture was poured into crushed ice, the mixture was neutralized by addition of sodium hydroxide and extracted three times with dichloromethane (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel (heptane/ethyl acetate 80:20->30:70 gradient) and the desired product was obtained as a light brown solid (150 mg, 45%).
Reaction SMILES: [Na].C(O[CH:7]=[CH:8][C:9](=O)[C:10]([Cl:16])([F:15])[C:11]([F:14])([F:13])[F:12])CCC.[C:18]([NH2:24])(=[O:23])[CH2:19][C:20]([NH2:22])=[O:21]>CO>[Cl:16][C:10]([C:9]1[NH:22][C:20](=[O:21])[C:19]([C:18]([NH2:24])=[O:23])=[CH:7][CH:8]=1)([F:15])[C:11]([F:12])([F:13])[F:14]
Reactant: CCCCOC=CC(=O)C(F)(Cl)C(F)(F)F
Reactant: NC(=O)CC(N)=O
Agent: [Na]
Solvent: CO
Product: NC(=O)c1ccc(C(F)(Cl)C(F)(F)F)[nH]c1=O

Procedure:
0.33 g (14.4 mmol) of sodium were dissolved in 50 ml of methanol, 3.16 g (12.03 mmol) of 1-butoxy-4-chloro-4,5,5,5-tetrafluoropent-1-en-3-one and 1.27 g (12.03 mmol) of malonamide were added and the mixture was heated under reflux for 7 h. The mixture was concentrated, and 1N hydrochloric acid was then added. The resulting precipitate was filtered off with suction and dried. This gave 380 mg (12% of theory) of a yellowish powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:30]3[CH:31]=[CH:32][C:33]4[C:37]([CH:38]=3)=[N:36][N:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:34]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:39]([N:35]1[CH:34]=[C:33]2[C:37]([CH:38]=[C:30]([C:8]3[CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:31]=[CH:32]2)=[N:36]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
To a suspension of tert-butyl 4-{4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]phenyl}piperazine-1-carboxylate (610 mg, 1.02 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at rt for 17 h. The mixture was evaporated to dryness and saturated, aqueous NaHCO3 was added to the residue. The resulting solid was collected by filtration and was dried in vacuo to afford 489 mg (96%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.99-7.91 (m, 3 H), 7.81 (d, 1 H), 7.65 (s, 1 H), 7.41-7.25 (m, 5 H), 7.19 (d, 1 H), 7.06-6.96 (m, 3 H), 5.65 (s, 2 H), 3.14 (s, 4 H), 2.89 (s, 4 H); ES-MS m/z 501.4 [M+H]+, HPLC RT (min) 2.25.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.CC1O[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=CC=2)=[N:24]C=1CCO.Br[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>>[CH3:20][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:24]1[CH2:25][CH2:27][CH2:32][CH:31]1[CH3:30]
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: Brc1ccccn1
Product: Cc1oc(-c2ccc(-c3ccccn3)cc2)nc1CCN1CCCC1C

Procedure:
The titled compound is prepared in substantial accordance with the procedures found in Example 4, Intermediate 13, and Example 75 using 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (see Intermediate 3) and 2-bromopyridine. MS (m/e): 348.3 (M+1)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>O1CCCC1.CCCCCC.C(OCC)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:15]([OH:20])[OH:16]
Reactant: COc1ccccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccccc1B(O)O
Reaction time: 1.5 h

Procedure:
To a stirred, cold (-78° C.) solution of 2-iodoanisole (2.85 ml, 5.6 g) in 50 ml of tetrahydrofuran under nitrogen was added 10.0 ml of 2.5M n-butyl lithium in hexane. After 15 min. triisopropyl borate (3.38 ml, 4.7 g) was added and the reaction was allowed to come to and remain at room temperature for 1.5 hr. The mixture was poured into an excess of 2N hydrochloric acid and diethyl ether was added. The resulting mixture was stirred vigorously for 30 min. and the phases were separated. The ether layer was washed with aqueous sodium bisulfite until colorless and then with saturated sodium chloride solution and then dried over magnesium sulfate. Concentration of the ether layer gave the crude boronic acid which crystallized from ether to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[NH4+:26]>C1COCC1.Cl[Hg]Cl>[NH2:26][C:12]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]
Reactant: [NH4+]
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: Cl[Hg]Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NC(N)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.0 g, 2.8 mmol), 30% ammonium hydroxide (8.5 mL), HgCl2 (0.76 g, 2.8 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a white solid (0.90 g, 97% yield) and this compound was used without further purification. LCMS: m/z 321 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH2:28])=[O:26].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH:39]([C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=2[F:56])[C:40]2[N:45]=[CH:44][C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.ClCCl.ClCCl.CCCCCC>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:27][NH:28][C:46](=[O:47])[C:43]1[CH:42]=[CH:41][C:40]([CH:39]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)(=[O:37])=[O:38])[C:49]2[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:50]=2[F:56])=[N:45][CH:44]=1)=[O:26]
Reactant: NNC(=O)c1ccco1
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(NNC(=O)c1ccco1)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 57.9 %

