Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Reactant: CCOC(=O)CCCCCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 0 °C

Procedure:
A suspension of 4-chloro-3-nitro[1,5]naphthyridine (9.0 g, 42.9 mmol) in chloroform (180 mL) was cooled to approximately 0° C. Ethyl 6-aminohexanoate hydrochloride (12.6 g, 64.4 mmol) and triethylamine (16.6 mL, 119 mmol) were sequentially added with stirring, and the reaction was stirred for 15 minutes. The mixture was diluted with chloroform (180 mL), washed with 1% aqueous sodium carbonate (3×125 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide ethyl 6-(3-nitro[1,5]naphthyridin-4-ylamino)hexanoate as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[CH:34](=O)[CH2:35][CH3:36]>>[CH2:1]([O:8][C:9]1[C:10]([N:22]([CH2:34][CH2:35][CH3:36])[C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:11][C:12]2[C:13]([CH3:21])=[CH:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCC=O
Reactant: CCCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Product: CCCCCCOc1cc2c(cc1N(CCC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 100 %

Procedure:
Following General Procedure P, ethyl 4-(3-n-heptyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-ylamino)benzoate (Compound 113, 0.024 g, 0.05 mmol) was reacted with propionaldehyde to afford 0.026 g (100%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][CH:2]([CH2:10]Br)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].C(=O)([O-])[O-].[K+].[K+]>COC1C=CC(O)=CC=1.C(#N)C>[Br:1][C:2](=[CH2:10])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(Br)CBr
Agent: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(Br)C(=O)OCCCC
Yield: 90.9 %

Procedure:
The product (300 g) of Step 1 and p-methoxyphenol (2 g) was added to a 2 l. round bottom flask fitted with a thermometer, condenser, stirrer and inlet for nitrogen, and containing acetonitrile (1000 ml) and anhydrous potassium carbonate (330 g). The reaction mixture was stirred under reflux for 8 hours and cooled, and the salts were filtered off. The filtrate was evaporated under reduced pressure to remove the solvent, and the residue was dissolved in dichloromethane. The solution was dried (Na2SO4), filtered and evaporated. Distillation of the residue afforded n-butyl 2-bromoacrylate (196 g; 90%), b.p. 90°/15 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:17]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:17]
Reactant: CNc1cc(N2CCN(C)CC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCN(C)CC2)c(Cl)cc1N

Procedure:
The sub-title compound was prepared from 4-chloro-5-(4-methyl-piperazin-1-yl)-2-nitro-N-methyl-aniline (500 mg, 1.8 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy to example 1 step (f).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[Br:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]([CH3:13])=[N:11][CH:12]=1.COC(OC)N(C)C.O>C(O)(C)C>[Br:6][C:7]1[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10](/[CH:13]=[CH:3]/[N:2]([CH3:5])[CH3:1])=[N:11][CH:12]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CN(C)/C=C/c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
N,N-Dimethylformamide (270 kg), 5-bromo-2-methyl-3-nitropyridine (90.0 kg, 415 mol), and N,N-dimethylformamide dimethyl acetal (108.0 kg, 906.3 mol) were added to a 2000 L vessel at RT. The reaction mixture was stirred at RT for 30 minutes, then heated to 90±5° C. over a 3-hour period and maintained at this temperature for 4 hours. The mixture was subsequently cooled to 25±5° C. Water (945 kg) was added while keeping the temperature of the mixture at 25±5° C. After the addition of water, the reaction mixture was stirred for 2 hours. The solids were centrifuged to obtain wet product, which was slurried in isopropanol (207 kg) for 1 hour at 25±5° C. The solids were centrifuged again to obtain the title compound as a wet solid (105 kg, 92.5 wt % assay). The product was used in the next step without additional drying.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN([CH:31]=[O:32])C>C1COCC1>[CH3:27][O:26][C:21]1[C:22]([CH:31]=[O:32])=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(C=O)cccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 17.4 g (0.15 mol) of dry TMEDA in 600 mL of hexanes, 60.0 mL (0.15 mol) of 2.5 M nBuLi in hexanes was added at room temperature. This mixture was stirred for 30 min, and then 27.6 g (0.15 mol) of 2-phenylanisol was added. This mixture was stirred for 4 hr at 55° C., then heated to 100° C., and a solution of 28.0 g (0.38 mol) of DMF in 200 mL of THF was added dropwise with vigorous stirring. The resulting mixture was evaporated to dryness, and the product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-diethyl ether from 100:1 to 20:1, vol.) to yield 26.1 g (82%) of the title product.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[O:3]1.[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].[OH-].[Na+]>C(O)C.[Cl-].[Na+]>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH:5]=[C:4]([CH:8]=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)[O:3]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccc(C#N)cc2)=CC1=O
Yield: 52.7 %

