Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)[CH2:10][O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O.O>[CH3:12][O:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]1[CH:33]=[CH:32][CH:31]=[C:15]([CH2:16][CH2:17][NH:18][C:19]2[C:20](=[O:30])[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]3[CH:42]=[C:43]4[C:38](=[CH:39][CH:40]=3)[NH:37][CH:36]=[C:35]4[CH3:34])=[O:29])[C:22]([CH3:25])=[CH:23][N:24]=2)[CH:14]=1
Reactant: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)O)c2=O)c1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COCC(NC(=O)OC(C)(C)C)c1cccc(CCNc2ncc(C)n(CC(=O)NCc3ccc4[nH]cc(C)c4c3)c2=O)c1
Reaction time: 72 h
Yield: 56.8 %

Procedure:
A mixture of 2-[3-[(3-{(1R/S)-1-[(tert-butoxycarbonyl)amino]-2-methoxyethyl}phenethyl)amino]-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 123) (35 mg, 0.076 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (13 mg, 0.08 mmol), HOBT (11 mg, 0.08 mmol), WSCDl.HCl (16 mg, 0.08 mmol) and N-methylmorpholine (16 ml, 0.15 mmol) in N,N-dimethylformamide (2 ml), was stirred at room temperature for 18 hrs. Additional (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (8 mg, 0.038 mmol), was added, and stirring continued for a further 72 hrs at room temperature. The reaction mixture was poured into water (10 ml), and the resulting precipitate filtered, and dried to give the desired product, (26 mg, 57%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=1)[C:15](O)=[O:16])([O-:3])=[O:2].[NH:43]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:54]([O:53][C:51](=[O:52])[CH2:50][N:43]([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:40]=[CH:41][CH:42]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:13]=1)[CH3:55]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2cccc([N+](=O)[O-])c2)cc(C(=O)O)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2cccc([N+](=O)[O-])c2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A solution of 4.0 g (6.83 mmol) of 3-[3-(3-nitrophenoxy)propoxy]-5-(octadecyloxy)benzoic acid in 65 ml of thionyl chloride was stirred at reflux for 2.5 hours. The excess thionyl chloride was removed at reduced pressure and the residual solid acid chloride was dissolved in 75 ml of methylene chloride and added dropwise to a stirred, ice bath cooled solution of 1.5 ml of diethyl iminodiacetate (8.5 mmol) and 1.9 ml (13.7 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred in the cooling bath for 30 minutes, at room temperature for 20 hours and then was washed with NaHCO3 solution. The dried organic layer was concentrated at reduced pressure to an oil which was purified by HPLC using 25% ethyl acetate-hexane to give 4.32 g (84% yield) of N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(3-nitrophenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as an oil. The structure was confirmed by the nmr and mass spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[C:27](/[CH3:32])=[CH:28]/[C:29](O)=[O:30])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>>[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](/[C:27](/[CH3:32])=[CH:28]/[C:29]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:30])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C)c1

