Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=O)[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].S(Cl)(Cl)=O.C[N:26](C=O)C.N>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([NH2:26])=[O:20])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: N#Cc1ccc2c(cc(C(=O)O)n2CC(F)(F)F)c1Cl
Reactant: CN(C)C=O
Agent: N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2c(cc(C(N)=O)n2CC(F)(F)F)c1Cl
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylic acid (0.026 g, 0.086 mmol) in toluene (3 mL) was added thionyl chloride (0.01 g, 0.09 mmol) and a catalytic amount of DMF. The mixture was heated at 60° C. The reaction was followed by TLC at 30 min intervals, and additional thionyl chloride was added accordingly (an additional 0.082 g, 0.68 mmol was added). Upon cooling, a solution of NH3 in MeOH (2M, 5 mL) was added and the mixture was stirred rapidly for 5 min. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (10-80% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-MeOH-hexanes to afford the title compound as a white solid (0.017 g, 65% yield): MS (ES) m/z 302 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][CH:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:28]3[NH:27][C:26]4[CH:22]([CH2:21][O:20][CH3:19])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: COCC1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 45 °C
Yield: 46.1 %

Procedure:
A microwave tube was charged with 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701; 316 mg, 0.89 mmol), 6-(methoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (485b, 323 mg, 1.11 mmol), X-Phos precatalyst II (Sigma-Aldrich; 35 mg, 0.044 mmol) and K3PO4 (563 mg, 2.65 mmol). The tube was sealed and purged with argon for 5 minutes. 1,4-dioxane (2.6 mL) and water (0.65 mL) were added and Ar (g) was bubbled through the mixture for 5 min. The tube was heated at 45° C. in an oil bath for 90 min. The reaction mixture was cooled to RT and EtOAc and water were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-10% MeOH in CH2Cl2), to provide rac-2-(tert-butylamino)-8-(6-(methoxymethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one (485) (160 mg, 0.41 mmol, 46% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.19 (br. s., 1H), 8.07 (dd, J=7.82, 1.76 Hz, 1H), 8.00 (dd, J=7.63, 1.76 Hz, 1H), 7.22 (t, J=7.73 Hz, 1H), 6.83 (d, J=1.57 Hz, 1H), 5.85 (s, 1H), 4.65-4.72 (m, 1H), 4.61 (s, 1H), 3.65 (dd, J=9.00, 5.48 Hz, 1H), 3.55 (s, 3H), 3.46 (t, J=8.61 Hz, 1H), 3.41 (s, 3H), 1.65 (s, 9H). m/z (ES, +ve) 396.0 (M+H)+.
Reaction SMILES: Cl.NO.[OH-].[K+].CC1[N:8]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:20]=[CH:19][N:18]=2)C(C)=CC=1>C(O)C>[N:24]1([CH2:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH2:15][CH2:14][CH2:13][NH2:8])[CH:22]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(C)n1CCCOc1cc(CN2CCCCC2)ccn1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Product: NCCCOc1cc(CN2CCCCC2)ccn1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 8.6 g of hydroxylamine hydrochloride in 26 ml of ethanol, stirred at the room temperature for 30 minutes, a solution of 2.8 g of 85% potassium hydroxide in 10 ml of 50% ethanol is added. The resulting solution is stirred 10 minutes and added with 8.7 g of 2-[3-(2,5-dimethylpyrrol-1-yl)propoxy]-4-piperidinomethylpyridine. The mixture is heated with reflux for 6 hours, filtered, washed with ethanol, acidified with N hydrochloric acid and washed twice with 30 ml of ethyl acetate. The pH of the aquoeus solution is adjusted to 8, then the solution is washed twice again with 30 ml of ethyl acetate and made clearly basic by addition of a concentrated solution of potassium hydroxide. The solution is extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and the solvent is evaporated off. Thus, there is obtained 5.3 g of 3-(4-piperidinomethylpyrid-2-yloxy)propylamine as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:22]([NH2:25])(=[NH:24])[CH3:23].C([O-])(=O)C.[Na+].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:16]([C:15]1[N:24]=[C:22]([CH3:23])[NH:25][C:10](=[O:12])[C:9]=1[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(I)cc1)C(=O)OCC
Agent: CC(=O)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(I)cc1
Yield: 20 %

