Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:29][C:13]2=[CH:14][C:15]3[C:16](=[O:28])[N:17]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:18](=[O:22])[C:19]=3[C:20]([CH3:21])=[C:12]2[N:11]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:29][C:13]2=[CH:14][C:15]3[C:16](=[O:28])[N:17]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[C:18](=[O:22])[C:19]=3[C:20]([CH3:21])=[C:12]2[N:11]=1
Reactant: COc1nccc(Cl)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(CCN(C)C)C2=O
Temperature: 47.5 °C

Procedure:
A solution of 2-(4-chloro-2-methoxypyridin-3-yl)-6-(2-(dimethylamino)ethyl)-4-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione in a mixture of 1,4-dioxane (14 mL) and concentrated HCl (2.5 mL) was heated at 45-50° C. for 14 h. After the end of reaction was established by TLC, the reaction mixture was concentrated under vacuum to afford a crude product as a yellow solid, which was used for the next step without further purification. Mass (ESI, positive) m/z 400.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=4[CH3:29])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-methoxy-2-methylaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.91 (bs, 1H), 7.61 (d, 1H, J=2.1 Hz), 7.17 (d, 1H, J=3.0 Hz), 7.05 (d, 1H, J=9.3 Hz), 7.03 (dd, 1H, J=3.0 and 8.7 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.68-6.60 (m, 2H), 6.55 (dd, 1H, J=2.1 and 8.1 Hz), 4.26 (s, 4H), 3.70 (s, 3H), 2.22 (s, 3H); 19F NMR (282 MHz, CDCl3): −47450; LCMS: purity: 99%; MS (m/e): 383(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[N+:12]([C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1)([O-:14])=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[C:22](=[O:21])[C:17]2[C:18](=[CH:24][CH:25]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:19]1=[O:20]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCc1ccc(Cl)cc1Cl
Temperature: 150 °C
Reaction time: 2 h

Procedure:
2-(2,4-dichlorophenyl)ethanamine was suspended in toluene with 4-nitrophthalic anhydride (1 eq) and heated to 150° C. After 2 hours, the reaction was cooled and checked for completion by LC/MS. The solvent was then removed in vacuo and the resulting product was taken on to the next step without further purification. Rt 3.36 minutes (HP LCMS), LC/MS m/z 365.1 (MH+).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][NH:25][N:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:31]([O:30][C:28]([C:27]1[C:23]([C:22]([F:33])([F:34])[F:21])=[N:24][N:25]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:26]=1)=[O:29])[CH3:32]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Triphenylmethyl chloride (1.1 g, 3.6 mmol) was added to a solution of ethyl 3-(trifluoromethyl)-pyrazole-4-carboxylate (0.75 g, 3.6 mmol) and triethylamine (1 mL, 7.2 mmol) in N,N-dimethylformamide (12 mL). This mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue was diluted with water (30 mL) and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and chromatographed (10% ethyl acetate/petroleum ether) to give 3-trifluoromethyl-1-trityl-1H-pyrazole-4-carboxylic acid ethyl ester (1.28 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:23]([C:39]([F:42])([F:41])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:23]([C:39]([F:41])([F:42])[F:40])=[CH:22][N:21]=2)=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Reaction time: 18 h