Procedure:
0.46 g of compound 3 was obtained in a similar manner to those described in the Example 1 and 2 using 2.16 g of ethyl 4-(2-aminophenoxy)butyrate and 1.04 g of 3-(1-methylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([NH:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([NH:39][C:20]([C:19]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:18]=1[NH:17][C:15]([CH:9]1[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])=[O:22])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Cl)cc1NC(=O)C1CCCC(=O)N1Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(Cl)cc1NC(=O)C1CCCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Formula I where R1, R2, R4, R6, R7, R8 and R9 are H; R3 is Chloro; R5 is Benzyl, R10 is Benzyl; and V is CR′R″ where R′ and R″ are H: To a solution of 2-[(1-benzyl-6-oxo-piperidine-2-carbonyl)-amino]-4-chloro-benzoic acid (165 mg, 0.427 mmol) in 5 mL of DMF was added EDC (245 mg, 1.28 mmol) and the mixture stirred at room temperature. After 1 hour, benzylamine (140 μL, 1.28 mmol) was added, and the reaction mixture was stirred at room temperature for an additional 3 hours. After evaporating the solvents, the residue was dissolved in 100 mL of DCM, and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and filtered. The solvent was removed to afford crude 1-benzyl-6-oxo-piperidine-2-carboxylic acid (2-benzylcarbamoyl-5-chloro-phenyl)-amide, a compound of Formula 402. This was dried under vacuum and then added to a mixture of 10 mL of ethylene glycol and sodium hydroxide (17 mg, 0.425 mmol), followed by stirring at 130° C. for two days with monitoring by LC-MS. The mixture was then poured into 100 mL of water. After extraction with DCM, the resulting crude product was purified over silica gel (stepwise gradient 1:4, 1:2, 1:1, 2:1, 4:1 with ethyl acetate:hexanes as eluent) to give the desired pure product of Formula I, 3-benzyl-2-(1-benzyl-6-oxo-piperidin-2-yl)-7-chloro-3H-quinazolin-4-one (20 mg, 10%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][S:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)(=[O:21])=[O:20]>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:24][CH2:23][O:22][S:19]([CH3:18])(=[O:21])=[O:20])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CS(=O)(=O)OCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOS(C)(=O)=O)c(C=O)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 27,3 g (125 mmol) 1,2-bis-methanesulfonyloxy-ethane ((J. Med. Chem.; 47; 17; (2004); 4300-4315) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 5 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate:hexane 1:6, ethyl acetate→1:2). The desired product 4a was obtained in 78% yield (21.4 g, 78 mmol) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:15]3[C:14](=[O:16])[N:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[C:11]=3[C:10](=[O:24])[N:9]=2)=[CH:4][CH:3]=1.[C:25]([O:33]C([O-])=O)([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:29][CH:28]([O:27][C:25]([N:13]1[C:12]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:11]2[C:15](=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]([C:25]([O:27][CH:28]([CH2:30][CH2:31][CH3:32])[CH3:29])=[O:33])[C:10]2=[O:24])[C:14]1=[O:16])=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(C)OC(=O)OC(=O)[O-]
Reactant: O=c1nc(-c2ccc(Cl)cc2)c2c(=O)nc(-c3ccc(Cl)cc3)c1=2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCC(C)OC(=O)N1C(=O)C2=C(c3ccc(Cl)cc3)N(C(=O)OC(C)CCC)C(=O)C2=C1c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
4.28 g of 3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione, 5.91 g 2-pentyl dicarbonate from Example B2, 0.40 g of 4-dimethylaminopyridine and 500 ml of dry tetrahydrofuran are mixed and the mixture is stirred at 55° C. for 4 hours. The suspension is filtered off with suction on a glass microfilter supporting a cotton filter, the solvent is evaporated off under reduced pressure, and the residue is admixed with 50 ml of isopropanol. After 30 minutes the precipitate is filtered off with suction and washed with 15 ml of isopropanol, and the yellow product is dried under reduced pressure to leave 2.86 g (41% of theory) of 2,5-di-2-pentyloxycarbonyl-3,6-di-(4′-chlorophenyl)-pyrrolo[3,4,c]pyrrole-1,4-dione as yellow powder. NMR (CDCl3) [ppm]: δ=7.65 ppm (d, 4H), 7.46 (d, 4H), 4.98 (m, 2H), 1.67-1.35 (m, 8H), 1.26 (d, 6H), 0.88 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH:31][S:36]([CH:33]2[CH2:35][CH2:34]2)(=[O:38])=[O:37])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Reaction time: 16 h
Yield: 67 %

