Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.Br[C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][N:54]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1.O>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:53]1[CH:58]=[C:57]([CH3:59])[CH:56]=[CH:55][N:54]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2B2OC(C)(C)C(C)(C)O2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C)ccn2)nc1
Temperature: 80 °C
Reaction time: 120 h
Yield: 44.6 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (200 mg) is dissolved in 1,4-dioxane (4 ml) and thereto are added 2-bromo-4-methyl-pyridine (70 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg) and cesium carbonate (133 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. for 5 days. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→14:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(4-methyl-pyridin-2-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (85 mg). MS (m/z): 701 [M+H]+
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH:11]1[O:16][CH:15]([C:17]2[O:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[C:14]2=[C:23]3[N:35]([CH3:36])[C:34](=[O:37])[N:33]([CH3:38])[C:32](=[O:39])[C:24]3=[C:25]([C:26]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)[N:13]2[CH2:12]1)=[O:8]>C1COCC1>[Cl:22][C:19]1[O:18][C:17]([CH:15]2[C:14]3=[C:23]4[N:35]([CH3:36])[C:34](=[O:37])[N:33]([CH3:38])[C:32](=[O:39])[C:24]4=[C:25]([C:26]4[S:27][CH:28]=[C:29]([CH3:31])[N:30]=4)[N:13]3[CH2:12][CH:11]([CH2:10][N:9]3[CH2:4][CH2:5][CH2:6][C:7]3=[O:8])[O:16]2)=[CH:21][CH:20]=1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)CCCBr)OC3c2ccc(Cl)o2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2CCCC2=O)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C

Procedure:
Sodium hydride (60% wt in mineral oil, 26.8 mg, 0.671 mmol) was added to a solution of 4-bromo-N-((10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazin-8-yl)methyl)butanamide (82 mg, 0.134 mmol) in THF (6711 μl). The mixture was heated at reflux for 1 hour, then cooled to room temperature and quenched with water (30 ml). The mixture was extracted with ethyl acetate (2×30 ml). The combined organic extracts were washed with brine, passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1
Reactant: COC(=O)C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C(Cc1ccc(C#N)cc1)C1CCCN1

Procedure:
(R)-1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl-acetic acid methyl ester (0.5 g, 2.06 mmol) is treated with lithium bis(trimethylsilyl)amide and 4-bromomethylbenzonitrile (1.0 g, 5.14 mmol) as described in EXAMPLE 1B to give 3-(4-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester as a mixture of stereoisomers. This material is coupled with biphenyl-4-carboxylic acid to give 2-[1-(Biphenyl-4-carbonyl)-pyrrolidin-2-yl]-3-(4-cyanophenyl)-propionic acid methyl ester (0.5 g, 1.1 mmol). This material is converted to the title compound (0.47 g, 0.83 mmol) by the procedure described in EXAMPLE 1C. 1H NMR (DMSO-d6, 300 MHz) □ 9.35-9.11(m,4H), 7.78-7.32 (m, 13H), 4.52, 4.36(two m, 1H), 3.58, 3.51 (two s, 3H), 3.50-3.25(m,3H), 3.14-2.95(m, 1H), 2.95-2.80(m, 1H), 2.20-1.55(m, 4H). MS m/z: [M+H]+=456
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[F:9][C:5]1[C:6]([I:8])=[CH:7][C:2]([NH:11][NH2:12])=[N:3][CH:4]=1
Reactant: NN
Reactant: Fc1cc(I)c(F)cn1
Solvent: CCO
Solvent: O
Product: NNc1cc(I)c(F)cn1
Temperature: 50 °C
Reaction time: 19 h
Yield: 35 %

Procedure:
A solution of 2,5-difluoro-4-iodopyridine (1.35 g, 5.602 mmol) in ethanol (7 mL) was treated with hydrazine hydrate (2.75 mL) and the mixture was stirred at 50° C. for 19 hours. The mixture was concentrated in vacuum and the resulting solid triturated with water, filtered, rinsed with more water and dried to yield the title compound (0.57 g, 35%) that was used in the following steps without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[C:19]([O:22][CH2:23][CH2:24]Br)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:4]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(=O)OCCBr
Product: CCOC(=O)CO[C@@H]1C[C@@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C1
Yield: 46.1 %