Procedure:
Triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0.095 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol) and 2-furancarboxylic acid hydrazide (29 mg, 0.23 mmol) were added to a solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (80 mg, 0.19 mmol), which had been obtained in Example 338, in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 7.5 hours. The reaction mixture was diluted with dichloromethane, followed by successive washing with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel colunm and a fraction obtained from the elution portion with dichloromethane:methanol=50:1 was concentrated under reduced pressure. The solid thus obtained was recrystallized from dichloromethane-hexane, whereby the title compound (58 mg, 0.11 mmol, 58%) was obtained as a white powder.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:3].P([N:33]=[N+:34]=[N-:35])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C1CCN2C(=NCCC2)CC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[N:33]([CH:2]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:3])=[N+:34]=[N-:35]
Reactant: COC(=O)c1ccc2cc(C(C)O)oc2c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2cc(C(C)N=[N+]=[N-])oc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.7 %

Procedure:
To a solution of methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (1.10 g, 4.99 mmol) in toluene (20 mL) were added diphenyl azidophosphate (1.62 mL, 7.50 mmol) and DBU (1.50 mL, 9.98 mmol), and the mixture was stirred at room temperature for 2.5 hr. Ethyl acetate was added thereto, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 2:3) to give the title compound (1.22 g, yield 88%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[CH3:10]
Reactant: Fc1cc(I)ccn1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1cc(I)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2 g, 8.97 mmol), diethyl amine (2.77 ml, 26.9 mmol, 3 eq) and K2CO3 (2.48 g, 17.94 mmol, 2 eq) in DMF (20 mL) is stirred for 18 h at 100° C., allowed to cool to rt, diluted with EtOAc/H2O and extracted with EtOAc. The organic phase is washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (Hex/Et2O, 98:2) to afford 2.3 g of the title compound as a yellow oil: ESI-MS: 277.1 [M+H]+; TLC: Rf=0.52 (Hex/Et2O, 98:2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4](C)[C:3]=1C=C.CS(N)(=O)=O.[O-]S([O-])=O.[Na+].[Na+].[C:25]([OH:29])(C)([CH3:27])[CH3:26].[OH2:30]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:3])[C:26]=1[C@H:25]([OH:29])[CH2:27][OH:30]
Reactant: C=Cc1c(C)cc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)O
Reactant: O
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The reaction mixture of 1-bromo-3-methyl-5-nitro-2-vinylbenzene (65C) (12.3 g, 50.83 mmol), AD-mix a (71 g), MeSO2NH2 (4.8 g, 50.8 mmol) in t-butyl alcohol/H2O (1:1) (200 ml) was stirred at 0° C. for 3 days. Na2SO3 (˜6 g) was added to quench the reaction, stirred at rt for 40 min. The reaction mixture was washed by water, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 6.96 g of 65D and recovered 2.3 g of 65C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22][CH3:23])=[C:16](I)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:27]([OH:30])[C:28]#[CH:29]>C(NCC)C.C1COCC1.C(Cl)Cl.[Cu](I)I.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>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([O:22][CH3:23])=[C:16]([C:29]#[C:28][CH2:27][OH:30])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCNCC
Solvent: ClCCl
Product: COc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Yield: 68 %

Procedure:
N-(4-chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (250 mg), copper iodide (40 mg) and dichlorobis(triphenylphosphine)palladium (30 mg) are dissolved in a mixture of diethylamine (15 mL) and THF (15 mL). To this is added propargyl alcohol (452 μL). The mixture is heated at reflux for 1 h, cooled to room temperature, diluted with CH2Cl2, washed with 1N HCl, brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (CH2Cl2/MeOH 1/0, 45/1, 19/1, 9/1) and the resulting product is recrystalized from MeOH to afford 144 mg (68%) of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (CDCl3) δ8.80, 8.60, 7.32, 4.65, 4.57, 4.13, 3.98; IR (diffuse reflectance) 2425, 2350, 2318, 2233, 1921, 1662, 1607, 1551, 1512, 1492, 1465, 1397, 1380, 1292, 809, cm−1; MS (El) m/z 411 (M+), 244, 86, 84, 80, 79, 78, 65, 63, 61, 51; HRMS (FAB) calcd for C21H18ClN3O4+H1 412.1064, found 412.1067.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][CH:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[CH:17](O)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CS(C)=O>[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[CH:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
54.6 g (0.1 mole) of the tosylate of 1,1-bis-(2,4-dichlorophenoxy)-3,3-dimethylbutan-2-ol in 200 ml of dry dimethylsulfoxide were mixed with an equimolar amount of potassium tert.-butylate. The mixture was stirred for 30 minutes at room temperature, after which hydrolysis was effected with water, the mixture was extracted twice with the same volume of ethyl acetate, the extracts were dried and the solvent was distilled off under reduced pressure.