Procedure:
1.5 g of crude tert-butyl(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}phenyl)carbamate (2.7 mmol, 1 eq.) were dissolved in 10 mL pyridine and 457 mg cyclopropyl sulfonyl chloride (3.3 mmol, 1.2 eq.) and stirring was continued at that temperature for 16 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was reextracted with DCM. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography yielding 1.19 g of the target compound (67% yield).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)c1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.05 mmol of 2-isopropylbenzenethiol, and 1.05 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with ether to afford a solid (m.p. 216-217° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=6.8 Hz, 6 H), 3.20 (m, 1 H), 3.77 (bs, 2 H), 5.64 (d, 1 H), 6.45 (t, 1 H), 6.92 (t, 1 H), 7.12 (d, 1 H), 7.32-7.48 (m, 10 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>>[B:15]([OH:20])([OH:16])[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cn1
Yield: 71.9 %

Procedure:
5-Bromo-2-methoxypyridine (5.0 mL, 39.1 mmol) was treated with n-BuLi (1.6 M in hexanes, 26.9 mL, 43.0 mmol), triisopropyl borate (10.8 mL, 46.9 mmol) and HCl(aq) (2.7 N, 37.6 mL) as for 1 to give the title compound 3 (4.3 g, 89% yield) as a white solid: 1H NMR (CD3OD) δ 8.42 (m, 1H), 7.95 (br s, 1H), 6.76 (br s, 1H), 3.91 (s, 3H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>CN1C(=O)CCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:2]2[N:11]=[C:10]([O:12][CH3:13])[C:9]3[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=3)[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc2nc(Cl)nc(OC)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(OC)c2cc1OC
Yield: 15 %

Procedure:
A mixture of 2-chloro-4,6,7-trimethoxy-quinazoline (0.8 g, 3.14 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.28 mmol, 2.0 equiv; commercially available) in anhydrous NMP (8 mL) and triethylamine (2 mL) was heated by microwave irradiation to 170° C. for 1 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified by column chromatography on silica eluting with a gradient of toluene/ethyl acetate (4:1→2:1) providing 0.2 g (15%) of the title compound. MS (ISP): 419.4 [M+H]+.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>CN(C=O)C>[CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[C:7]([I:15])[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=c1[nH]cnn2c(C3CCC3)ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Temperature: 55 °C

Procedure:
A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789 mg, 4.15 mmol) and N-iodosuccinimide (933 mg, 4:15 mmol) in anhydrous DMF (40 mL) was stirred overnight at rt. An additional 4 equiv of NIS was added and reaction was heated to 55° C. for 6 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic fractions were washed with 1M sodium thiosulfate (Na2S2O3) (1×), brine (1×), dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The solid was triturated with 20% EtOAc in DCM and filtered through a fritted Buchner funnel resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m, 1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH+], HPLC: tR=2.62 min (MicromassZQ, polar—5 min).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1.C(OCC)(=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of 27.5 g of 3-iodo-5-nitro-1H-indazole in 300 ml tetrahydrofuran at 0° C. in an atmosphere of nitrogen gas was added 6.1 g of 60% sodium hydride, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added 39.8 g of trityl chloride, followed by stirring at room temperature for 1 hour. Water was added and the mixture was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were washed with diethyl ether, to give 48.5 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=O)[C:5]([OH:7])=[O:6].[CH3:14][N:15]([CH3:26])[C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH:22]=O)=[CH:18][CH:17]=1>>[CH3:26][N:15]([CH3:14])[C:16]1[CH:25]=[CH:24][C:19]([CH:20]=[CH:21][CH:22]=[N+:11]([C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])[O-:13])=[CH:18][CH:17]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=CC=O)cc1
Product: Cc1cc(C(=O)O)ccc1[N+]([O-])=CC=Cc1ccc(N(C)C)cc1
Yield: 97.4 %

