Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8].[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2[S:25][C:24]([CH:26]=O)=[CH:23][C:21]=2[N:22]=1>>[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:20]2[S:25][C:24]([CH2:26][N:13]3[CH2:14][CH2:15][CH:10]([S:7]([C:3]4[S:2][CH:6]=[CH:5][N:4]=4)(=[O:9])=[O:8])[CH2:11][CH2:12]3)=[CH:23][C:21]=2[N:22]=1
Reactant: O=S(=O)(c1nccs1)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: O=S(=O)(c1nccs1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 31.9 %

Procedure:
4-(Thiazole-2-sulfonyl)-piperidine HCl salt (124 mg) was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]ppimidine-6-carbaldehyde 10 (130 mg) using standard reductive amination conditions. Aqueous work-up, purification on silica and trituration with hot ethyl acetate yielded 2-chloro-4-morpholin-4-yl-6-[4(thiazole-2-sulfonyl)-piperidin-1-ylmethyl]-thieno[3,2-d]pyrimidine (73 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 415. NMR (CDCl3): 2.03-2.18 (4H, m), 2.18-2.22 (2H, m), 3.12-3.16 (2H, m), 3.39-3.46 (1H, m), 3.84 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 5.20 (2H, br), 7.26 (1H, s), 7.79 (1H, d, J=3.0), 8.11 (1H, d, J=3.0), 9.29 (2H, s) MS (ESI+): MH+ 559.13 (100%)
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])=[O:17])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)C[C@H](N)C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 67.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (108 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.11 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-leucine N-benzylamide (123 mg, 570 umol, 1.5 eq). Workup as before provided 124 mg (68%) of L-leucine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].C(=O)(O)[O-:14].[Na+]>CS(C)=O.CCOCC>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:14])[CH2:10][C:11]#[CH:12]
Reactant: C#CCCOCCCCCCBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: C#CCCOCCCCCC=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
6-Bromohexylbut-3-ynyl ether (525 mg) in DMSO (2 ml) was added to a mixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C. with vigorous stirring and nitrogen bubbling through the solution. The mixture was stirred for 20 min at 150° C. and then allowed to cool to room temperature, diluted with Et2O and washed with water. The aqueous layer was extracted with Et2O and the combined ether layers were washed with dilute hydrochloric acid, brine, dried (MgSO4) and evaporated to dryness to give the title compound (325 mg): IR 1726 cm−1 MS(TSP+ve) m/z 186 (M+MH4)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([N:8]1[CH2:9][CH:10]2[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]2)[CH2:7]1)=[O:21]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc1OC
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel, and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4-dimethoxybenzoyl chloride (0.80 g, 3.92 mmol) in CH2Cl2 (10 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf = 0.31) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.87 g (73.1%) of off-white solid (34); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2950, 2915, 2845, 2820, 2770, 2750, 2710 (C--H), 1625 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3 H, CH3, J=6.4 Hz), 1.06 (d, 3 H, CH3, J=6.5 Hz), 1.62-1.75 [m, 3 H, H(5) and H(9)], 1.96 [bs, 1 H, H(1)], 2.43 [bd, 1 H, H(4)ax, J=9.7 Hz], 2.51 [bd, 1 H, H(6)ax, J=10.5 Hz], 2.62 [heptet, 1 H, CH(CH3)2, J=6.4 Hz], 2.74 [bd, 1 H, H(6)eq, J=9.9 Hz], 3.00-3.09 [m, 2 H, H(4)eq and H(2)ax ], 3.32 [bd, 1 H, H(8)ax, J=13.2 Hz], 3.83-3.94 [m, 7 H, H(8)eq and OCH3 ], 4.77 [bd, 1 H, H(2)eq, J=13.3 Hz], 6.84-6.94 (m, 3 H, Ar--H); 13C NMR (DCCl3) ppm 16.46, 19.15 (CH3), 29.13 [C(1)], 29.86 [C(5)], 32.36 [C(9)], 46.71 [C(2)], 52.25 [C(4)], 52.65 [C(8)], 54.35 [CH(CH3)2 ], 54.68 [C(6)], 55.88, 55.93 (OCH3), 110.50, 119.64, 130.23, 148.78, 149.39 (Ar--C), 169.90 (C=O). Anal. Calcd. for C19H28N2O3 : C, 68.65; H, 8.49. Found: C, 68.58; H, 8.47.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(Cc2ccncc2)nnc(N2CCN[C@H](C)C2)c1C
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccncc4)c(C)c3C)C[C@H]2C)cn1
Yield: 55.6 %