Procedure:
A solution of 2.46 g (6.33 mmol) ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate, 6.0 g (63.3 mmol) acetamidine hydrochloride, 5.2 g (63.3 mmol) sodium acetate, and 84 mg (0.381 mmol) 2,6-di-tert-butyl-4-methylphenol in 30 mL DMF was heated to 153° C. for 12 hours. The cooled reaction mixture was poured into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgSO4, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 1/65/34 AcOH/EtOAc/hexane to give 485 mg of the title compound, 20% yield. Unreacted ethyl 2-[(4-iodophenyl)methyl]-3-oxoheptanoate was recycled. Rf 0.25 in 1/65/34 AcOH/EtOAc/hexane, visualized by UV and ninhydrin stain;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cu]I>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]([C:6]2[CH:7]=[C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])[CH:3]=[CH:4][C:5]=2[CH3:23])[CH2:17]1
Reactant: Cc1ccc(Br)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Cc1ccc(N2CCOC2=O)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
A mixture solution of 2-(5-bromo-2-methyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.36 g, 3.64 mmol), oxazolidin-2-one (330 mg, 3.82 mmol), copper(I) iodide (139 mg, 0.73 mmol), N,N′-dimethyl-ethane-1,2-diamine (0.157 mL, 1.46 mmol), and potassium carbonate (1.51 g, 10.9 mmol) in acetonitrile (25 mL) was stirred at 90° C. for 72 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL×2), washed with saturated aqueous ammonium chloride solution (50 mL×3) and brine (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30-50% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-[2-methyl-5-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.4 g, 29%) as a white solid: MS (ESI) M+1=381.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. Reaction mixture was concentrated to get the residue. Cold water was then added, filtered the solid precipitated to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.C[CH2:18][N:19]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:19][CH3:18])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of 5-fluoro-2-nitrobenzoic acid (4.775 g, 25.8 mmol), methylamine hydrochloride (2.626 g, 38.9 mmol), EDCI (5.982 g, 31.2 mmol), HOBt (4.227 g, 31.3 mmol) and triethylamine (7.2 mL, 51.65 mmol) in DMF (50 mL) was stirred at room temperature for 24 h. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (combiflash-companion; ethyl acetate/hexanes gradient) to give the title compound as a yellow solid (yield: 90%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 124.8 %

Procedure:
To the solution of 1-Boc-piperidine-3-carboxylic acid (6.9 g, 30 mmol) in DMF (10 mL) and dichloromethane (40 mL) were added N,O-dimethylhydroxylamine hydrochloride (3.22 g, 33 mmol), HATU (12 g, 31.5 mmol) and triethylamine (9 mL). The reaction mixture was stirred overnight. After most of the solvent was removed and diluted with EtOAc, the organic layer was washed with water and brine, Dried and evaporation to give 10.2 g of crude product as light yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[C:3]=2[CH3:21])[CH2:24]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (53.0 mg, 0.150 mmol) and 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine in toluene to give 1-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.69 (1H, m), 7.50-7.59 (1H, m), 6.89-7.09 (1H, m), 6.06 (1H, d, J=2.0 Hz), 4.21-4.36 (1H, m), 4.00 (1H, d, J=8.8 Hz), 3.68-3.92 (4H, m), 3.50-3.68 (2H, m), 3.11 (3H, dd, J=5.9, 3.7 Hz), 2.92-3.06 (2H, m), 2.52-2.70 (2H, m), 1.94-2.18 (6H, m), 1.49-1.64 (6H, m). Mass Spectrum (ESI) m/e=508.3 (M+1).
Reaction SMILES: BrC1C=CC2C3C=C4C(CCCCCCCC)(CCCCCCCC)C5C(=CC=C(Br)C=5)C4=CC=3C(CCCCCCCC)(CCCCCCCC)C=2C=1.BrC1C=CC(N(C2C=CC(Br)=CC=2)C2C=C[C:66]([C:69](C)([CH3:72])[C:70]#[N:71])=CC=2)=CC=1.[CH3:81][C:82]1([CH3:122])[C:86]([CH3:88])([CH3:87])[O:85][B:84]([C:89]2[CH:94]=[CH:93][C:92]([N:95]([C:107]3[CH:112]=[CH:111][C:110]([B:113]4[O:117][C:116]([CH3:119])([CH3:118])[C:115]([CH3:121])([CH3:120])[O:114]4)=[CH:109][CH:108]=3)[C:96]3[CH:101]=[CH:100][C:99]([C:102]([CH3:106])([CH3:105])[C:103]#[N:104])=[CH:98][CH:97]=3)=[CH:91][CH:90]=2)[O:83]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1.O1CCOCC1.O>[CH3:120][C:115]1([CH3:121])[C:116]([CH3:118])([CH3:119])[O:117][B:113]([C:110]2[CH:111]=[CH:112][C:107]([N:95]([C:92]3[CH:91]=[CH:90][C:89]([B:84]4[O:85][C:86]([CH3:88])([CH3:87])[C:82]([CH3:122])([CH3:81])[O:83]4)=[CH:94][CH:93]=3)[C:96]3[CH:97]=[CH:98][C:99]([C:102]([CH3:105])([CH3:106])[C:103]#[N:104])=[CH:100][CH:101]=3)=[CH:108][CH:109]=2)[O:114]1.[CH:69]([C:70]#[N:71])([CH3:72])[CH3:66]
Reactant: CC(C)(C#N)c1ccc(N(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1
Agent: CC(C)(C#N)c1ccc(N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2cc3c(cc21)-c1ccc(Br)cc1C3(CCCCCCCC)CCCCCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)C#N
Temperature: 90 °C