Procedure:
A suspension of methyl 2-(2-((2-((4-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A72) (0.589 g, 1.00 mmol) and 10% Pd/C (0.300 g) in EtOAc (13 mL) was stirred under a hydrogen atmosphere for 18 hours. A further portion of 10% Pd/C (0.300 g) was added and the resulting mixture stirred under a hydrogen atmosphere for 20 hours. The resulting mixture was filtered through a pad of Celite, washing with EtOAc and the filtrate concentrated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 20-60% EtOAc in cyclohexane) to give the title compound A73 as a light yellow gum (0.443 g, 74%); 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.44 (s, 1H), 7.28-7.25 (m, 6H), 4.49 (brs, 2H), 3.77-3.70 (m, 7H), 3.42 (brs, 2H), 3.15-2.95 (m, 5H), 1.51 (s, 9H). LCMS-B: rt 8.469 min; m/z 589 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: Brc1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccccc1-n1c2ccccc2c2cnccc21
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A mixture of 84.1 g (500 mmol) of 5H-pyrido[4,3-b]indole [244-69-9], 147.1 g (520 mmol) of 2-bromoiodobenzene [583-55-1], 103.7 g (750 mmol) of potassium carbonate, 31.8 g (500 mmol) of copper powder and 300 g of glass beads (diameter 3 mm) in 800 ml of DMF is stirred at 130° C. for 24 h. After cooling, the mixture is filtered through a short Celite bed, the bed is rinsed with DMF, and the latter is removed in vacuo. The residue is dissolved in 1500 ml of dichloromethane, and the solution is washed three times with 500 ml of concentrated ammonia solution each time and dried over magnesium sulfate. After removal of the dichloromethane in vacuo, the oily residue is distilled in a short-path evaporator (p=5×10−3 mbar, T=120° C.). Yield: 56.1 g (173 mmol), 35%; purity: 98% (1H-NMR).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[C:4]([F:15])[CH:3]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([CH2:24][C:25]2[CH:26]=[C:27]([O:40][CH2:41][CH3:42])[C:28](I)=[C:29]([O:31][S:32]([CH:35]([CH2:37][CH3:38])[CH3:36])(=[O:34])=[O:33])[CH:30]=2)=[CH:19][N:18]=1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[C:27]([O:40][CH2:41][CH3:42])=[CH:26][C:25]([CH2:24][C:20]3[C:21]([NH2:23])=[N:22][C:17]([NH2:16])=[N:18][CH:19]=3)=[CH:30][C:29]=2[O:31][S:32]([CH:35]([CH2:37][CH3:38])[CH3:36])(=[O:33])=[O:34])=[CH:3][C:4]=1[F:15]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1I
Reactant: O=C(Nc1ccc(Br)cc1F)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1-c1ccc(N)c(F)c1

Procedure:
Starting from 241 mg (0.84 mmol) N-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-acetamide and 214 mg (0.422 mmol) butane-2-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 85 mg of the tide compound are obtained as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)NCC(=O)OCc2ccccc2)c2ccccc2)=C(C)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)NCC(=O)O)c2ccccc2)=C(C)C1=O
Yield: 98.5 %

Procedure:
Benzyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoylglycinate (0.78 g) in ethanol (8 ml) was hydrogenated in the presence of 5% palladium-charcoal (0.08 g) at room temperature. After the reaction was completed, the catalyst was removed by filtration. The solution was treated with ferric chloride (0.51 g) in water (5 ml) at room temperature for 20 min. with stirring. The reaction mixture was worked up in the usual manner. The product was recrystallized from ethylacetate to give 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoylglycine (0.63 g, 98%), mp 162°-164° C.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)=[O:2].[Cl:28]N1C(=O)CCC1=O>O1CCCC1>[Cl:28][C:6]1[CH:7]=[C:8]([C:24]([O:26][CH3:27])=[O:25])[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[N:10][C:5]=1[CH2:4][NH:3][CH:1]=[O:2]
Reactant: COC(=O)c1ccc(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 106 %

Procedure:
tert-Butyl 4-{6-[(formylamino)methyl]-3-(methoxycarbonyl)pyridin-2-yl}piperazine-1-carboxylate (4.85 g, 0.0128 mol) and N-chlorosuccinimide (2.1 g, 15 mmol) was stirred in tetrahydrofuran (85 mL) at 50° C. for 16 hours. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-80%) gave the desired compound (5.6 g, 100%). LCMS calculated for C18H26ClN4O5 (M+H)+: m/z=413.2. found: 412.9.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17]([F:23])[C:16]=1[F:24]>CC(O)=O.[Pd]>[CH3:26][N:2]([CH3:1])[C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[C:17]([F:23])[C:16]=1[F:24]
Reactant: CC(=O)c1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1

Procedure:
N,N-dimethyl-5-acetyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (30 g, 0.802 mol) is dissolved in HOAc (150 ml) and hydrogenated (55 psi) with a 10% Pd/C (1.5 g) catalyst for 8 hours. The catalyst is removed by filtration through Celite and the filtrate poured into water (500 ml) and EtOAc (500 ml). The organic layer is washed with water (750 ml), neutralized with saturated Na2CO3 solution (500 ml) and washed with brine (500 ml). Evaporation on a rotovap followed by trituration with hexanes gives N,N-dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide, m.p. 105-106°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](OCC)=[O:12])=[C:7]2[C:16]([O:18]CC)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](=[O:12])[N:22]=[N:23][C:16](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2c(Cl)cccc2c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1c(Cl)cccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred solution of diethyl 7-chloroindole-2,3-dicarboxylate (0.6 g, 2.0 mM) in ethanol (4 mL) was added hydrazine hydrate (2 mL, 40 mM). The resulting solution was heated to reflux for 3 hrs during which time a white precipitate formed. The solid was filtered, suspended in acetic acid (2 mL), and warmed to reflux for several minutes. The mixture was then cooled to room temperature and the solid filtered and dried. This provided the titled compound as a white solid (0.11 g, 23%), mp >250° C. NMR (d6 -DMSO): 12.92 (s, 1H), 11.66 (s, 2H), 8.08 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz), 7.32 (t, J=8 Hz). MS(CI): 236(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[ClH:11].NCCC1C=CC(OC)=C2C=1[CH2:17][C:18](=[O:26])[NH:19]2>>[ClH:11].[NH2:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]2[C:5]=1[CH2:17][C:18](=[O:26])[NH:19]2
Reactant: COc1ccc(CCN)c2c1NC(=O)C2
Reactant: COc1ccc(CN)cc1
Agent: Cl
Product: COc1ccc(CN)c2c1NC(=O)C2