Procedure:
A solution of 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM), 4-cyanobenzaldehyde (1.7 g, 13.1 mM) and 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM) in ethanol (50 mL) was stirred 24 hours at room temperature. The reaction mixture was diluted with saturated aqueous sodium chloride (200 mL) and extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow solid. The crude product was purified by column chromatography (silica gel, 9:1, hexane-ethyl acetate) to afford pale yellow crystals (1.5 g, 53% yield), m.p. 169.5°-170.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([Cl:20])=[C:7]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:8]=[C:9]([Br:11])[CH:10]=1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([CH2:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]=1[Cl:20])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Br)cc(C(=O)c2ccccc2)c1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(Br)cc(Cc2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
To a solution of methanone 167 (7.9 g, 22.6 mmol) in TFA (90 mL) were added triethylsilane (18.5 mL, 113 mmol) and catalytic triflic acid at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 hours. The mixture was evaporated in vacuo. The residue was diluted with EtOAc (150 mL) and neutralized with aq. Saturated NaHCO3 solution. The mixture was extracted with EtOAc (150 mL×1). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the compound 168 (6.1 g, 80.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CN1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)nnc3c2)c1
Temperature: 100 °C

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.315 mmol, 1.0 equiv), 1-(3-bromo-benzenesulfonyl)-4-methyl-piperazine (0.472 mmol, 1.5 equiv), Pd2(dba)3 (0.0315 mmol, 0.1 equiv), Cs2CO3 (0.945 mmol, 3.0 equiv), and Xantphos (0.063 mmol, 0.2 equiv) were dissolved in 10 mL of dioxane, purged of air and placed under an argon atmosphere to reflux at 100° C. for 18 h. The reaction was cooled to room temperature and filtered to remove excess Cs2CO3. The filtrate was extracted with EtOAc and washed with saturated NaHCO3 and brine, and the organics were dried (Na2SO4). The organics were removed under reduced pressure to afford brown residue which was precipitated using DCM/Et2O (1:5 v/v) to give [7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine, as a yellow solid (45 mg, 27% yield). 1H NMR (DMSO-d6): δ 2.12 (s, 3H), 2.37 (m, 4H), 2.71 (s, 3H), 2.95 (m, 4H), 3.83 (s, 3H), 7.06 (dd, J=8.9 Hz, J=3.1 Hz, 1H), 7.14 (d, J=3.1 Hz, 1H), 7.41 (dd, J=6.3 Hz, J=1.1 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.67 (t, J=8.1 Hz, 2H), 8.06 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.9 (bs, 1H). MS (ES+): m/z=540 LC retention time 2.70 min.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])(=O)C.Cl>O1CCOCC1>[NH2:4][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(C)ccc(C(=O)O)c1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
3-Acetamido-4-methyl-2-nitrobenzoic acid (65 g, 273 mmol) was taken in dioxane (350 mL) and treated with 5 N aqueous HCl (150 mL). The reaction was stirred at 80° C. for 16 h. The dioxane was removed under reduced pressure and the residue poured onto crushed ice. The resulting precipitate was filtered off. The filtrate was extracted with ethyl acetate (2×). The organic layer and the solid were combined and concentrated under vacuum to give 3-amino-4-methyl-2-nitrobenzoic acid (45 g, 84% yield) as a yellow solid. MS (M+H)+ 197.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH2:39][CH3:40].[Cl:41][C:42]1[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44][N:45]([CH2:48][C:49](O)=[O:50])[C:46]=1[CH3:47]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:49](=[O:50])[CH2:48][N:45]3[C:46]([CH3:47])=[C:42]([Cl:41])[C:43]([C:52]([F:55])([F:54])[F:53])=[N:44]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH2:39][CH3:40]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CCOc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-ethoxyphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.20 (d, 1H), 6.66 (s, 1H), 6.48 (d, 1H), 5.38 (s, 2H), 4.08 (q, 2H), 3.61 (m, 4H), 3.25 (m, 2H), 3.16 (m, 2H), 2.18 (s, 3H), 1.33 (t, 3H) ppm; MS (ES) M+H expected=465.1, found 465.0.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[CH:17][CH:16]=[C:15]([O:23]COC)[C:14]=3[CH3:27])[CH2:7][CH2:6]1)(=[O:4])[CH3:3]>O1CCOCC1>[ClH:1].[C:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:22])[C:20]=2[CH3:21])=[CH:17][CH:16]=[C:15]([OH:23])[C:14]=3[CH3:27])[CH2:9][CH2:10]1)(=[O:4])[CH3:3]