Procedure:
With 20.0 g of tert-butyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-hydroxypyrrolidine-1-carboxylate and 25.9 g of bromoethyl acetate as starting material, 12.3 g of the title compound obtained by a similar procedure to Step 139-1.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11](C4C=CC=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH2:28]([O:30][C:31]1[CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH3:29]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:33]4[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH2:28][CH3:29])[CH:32]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Product: CCOc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)ccc1OC
Yield: 42.7 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2-(3-ethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (106.3 mg, 0.411 mmol) as a starting material to afford 51.0 mg (42.7%) of (R)-4-((R)-1-((1-cyclopropyl-5-(3-ethoxy-4-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:. 1H NMR (300 MHz, DMSO-d6) δ 8.058 (s, 1H), 7.576 (s, 1H), 7.367 (d, J=1.2 Hz 1H), 7.184 (s, 1H), 7.155 (d, J=1.8 Hz, 1H). 6.99 (t, J=4.4 Hz 2H), 4.84 (t J=5.9 Hz, 1H), 4.11 (dd, J=7.2, 6.6 Hz, 2H), 3.768 (s, 3H), 3.709-3.637 (m, 1H), 3.38 (t, J=9 Hz, 1H) 3.18 (dd, J=6.9, 9.3 Hz, 1H), 2.83-2.75 (m, 1H), 2.379-2.207 (m, 2H), 1.358-1.282 (m, 6H), 1.125-1.00 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29N3O4:435.22; found 436.18.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][C:14](OC(C)(C)C)=O)[CH:8]=2)[N:3]=1.CC1C(=O)NC2C(N=1)=CC(CC(OC(C)(C)C)=O)=CC=2.[C:41]1([C:47]2[N:52]=[N:51][C:50]([NH:53][NH2:54])=[CH:49][CH:48]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([CH2:13][C:14]1[N:51]3[N:52]=[C:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:48]=[CH:49][C:50]3=[N:53][N:54]=1)[CH:8]=2
Reactant: Cc1nc2ccc(CC(=O)OC(C)(C)C)cc2[nH]c1=O
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1nc2cc(CC(=O)OC(C)(C)C)ccc2[nH]c1=O
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2ccc(Cc3nnc4ccc(-c5ccccc5)nn34)cc2[nH]c1=O
Temperature: 150 °C