Procedure:
According to the protocol described below for example 46, 4,5-dimethyl-3-((R)-3-methylpiperazin-1-yl)-6-pyridin-4-ylmethyl-pyridazine (155 mg, 0.51 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (99 mg, 0.56 mmol) afforded the title compound as an orange oil (123 mg, 56%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10]C)=[O:9])=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].O>C1COCC1>[O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([OH:10])=[O:9])=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1-c1cnco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1-c1cnco1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of methyl 2-(1,3-oxazol-5-yl)benzoate (4.0 g) in THF (40 mL) was added 2 N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature stirred for 2 days. To the reaction mixture was added water, and the mixture was washed with tert-butyl methyl ether. The pH of the obtained aqueous layer was adjusted to 2 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/petroleum ether to give the title compound (3.3 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:34]([CH2:35][CH2:36][OH:37])[CH2:33][CH2:32][OH:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCNCCO
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN(CCO)CCO

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and bis-(2-hydroxy-ethyl) amine was converted to 22.2 mg of the title compound (free base), mass spectrum (electrospray, m/e): M+H 514.0 and 60.7 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 514.0.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]3[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23][C:22]3=[O:29])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3([C:2]4[C:3]5[CH:11]=[CH:10][CH:9]=[N:8][C:4]=5[N:5]=[CH:6][N:7]=4)[C:22](=[O:29])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Clc1ncnc2ncccc12
Reactant: O=C1NC(=O)C(c2ccc3c(c2)CCC3)C(=O)N1
Product: O=C1NC(=O)C(c2ccc3c(c2)CCC3)(c2ncnc3ncccc23)C(=O)N1
Temperature: 130 °C

Procedure:
A slurry of 4-chloro-pyrido[2,3-d]pyrimidine (1.656 g, 10 mM) and 5-(5-indanyl) barbituric acid (2.443 g, 10 mM) is stirred in an oil bath. The temperature is raised to 130° C. in a period of 15 min. Then the temperature is further increased from 130° C. to 170° C. During this period apparently a reaction occurs since the slurry solidifies. The resulting solid is maintained for further 10 min at about 170° C. Then the reaction mixture is cooled, triturated with sodium bicarbonate solution and hexane. The solid is filtered off, washed with water and dried under vacuum. The raw product is submitted to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(Br)c1

Procedure:
To a solution of 2.0 g (9.3 mmol) of 3-bromo-4-methylbenzoic acid in 25 mL of dichloromethane was added 5.6 mL (11.2 mmol) of oxalyl chloride and 100 μL of N,N-dimethylformamide. The resultant mixture was stirred at ambient temperature for 2 hours, concentrated in vacuo, and the residue suspended in methanol. The solution was concentrated in vacuo and the residue purified by flash column chromatography (biotage) using 5% ethyl acetate/hexanes as eluent to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (d, 1H, J=8 Hz), 7.33 (d, 1H, J=8 Hz), 3.94 (s, 3H), 2.48 (s, 3H). HPLC/MS (ESI) m/z (M+H)=231.0 (3.63 min).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1.C(N(CC)CC)C.[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[N:26]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:5]1[CH2:6][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:20][CH:3]([CH2:2][O:1][S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ncccn1)CC(CO)O2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3ncccn3)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.45 g, 3.98 mmol) in dichloromethane (15 mL) was added triethylamine (1.66 mL, 11.9 mmol) and 4-(dimethylamino)-pyridine (195 mg, 1.59 mmol) at 0° C. Tosyl chloride (910 mg, 4.78 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Silica gel column chromatography (0-80% ethyl acetate/hexanes) provided tert-butyl 4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.83 g, 3.53 mmol, 89%). ESI-MS m/z calc. 518.2. found 519.3 (M+1)+; Retention time: 1.83 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.60 (t, J=4.8 Hz, 1H), 4.67-4.48 (m, 2H), 4.12 (d, J=4.6 Hz, 2H), 3.89 (ddd, J=12.0, 7.5, 4.6 Hz, 1H), 3.71-3.56 (m, 2H), 3.05 (ddd, J=20.6, 17.0, 8.8 Hz, 2H), 2.80-2.65 (m, 2H), 2.46 (s, 3H), 1.88 (d, J=14.1 Hz, 1H), 1.50 (dt, J=7.9, 4.0 Hz, 2H), 1.45 (s, 9H), 1.38-1.27 (m, 1H).
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1.[NH:22]([CH3:24])[CH3:23].Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(-c2ccc(C(=O)O)cc2)nc2ccc(O)cc12
Temperature: 160 °C
Yield: 32.2 %