Reactant: COCOc1ccc2c(=O)c(C)c(N3CCN(C(C)=O)CC3)oc2c1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2oc3c(C)c(O)ccc3c(=O)c2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A 4 N solution of hydrochloric acid in dioxane (1 mL) was added to a solution of 2-(4-acetylpiperazin-1-yl)-7-(methoxymethoxy)-3,8-dimethyl-4H-chromen-4-one (60 mg, 0.17 mmol) obtained in Example 37-4 in dioxane (3 mL), and the mixture was stirred at room temperature for 15 minutes. The deposited crystals were washed with dioxane and isopropyl ether and then collected by filtration to obtain 36 mg of the title compound (yield: 63%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[NH:8][C:7]2[CH:9]=[N:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]1=[O:13].OO.[OH-].[Na+]>Cl.O1CCOCC1.O>[CH3:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[CH:12]=[CH:11][N:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CC1Nc2cnccc2NC1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cnccc2[nH]c1=O
Temperature: 75 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
To a suspension of 3-nitro-pyridin-4-ylamine (15 g) in DCM (250 mL) was added triethyl amine (30 mL), Boc2O (23.5 g) and DMAP (1.31 g). The mixture was stirred at ambient temperature for 2 days. The solid was filtered off, and the filtrate was concentrated in vacuo. The residue was washed with MTBE. The yellow crystal was collected to afford (3-nitro-pyridin-4-yl)-carbamic acid tert-butyl ester (17 g). This material and ethyl pyruvate (100 mL) were dissolved in ethanol (150 mL) and treated with hydrogen gas (50 psi) in the presence of 10% palladium on charcoal (3 g) at 50° C. for two days. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica (eluent: pentane/EtOAc 10:1→2:1) to afford 2-(4-tert-butoxycarbonylamino-pyridin-3-ylamino)-propionic acid ethyl ester (5 g) as a yellow solid. A larger sample of this compound prepared in a similar manner (9 g) was stirred in 4M HCl in 1,4-dioxane (40 mL) at ambient temperature for 5 h. The precipitated solid was filtered off, washed with MTBE, and dried. The filtrate was concentrated to dryness, washed with MTBE, and dried to afford a second crop of the product. Total yield of 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one hydrochloride (5 g) as a white solid. 2.2 g of this material was suspended in water (20 mL) and treated with 30% aq hydrogen peroxide (1.2 mL) and NaOH (to adjust pH to 7-8). The mixture was stirred at 75° C. for 2 days. More 30% aq hydrogen peroxide (0.15 mL) was added, and stirring was continued for 2 additional days. The volatiles were removed in vacuo. The residue was washed with EtOAc to afford 3-methyl-1H-pyrido[3,4-b]pyrazin-2-one (0.8 g) as a yellowish solid. 0.7 g of this material and PyBroP (2.11 g) were suspended in DMF (3 mL). DIPEA (1.16 mL) was added and the mixture was stirred at ambient temperature overnight. The precipitated solid was filtered off, washed with ethanol, and dried to afford 2-(benzotriazol-1-yloxy)-3-methyl-pyrido[3,4-b]pyrazine (0.7 g) as a white solid. 430 mg of this material was suspended in ethanol (13 mL) and treated with hydrazine hydrate (0.5 mL) at 85° C. for 20 min. The solid was filtered off, washed with ethanol, and dried to afford IId (180 mg) as a yellowish solid sufficiently pure for the next step.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][CH:31]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)N(C1CCNCC1)C1CC1
Product: O=C(CCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC(N(C2CC2)S(=O)(=O)c2ccccc2C(F)(F)F)CC1