Procedure:
A mixture of tert-butyl 2-(2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)acetate (0.10 g, 0.36 mmol), tert-butyl 2-(3-methyl-2-oxo-1,2-dihydroquinoxalin-6-yl)acetate (0.10 g, 0.36 mmol), 1(6-phenylpyridazin-3-yl)hydrazine (0.081 g, 0.44 mmol) and p-toluenesulfonic acid monohydrate (0.069 g, 0.36 mmol) in 3 mL of dioxane was heated with microwave at 150° C. for 1 hour. The mixture was diluted with 70 mL of EtOAc and 40 mL of satd. NaHCO3 solution. The organic phase was separated and was washed with 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to resolve the regiostereomers as example compounds 494 and 495. For each regiosteroemer MS (ESI pos. ion) m/z: 369 (MH+). Calc'd exact mass for C21H16N6O: 368.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[NH:27][C:28](=[O:30])[CH3:29]>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:23][C:24]4[CH:25]=[C:26]([NH:27][C:28](=[O:30])[CH3:29])[CH:31]=[CH:32][CH:33]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(=O)Nc1cccc(Nc2ncc3ccc(-c4cccc(COC(C)(C)C)c4)n3n2)c1
Yield: 39 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3′-aminoacetanilide (0.0689 g, 0.459 mmol) were reacted to afford N-{3-[7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-acetamide as an orange foam (62 mg, 39%). LCMS: 430 (M+H); 1H-NMR (DMSO-d6): 9.84 (s, 1H), 9.46 (s, 1H), 8.98 (s, 1H), 8.12 (s, 1H), 8.06 (d, 1H, J=7.71 Hz), 7.72 (s, 1H), 7.63 (d, 1H, J=7.71 Hz), 7.44 (t, 1H, J=7.71 Hz), 7.35 (d, 1H, J=7.71 Hz), 7.22 (m, 2H), 7.19 (d, 1H, 4.65 Hz), 6.96 (d, 1H, J=4.65 Hz), 4.46 (s, 2H), 2.03 (s, 3H), 1.22 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:22]([Li])CCC.CI.O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:22][C:11]1[S:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:12]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Solvent: CCOCC
Solvent: CI
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C)sc2-c2ccc(OC)cc2)cc1
Yield: 64 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (4.4 g, 15 mmole) in 100 ml of toluene was dried by distilling off 75 ml of toluene. The solution was diluted with 150 ml of diethyl ether, cooled to 0°, and treated dropwise with 1.6M n-butyl lithium (13.5 ml, 1.4 equiv.). The reaction mixture was heated at reflux for 1.5 hours, cooled to 5°, treated with a solution of methyl iodide (2 ml, 2.1 equiv.) in 10 ml of diethyl ether, and then heated at reflux for an additional 2.5 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were washed with 1N HCl and brine, dried, and concentrated in vacuo. Recrystallization from ethanol provided the title compound (3 g, 64%), m.p. 93°-97°. Proton nuclear magnetic resonance (NMR) was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[O:8])=[C:4]([Cl:11])[CH:3]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a suspension of 4-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and dimethylformamide (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the subtitle compound as a solid (4.28 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18](I)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
To a mixture of N-benzyl-2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.557 mmol), pyridine-4-boronic acid (137 mg, 1.11 mmol) and Pd(Ph3P)2Cl2 (40 mg, 0.042 mmol) in dioxane (3 mL), aq. Na2CO3 (120 mg, 1.13 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 4 h. It was concentrated in vacuo. The residue was purified by HPLC to give N-benzyl-2-chloro-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg).
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O:30][CH:31]([CH2:37][O:38][N+:39]([O-:41])=[O:40])[CH2:32][CH2:33][CH2:34][CH2:35]O)([O-:29])=[O:28].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CC(O)=O>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([O:30][N+:27]([O-:29])=[O:28])[CH2:37][O:38][N+:39]([O-:41])=[O:40])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=[N+]([O-])OCC(CCCCO)O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)OC/C(=C(\C(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Yield: 63.2 %

Procedure:
A solution of 2.5 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid, 10 mmol of 5,6-bis(nitrooxy)hexan-1-ol, 15 mmol of DMAP and 10 mmol of EDCI was stirred at rt for 3 h. Then, AcOH (2-mL) was added and the mixture was filtered through a pad of silica gel and washed with EtOAc, evaporated, purified by flash chromatography (15-50% EtOAc/hexane) to afford 2.45 g of the desired compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.79 (d, 2H), 7.45 (d, 2H), 7.21-7.16 (m, 1H), 7.13-7.08 (m, 2H), 5.52-5.44 (m, 1H), 5.21 (s, 1H), 4.98 (dd, 1H), 4.72 (dd, 1H), 4.29 (t, 2H), 3.09 (s, 3H), 1.92 (s, 3H), 1.89-1.74 (m, 4H), 1.60-1.48 (m 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][S:15][C:16]([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)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:46]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][NH2:54])=[CH:48][CH:47]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8]([C:9](=[O:11])[NH:54][CH2:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[CH:47][CH:48]=1)[CH2:12][CH2:13][CH2:14][S:15][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 29 (200 mg, 0.41 mmol) and HOBt (66 mg, 0.49 mmol) in DMF (2 mL), were added 4-biphenylethylamine (124 mg, 0.62 mmol) and DIC (78 μL) respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (0.5N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, with a saturated sodium hydrogen carbonate solution, and again with brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed using 30% ethyl acetate in hexanes. 1H-NMR (CDCl3, 400 MH: 1.55(s, 9H); 1.41–1.57(m, 2H); 2.04–2.28(m, 6H); 2.54(m, 1H); 2.80(m, 2H); 3.45–3.55(m, 2H), 5.66(m, 1H); 7.19–7.57(m, 24H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[C:20]([C:36]([F:39])([F:38])[F:37])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:41]>C(O)C>[ClH:41].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:20]([C:36]([F:37])([F:38])[F:39])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1ccc(CCCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CCCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 10-2 (730 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (550 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:17](=[O:18])[N:11]3[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]3=[CH:9][CH:8]=2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CC1N=CN(C2C(=O)NC(C(O)=O)=CC=2)C=1.Cl.[Cl:43][CH2:44][CH2:45]NCCCl.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[Cl:43][CH2:44][CH2:45][N:14]1[CH2:13][CH2:12][N:11]2[C:17](=[O:18])[C:7]([N:5]3[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]3)=[CH:8][CH:9]=[C:10]2[C:15]1=[O:16]
Reactant: ClCCNCCCl
Reactant: Cc1cn(-c2ccc3n(c2=O)CCNC3=O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3n(c2=O)CCN(CCCl)C3=O)cn1
Reaction time: 0.17 h