Procedure:
Using 65 g of p-methoxybenzylamine for the starting material of Example 1 gives 4-aminomethyl-7-methoxy-2(3H)-indolone hydrochloride. This material (2 g) was converted to the base and alkylated using 1 mole equivalent of isovaleraldehyde as in Example 2 to give 4-isopentylaminomethyl-7-methoxy-2(3H)-indolone hydrobromide and 4-isopentylaminomethyl-7-hydroxy-2(3H)-indolone hydrobromide after demethylation using boron tribromide in methylene chloride at -20°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13].[N+:25]([C:28]1[CH:38]=[CH:37][C:31]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].[OH-].[Na+]>O.O1CCCC1>[OH:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[C@H:6]([C:2]2[N:1]([C:34]([O:33][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:38][CH:37]=3)=[O:35])[CH:5]=[CH:4][N:3]=2)[CH2:10]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1ncc[nH]1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1c1nccn1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 63 %

Procedure:
To a solution of (2S,4R)-2-(imidazol-2-yl)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.0 g) in a mixture of water (10 ml) and tetrahydrofuran (20 ml) was dropwise added a solution of 4-nitrobenzyloxycarbonyl chloride (0.85 g) in tetrahydrofuran (5 ml) under ice-cooling with stirring, keeping the pH between 9 and 10 with 4N aqueous sodium hydroxide. The mixture was stirred under the same condition for 1 hour, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (2S,4R)-4-hydroxy-2-[N-(4-nitrobenzyloxycarbonyl)imidazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (970 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:32]([CH3:33])[CH3:31])=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 74.7 %

Procedure:
Following the procedure of Example 7, 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 74.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:36][O:37][CH2:38][C:39]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)=[O:40]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: COCC(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1

Procedure:
A mixture of N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.0 mg, 0.0413 mmol), methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol, Aldrich, Cat. No. M9653) in dimethylsulfoxide (DMSO) (0.5 mL) was stirred at r.t. for 4 h. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=557.2.
Reaction SMILES: Cl.C(O[C:7](=O)[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:7])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C)Cc2ccccc2)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropane acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2×s), 2.12 and 2.17 (3H, 2×s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2×s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.Cl[C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[I-].C(N(CC)CC)C>COCCOC>[CH3:20][C:17]1[N:16]=[N:15][C:14]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1ccc(C#Cc2cccnc2)nn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 3-[(trimethylsilyl)ethynyl]pyridine (0.175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80° C. after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80° C. for 12 hour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) δ 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).
Reaction SMILES: [N+](C1C=CC(C([O:10][CH2:11][CH2:12][C:13]([CH3:26])([CH3:25])[CH2:14][CH:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:16][O:17][N+:18]([O-:20])=[O:19])=O)=CC=1)([O-])=O.[OH-].[Na+]>C1COCC1.CCO.C(=O)(O)[O-].[Na+]>[N+:18]([O-:20])([O:17][CH2:16][CH:15]([O:21][N+:22]([O-:24])=[O:23])[CH2:14][C:13]([CH3:26])([CH3:25])[CH2:12][CH2:11][OH:10])=[O:19]
Reactant: CC(C)(CCOC(=O)c1ccc([N+](=O)[O-])cc1)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(CCO)CC(CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-dimethyl-5,6-bis(nitrooxy)hexyl 4-nitrobenzoate (1.9 g, 4.73 mmol) in THF:EtOH 1:1 (12 ml) a aqueous solution of NaOH 3N (3.8 ml, 11.4 mmol) was added and the mixture was stirred at room temperature for 3 hrs. Then the mixture was diluted with a saturated solution of sodium bicarbonate and the product was extracted with EtOAc (3×30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure, affording the title compound which was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1cccnc1
Product: CCN1c2ncc(COc3cccnc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 72 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 183°-184° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-hydroxypyridine. The yield was 72% of theory.