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butanoyl]piperidin-4-yl}-2-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-2-trifluoromethylbenzenesulfonamide and 4,4-bis(4-fluorophenyl)butanoic acid which can be prepared according to Sindelar et al. (Collection of Czechoslovak Chemical Communications 38(12): 3879-3901 (1973)). LC: 100%. MS: m/z=607 (M+H+). 1H NMR (CDCl3): δ 8.29 (1H, d), 7.88 (1H, d), 7.72 (2H, m), 7.18 (4H, dd), 6.98 (4H, dd), 4.76 (1H, d), 4.25 (1H, m), 3.95 (1H, m), 3.72 (1H, d), 3.00 (1H, t), 2.55 (1H, t), 2.30 (5H, m), 1.84 (4H, m), 0.61 (2H, m), 0.49 (1H, m), 0.36 (1H, m); and
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[C:9]([Cl:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Solvent: CC(=O)O
Product: Fc1ccc(-c2c(Cl)sc3ncnc(Cl)c23)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
To a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (1 g, 4.06 mmol) in acetic acid (15 mL), N-chlorosuccinimide (1.08 g, 8.1 m. mol) was added and the mixture was stirred at 90° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL) and washed with sat. NaHCO3 solution (3×20 mL). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography to get the title product (200 mg, 16%) as pale yellow solid. 1H NMR (400 MHz, CDCl3 and CDCl3): δ 8.85 (s, 1H), 7.35 (m, 2H), 7.20 (m, 2H). MS (ESI) m/z: Calculated: 297.95; Observed: 299.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.O>C1COCC1>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[O:15][CH:16]=[CH:17][C:3]=12
Reactant: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC1=c2ccoc2=NCN1c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (24 mg, 0.044 mmol) in THF (1 mL), benzenesulfonyl chloride (6.8 uL, 0.053 mmol), and N,N-diisopropylethylamine (9 uL, 0.053 mmol) were added. After the mixture was stirred at room temperature for 6 h, water was added to quench the reaction. The solution was extracted with EtOAc. The organic layer was separated, dried (MgSO4), and filtered. The solvent was evaporated. The residue was purified by gilson to afford the desired product MS(ES) m/e 367 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3cc(N)cn3)c2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1csc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.95 min; [M+H]+=392.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH3:12]I>CO>[CH3:12][N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: CI
Reactant: COc1ccc[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cccn(C)c1=O

Procedure:
A mixture of 3-methoxy-2(1H)-pyridone (25 g., 0.2 moles), potassium hydroxide (16 g., 0.24 moles) and methyl iodide (45.4 g., 0.32 moles) in 400 ml. methanol is heated at reflux for 5 hours. The methanol is removed under reduced pressure leaving a solid redidue which is extracted with methylene chloride. The methylene chloride extracts are washed with water, a saturated salt solution, and dried over sodium sulfate. Evaporation of the dried extracts, under reduced pressure, affords 1-methyl-3-methoxy-2(1H)-pyridone as a colorless oil which solidifies on standing (26.2 g., 94%). The pyridone is very hygroscopic and rapidly liquifies on exposure to air.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[CH:36])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24](N)[C:23]=2[N:33]=1)[CH3:19]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:33]=1)[CH3:19]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.1 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.395 mg, 0.03 eq.), 3-iodonitrobenzene (3.5 g, 1.1 eq.), triethylamine (3.87 g, 3 eq.), and copper (I) iodide (0.145 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (3 g, 13 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred at ambient temperature for 3.5 hours. A precipitate was isolated by filtration and then recrystallized from dichloromethane to provide 2.6 g of 2-ethyl-1-[3-(3-nitrophenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline as a solid.