Procedure:
Synthesis of 242-chloroethyl)-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (P2). Potassium carbonate (195.4 g, 1414 mmol) was added to a mixture of 5-(4-methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, hydrochloride salt (C3) (34.5 g, 135 mmol) and 2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (37.8 g, 212 mmol) in N,N-dimethylformamide (670 mL), and the reaction was stirred for 10 minutes. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 83.5 g, 219 mmol) was added and stirring was continued for an additional 3 hours and 40 minutes. The reaction mixture was then poured into water (4 L) and stirred for 30 minutes. After extraction with dichloromethane (3×1 L), the combined organic layers were washed with saturated aqueous sodium chloride solution (3×3 L), dried over magnesium sulfate, filtered and concentrated in vacuo. Finally, most of the DMF was removed by using a methanol/liquid nitrogen cooler. The residue was stirred in ethyl acetate (approximately 50 mL) for 30 minutes. The solids were collected by filtration and washed with ethyl acetate and pentane, providing the title compound as a yellow solid. Yield: 23.0 g, 75.0 mmol, 56%. LCMS m/z 307.1 (M+1). 1H-NMR (300 MHz, CDCl3) δ 2.29 (br s, 3H), 3.80-3.93 (m, 6H), 4.38-4.44 (m, 2H), 7.13-7.16 (m, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 8.24 (d, J=1.0 Hz, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH:7]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:19]=[CH:18][C:16]([N:17]=[C:1]=[O:2])=[CH:15][CH:14]=2)[N:9]=[CH:10][N:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=Nc1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: -20 °C

Procedure:
Apparatus: 2 litre 3-neck-roundbottle flask, dropping funnel, short Vigreux column and condenser. A phosgene solution (20% in toluene, 118 ml; 223 mmol) diluted with toluene (800 ml) under N2-atmosphere is cooled to approximately −20° C. Then a solution of 4-(6-chloro-pyrimidin-4-yl-oxy)-aniline (Stage 21.1; 18.52 g, 83.6 mmol) in CH2Cl2 (400 ml) is added dropwise. The resulting suspension is heated to distil off approximately 400 ml of solvent. Distillation Is continued (boiling point: 110° C.), while a mixture of phosgene solution (20% in toluene, 59 ml) and toluene (500 ml) is added dropwise, followed by toluene (250 ml). The resulting clear solution (a 250 ml) in the reaction vessel is cooled to rt, filtered and the filtrate concentrated in vacuo. Distillation of the resulting waxy crude product on the Kugelrohr apparatus (0.2 mbar, 200° C.) gives the title compound as a solid: m.p.: 103° C.; MS: [M+1]+=302; 1H-NMR (CDCl3): 8.57 (s, 1H), 7.17 (d, 2H), 7.10 (d, 2H), 6.95 (s, 1H).