Procedure:
2,8-dibromo-6,6,12,12-tetraoctyl-6,12-dihydroindeno[1,2-b]fluorene (2.60 g), 2-(4-(bis(4-bromophenyl)amino)phenyl)-2-methylpropanenitrile (947 mg), 2-(4-(bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)phenyl)-2-methylpropanenitrile (2.84 g), potassium phosphate (4.27 g) and Aliquat 336 (2 drops) were dissolved in a mixture of toluene (32 mL), dioxane (16 mL) and water (16 mL). The solution was degassed for 15 minutes before adding tris(dibenzylideneacetone)dipalladium(0) (23 mg) and tri(o-tolyl)phosphine (46 mg) and heating to 90° C. for 17 hours. The reaction mixture was poured onto methanol (320 mL) and the resulting precipitate was filtered, dissolved in toluene (200 mL), washed with 1N NaOH, brine, water, dried (MgSO4) and concentrated. The residue was dissolved in toluene (150 mL) and passed through a pad of silica, washing through with toluene, toluene/THF and THF. The filtrates were concentrated and charcoal treated (3×0.53 g). The filtrates were concentrated and the solid taken up in THF (70 mL) and added dropwise to methanol (350 mL). The solid was filtered to give the target compound as a yellow solid. Yield: 3.3 g. Mn=11341 g/mol, n=11.2, Polydispersity=1.9.
Reaction SMILES: ClS(O)(=O)=O.C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C\C(O)=O.[N+:22]([C:25]1[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=1[O:27]/[C:28](=[CH:34]\[C:35]([O:37]CC)=O)/[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:24])=[O:23].[N+](C1C=CC=CC=1O/C(=C/C(OCC)=O)/C(OCC)=O)([O-])=O>>[N+:22]([C:25]1[C:26]2[O:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][C:35](=[O:37])[C:40]=2[CH:41]=[CH:42][CH:43]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: CCOC(=O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)/C=C\C(=O)O
Product: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 70 °C
Reaction time: 7 h
Yield: 70 %

Procedure:
After a reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 15 parts by weight of chlorosulfonic acid, 3 parts by weight of a mixture (content: 84.4% by weight, fumaric acid/maleic acid ratio=49/51) containing diethyl 2-(2-nitrophenoxy)fumarate and diethyl 2-(2-nitrophenoxy)maleate was added dropwise at an inner temperature of 50° C. or below. After completion of addition, the inner temperature was raised to 70° C. and the mixture was stirred and kept at the same temperature for 7 hours to obtain a reaction solution containing 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran (reaction yield: 70%). After cooled to room temperature, the reaction solution was gradually added into 24 parts by weight of water. After kept at an inner temperature of 60° C. for 1 hour, the mixture was gradually cooled to an inner temperature of 0° C. Precipitated crystals were filtered and dried to obtain 1.3 parts by weight of a crystalline mixture containing 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran and 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (the content of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran: 0.1% by weight; the content of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran: 86.4% by weight). The yield of 8-nitro-2-ethoxycarbonyl-4-oxo-4H-1-benzopyran was 0.1% and the yield of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran was 64%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5].[CH3:23][C:24]([CH3:26])=O>>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:24]([CH3:26])[CH3:23])=[CH:13][C:8]=2[CH2:7]1)=[O:5]
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2
Reactant: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCN(C(=O)c1ccc(Cl)cc1Cl)C2