Procedure:
30 mg of 4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid (Compound 26) was mixed with 1 mmol Me2NH.HCl and 0.5 ml DIEA in 3 ml DMF and heated to 160° C. for 30 minutes. The solvent was evaporated to dryness and water was added. The solid was filtered and washed with water and dried. The crude was triturated with acetone to obtain 10.5 mg of Compound 47. 1H NMR (DMSO-d6 300 MHz TMS): δ 13.2 (b, 1H), 10.28 (s, 1H), 8.22 (m, 2H), 8.11 (d, 1H), 7.99 (d, 1H), 7.50 (s, 1H), 7.39 (d, 1H), 7.26 (s, 1H), 3.24 (s, 6H), MS (ESI): m/z=309.30 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]4[NH:38][N:37]=[N:36][N:31]=4)=[CH:29][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)cc1
Reaction time: 48 h
Yield: 20 %

Procedure:
A suspension of compound 12 (0.041 g, 0.10 mmol) and trimethyltin azide (0.023 g, 0.11 mmol) in toluene (2 mL) was refluxed for 15 h. The reaction mixture was allowed to stand at rt for 48 h. The resulting suspension was filtered and washed with toluene (2×). The solid was treated with hydrogen chloride (4 M in dioxane, several mL) for 4 h at rt. The reaction mixture was concentrated on a rotary evaporator. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford 13 as a white solid (0.009 g, 20%). 1H NMR (CDCl3) δ 8.22 (br s, 1H), 8.05 (br m, 1H), 7.82 (br m, 3H), 7.52-7.38 (m, 5H), 7.30 (br m, 2H), 5.23 (s, 2H), 4.53 (br m, 1H), 2.27 (br m, 4H), 2.06 (br m, 2H), 1.84 (br m, 1H), 1.40 (br m, 3H); ESI-MS m/e 451.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([O-:3])=[O:2]
Reactant: O=C1OCCC1Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCC1Oc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2-nitrophenol (20 g, 0.14 mol) and K2CO3 (25.2 g, 0.18 mol) in 280 mL DMF was cooled to 0 ° C. 2-Bromobutyrolactone was added dropwise, the reaction was stirred for 45 min at 0° C., then stirred at room temperature for 3 hours (h). The mixture was poured into 2 L water containing approx. 200 g salt, and the solution was washed with 6×100 mL of 1:1 diethyl ether/ethyl acetate. The combined organics were washed with 2×100 mL sat'd aq. K2CO3, 5×100 mL water and 100 mL brine, dried (Na2SO4), and filtered. Solvent was removed in vacuo to yield the title compound as an off-white solid (21.88 g, 0.1 mol). 1H (CDCl3): 7.84 (d, 1H, J=7.9), 7.57 (t, 1H, J=7.5), 7.49 (d, 1H, J=7.9), 7.16 (t, 1H, J=7.5), 5.03 (t, 1H, J=7.4), 4.58 (m, 1H), 4.42 (m, 1H), 2.8-2.6 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=1[OH:29].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][C:21]1[C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1cccc([N+](=O)[O-])c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc([N+](=O)[O-])c1O
Yield: 67.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 590 mg of 2-amino-6-nitrophenol, and 734 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 5 ml of pyridine and 6 ml of N,N-dimethylformamide. 976 mg of N-(2-hydroxy-3-nitrophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[F:15][C:16]([F:23])([F:22])[C:17](=O)[CH2:18][C:19]#[N:20]>CCO>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:17]([C:16]([F:23])([F:22])[F:15])[CH:18]=1
Reactant: CCOC(=O)Cc1cccc(NN)c1
Reactant: N#CCC(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)Cc1cccc(-n2nc(C(F)(F)F)cc2N)c1
Yield: 57 %