Procedure:
The general procedure of Example 1 was repeated except that 132.4 g (731 mmols) of 3 -methyl-4-nitrobenzoic acid was used instead of p-nitrobenzoic acid and 118.6 g (677 mmols) of 4-dimethylaminocinnamaldehyde was used instead of 4-diethylaminobenzaldehyde, thereby obtaining 213.8 g (yield 97.4%) of α-[p-(dimethylamino)styryl]-N-(2-methyl-4-carboxyphenyl)nitrone with a purity of 96%. The results of the analyses of the thus obtained compound are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:12])[CH:3]=1.O[C:14]1C=CN(CCC(C)C)C(=O)C=1.C1(CN2C=CC(O)=CC2=O)CC1.C(OC1C=CNC(=O)C=1)C1C=CC=CC=1.BrCCC(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:11]([CH3:10])[CH3:14])[C:4](=[O:12])[CH:3]=1
Reactant: CC(C)CCn1ccc(O)cc1=O
Reactant: O=c1cc(Br)ccn1CC1CC1
Agent: O=c1cc(O)ccn1CC1CC1
Agent: O=c1cc(OCc2ccccc2)cc[nH]1
Solvent: CC(C)CCBr
Product: CC(C)CCn1ccc(Br)cc1=O

Procedure:
Intermediate D7 was prepared following the same procedure implemented for the synthesis of D3, using 4-hydroxy-1-(3-methylbutyl)-1H-pyridin-2-one as starting material, which was prepared by the same method used for the synthesis of intermediate D2, by reaction of 4-benzyloxy-1H-pyridin-2-one with 1-bromo-3-methylbutane.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([OH:18])=O)=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[NH:27][CH2:28][C:29]1[CH:34]=[CH:33]C=CC=1>>[CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:21])([CH2:19][OH:20])[C:16]([N:27]2[CH2:28][CH2:29][CH2:34][CH2:33]2)=[O:18])=[CH:11][C:10]=1[N+:22]([O-:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1ccccc1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)O)cc1[N+](=O)[O-]
Product: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 1c from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-3-hydroxy-2-methyl-propionic acid and N-methyl-benzylamine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][C:18]([N:20]=[C:21]=[O:22])=[O:19]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:21]([NH:20][C:18](=[O:19])[CH2:17][Cl:16])=[O:22])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C=NC(=O)CCl
Solvent: Cc1ccccc1
Product: O=C(CCl)NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
22.9 g (0.1 mol) of 3,5-bis-trifluoromethyl-aniline were dissolved in 150 ml of dry toluene. 11.9 g (0.1 mol) of chloroacetyl isocyanate in 50 ml of dry toluene were added. The mixture was stirred at 50° C. for 1 hour and then cooled to room temperature. The product which had precipitated was filtered off and rinsed with toluene/ligroin 1:2 and then dried. 26 g (74.5% of theory) of N-(3,5-bis-trifluoromethylphenyl)-N'-(chloroacetyl)-urea with a melting point of 170° C. were thus obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:31]3[CH2:38][C:37](=[O:39])[NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:31]3[C:38](=[CH:16][C:13]4[NH:12][C:9]5[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=5[C:14]=4[CH3:15])[C:37](=[O:39])[NH:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)c(C)c2C1=O
Yield: 39.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (53 mg, 39.4%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([O:25]C)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:30]=[CH:31][N:32]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[C:23]([OH:25])=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of methyl 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (210 mg, 0.49 mmol) in dioxane (10 mL) and water (10 mL) was added NaOH (150 mg, 3.75 mmol), The mixture was heated to 40° C. with stirring for 2 h. The solution was concentrated in vacuo, washed with dichloromethane (10 mL×3), then additional water (10 mL) was added and this solution was adjusted to pH=4 by addition of concentrated HCl. The solid formed was filtered to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.160 g, 78%) as a light yellow solid. 1H NMR (300 MHz, DMSO): δ 13.25 (s, 1H), 9.74 (s, 1H), 8.85 (s, 1H), 8.50 (s, 1H), 8.26-8.08 (m, 3H), 7.72-7.67 (m, 2H), 7.53-7.44 (m, 1H), 6.75 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.62-3.57 (m, 1H), 2.13-1.98 (m, 3H), 1.70-1.68 (m, 2H), 1.12 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 415, tR=1.68 min, HPLC: 98.2% at 214 nm, 98.37% at 254 nm, tR=6.21 min.