Procedure:
A solution of 1.2 g of crude 6-(2,4-dichlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3-c]pyridazine in 5 cc of acetone is heated on a water bath for 5 minutes. The title compound has a M.P. of 211°-214° (decomp., from methanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[Na].[Cl:18][C:19]1[CH:20]=[N+:21]([O-])[CH:22]=[C:23]([Cl:26])C=1S.C(N(C(C)C)C(C)C)C>C(O)(C)C.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8][C:11]1[C:19]([Cl:18])=[CH:20][N:21]=[CH:22][C:23]=1[Cl:26])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Reactant: [O-][n+]1cc(Cl)c(S)c(Cl)c1
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C#N)c(Sc2c(Cl)cncc2Cl)s1
Yield: 50.1 %

Procedure:
To a 5 mL Biotage microwave reaction vessel was charged with a solution of Ethyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (0.26 g, 1 mmol) in isopropanol (1.5 mL), 3,5-dichloro-1-oxido-pyridin-1-ium-4-thiol sodium salt (0.2 g, 1 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.645 g, 5.0 mmol). The resulting reaction mixture was sealed and heated at 150° C. for 10 minutes under microwave irradiation (Biotage Initiator 8). After cooling down, a precipitation was formed and the solid was removed by filtration. The organic solution was concentrated under vacuo to give a brown oil residue. The residue was re-dissolved in methanol (3 mL) and extracted with hexane (15 mL×4). The organic layer was separated and concentrated under vacuum to afford a solid as the title product (180 mg, 50% yield). MS m/z: 358.94, 360.94 [M+H]+.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+]>ClCCl>[Cl:1][C@H:2]1[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:5]([CH:19]=[O:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1
Reactant: CCCOC(=O)CCCCCC[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCOC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 54.5 %

Procedure:
A solution of 700 mg (1.73 mmol) of alcohol 11 in 4 mL of dichloromethane was added via pipette to a mixture of PCC (700 mg, 3.23 mmol), sodium acetate (350 mg, 4.26 mmol), and Celite (1.3 g) in 7 mL of DCM. The pipette was rinsed with an additional 3 mL of DCM to complete the transfer. The mixture was stirred sealed at 30° C. for 1.5 h. The mixture was worked up by filtration through 20 g of silica gel and washed with 200 mL of 1:4 EA:hexanes. The filtrate was concentrated in vacuo to yield 500 mg) of crude aldehyde 12. Further FCC purification on 10 g of silica gel yielded 380 mg of purified aldehyde 12 (54% yield) as an oil; 1H NMR (CDCl3); 0.93 (t, J=7.2 Hz, 3H), 1.31 (m, 10H), 1.42-1.90 (m, 17H), 1.94-2.44 (m, 4H), 2.28 (t, J=7.5 Hz, 2H), 2.52 (m, 1H), 2.68 (m, 1H), 3.48 (m, 2H), 3.81 (m, 2H), 4.01 (t, J=6.6 Hz, 3H), 4.06 (m, 1H), 4.5-4.64 (m, 2H), 9.75 (m, J=2.1, 9 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:10])=[CH:4][C:3]=1[CH3:17].BrC1C=CC(N)=CC=1C.[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][N:32]=1)=[O:30].OS(O)(=O)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[CH3:27][NH:28][C:29]([C:31]1[CH:36]=[C:35]([CH2:37][NH:16][C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:17])[CH:4]=2)[CH:34]=[CH:33][N:32]=1)=[O:30]
Reactant: CNC(=O)c1cc(C=O)ccn1
Reactant: Cc1cc(NC(=O)c2sccc2N)ccc1Br
Agent: Cc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(CNc2ccsc2C(=O)Nc2ccc(Br)c(C)c2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(4-bromo-3-methylphenyl) 3-aminothiophene-2-carboxamide (lequiv, prepared as described above for EXAMPLE 1, part 1, using 4-bromo-3-methylaniline instead of 4-trifluoromethoxyaniline) in THF at 0° C. in an open flask, was added 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde (prepared as described in International Patent Publication No. WO 01/23375) (1.1 equiv) in THF and 4M H2SO4 (0.1 equiv) and the mixture was stirred for 30 min at 0° C. Sodium borohydride (1 equiv) was added portionwise and the mixture was allowed to warm to RT and stirred for 2 h. Water was then added, the mixture was basified to pH 12 with 2M sodium hydroxide solution, and the resulting product was extracted into ethyl acetate. The combined extracts were washed with water followed by brine, dried (MgSO4), filtered and concentrated in vacuo to afford a yellow semisolid, which was purified by column chromatography eluting with a 95:5 mixture of hexane:ethyl acetate increasing gradually to a 50:50 mixture. MS (ES+): 459, 461 [MH+]