Procedure:
A mixture of ethyl (3-hydrazinophenyl)acetate (8.77 g, 0.028 mol, available from Example A5) and 4,4,4-trifluoro-3-oxo-butyronitrile (5.75 g, 0.042 mol) in EtOH (200 mL) was heated at reflux overnight. The mixture was concentrated and the residue purified by column chromatography to yield ethyl 2-(3-(5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetate (5 g, 57% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-d6): 7.50-7.43 (m, 3H), 7.30-7.33 (m, 1H), 5.81 (s, 1H), 5.75 (s, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.76 (s, 2H), 3.38 (s, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 314 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)C.[CH3:13][O-:14].[Na+]>CO>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:14][CH3:13]
Reactant: C[O-]
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccnc1OC
Yield: 70.9 %

Procedure:
A mixture of quinoxaline-6-carboxylic acid (2 g, 11.49 mmol) and thionyl chloride (30 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness using a rotary evaporator to afford quinoxaline-6-carboxylic acid chloride (crude quantitative). A solution of the above acid chloride (11.49 mmol) in DCM (50 mL) and pyridine (20 mL) was mixed with N,O-dimethyl hydroxylamine HCl salt (2.24 g, 23 mmol) and stirred at room temperature for 12 hours. The reaction was quenched by adding aqueous HCl (50 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield quinoxaline-6-carboxylic acid methoxy-methyl-amide (2 g, 80%). To a solution of the above Weinreb amide (2.0 g, 9.2 mmol) in THF (30 mL) at 0° C. was added methyl magnesium bromide (3.9 mL, 11.6 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then 1 hour at room temperature, quenched by adding aqueous HCl (20 mL, 1 N), extracted with DCM (3×100 mL), concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc=1:3) to yield 6-acetylquinoxaline (1.17 g, 74%). A solution of 2-chloronicotinic acid ethyl ester (5.0 g, 27 mmol) in MeOH (25 mL) was mixed with sodium methoxide (25.6 mL, 112.5 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding water (100 mL), extracted with DCM (3×100 mL), concentrated using a rotary evaporator to afford 2-methoxynicotinic acid methyl ester (3.2 g, 71%). A solution of 6-acetylquinoxaline (0.62 g, 3.6 mmol), 2-methoxynicotinic acid methyl ester (0.64 g, 3.8 mmol), and sodium hydride (0.46 g, 11.4 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL) and AcOH (20 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was re-dissolved in DCM (5 mL) and MeOH (3 mL) and was diluted with Hexanes (50 mL). The solid was removed by filtration and the filtrate was concentrated to afford the diketo compound (0.7 g, 60%). A solution of the above diketone (0.4 g, 1.3 mmol) in AcOH (50 mL) and sulfuric acid (conc., 15 drops) was stirred at reflux for 1 hour. Most of the solvent was removed using a rotary evaporator. The residue was re-dissolved in MeOH and neutralized with potassium carbonate to pH=8. The solid residue was removed by filtration, washed with MeOH and DCM. The filtrate was extracted with CH2Cl2 (3×100 mL) and concentrated using a rotary evaporator. The solid residue was purified by column (SiO2, Hexanes/EtOAc/MeOH=2:2:1) to afford 2-(quinoxalin-6-yl)-4H-pyrano[2,3-b]pyridin-4-one (90 mg, 24%); MS (ES) m/z: 276 (M+1); MP 272.3-274.8° C.