Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:33])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].[CH3:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:33][C:36](=[O:37])[C:35]([CH3:40])([CH3:39])[CH3:34])=[C:8]2[C:14]([Br:15])=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:12]([CH2:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(-c1ccc(Cl)cc1)n2Cc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc2c(c(Br)c(-c3ccc(Cl)cc3)n2Cc2ccc3c(c2)OCO3)c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To a suspension mixture of 1-benzo[1,3]dioxol-5-ylmethyl-3-bromo-2-(4-chloro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (320 mg, 0.60 mmol)(from Example 35(e)) in CH2Cl2 (3 mL) at 0° C. was added 2,2-dimethyl-propionyl chloride (87.4 mg, 0.73 mmol) and triethylamine (122 mg, 1.20 mmol). Resulting mixture was stirred at room temperature for 1.5 h. It was diluted with CH2Cl2 and washed with 0.1 N HCl aqueous solution, water and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluting with 5%-20% EtOAc in CH2Cl2) to give the title compound 361 mg. MS-(+)-ion: M+1=614.98, 613.02.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:16]([NH:18][C@@H:19]([C:36]([OH:38])=[O:37])[CH2:20][CH2:21][C:22]([N:24]1[C@@H:32]2[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][C@H:25]1[C:33]([OH:35])=[O:34])=[O:23])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[Na+:40].C(#N)C.O>O>[C:1]([NH:9][C@H:10]([C:16]([NH:18][C@@H:19]([C:36]([OH:38])=[O:37])[CH2:20][CH2:21][C:22]([N:24]1[C@@H:32]2[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][C@H:25]1[C:33]([O-:35])=[O:34])=[O:23])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na+:40]
Reactant: NCCCC[C@H](NC(=O)c1cccnc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NCCCC[C@H](NC(=O)c1cccnc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)[O-])C[C@@H]2CCCC[C@@H]21)C(=O)O

Procedure:
In 5 ml of water was dissolved 0.57 g of (2S,3aS,7aS)-1-(N2 -nicotinoyl-L-lysyl-gamma-D-glutamyl)octahydro-1H-indole-2-carboxylic acid (see Example 15), and 1 ml of 1N-NaOH was added. The resulting aqueous solution was subjected to CHP20P column chromatography (0%→20% acetonitrile/water gradient). Fractions containing the desired product were concentrated to dryness under reduced pressure. The residue was lyophilized to give 0.25 g of the captioned compound. [α]D26 : -24.6° (H2O).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.O=[C:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+].CO>[CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:18][CH2:19][N:20]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:21][CH2:22]4)=[CH:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C4CCOCC4)CC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (44.0 mg, 0.105 mmol), 4-oxotetrahydropyran (37.7 mg, 0.366 mmol) and sodium triacetoxyborohydride (100 mg, 0.471 mmol) in 1,2-dichloroethane (1.0 mL) was stirred at room temperature over the weekend. The reaction was diluted with saturated NaHCO3 (aq) and methanol. The mixture was concentrated to dryness and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((3-methyl-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.34 (26 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(C(N)=O)[C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>Cl>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]([CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN1CCC(C2(C(N)=O)Cc3ccc([N+](=O)[O-])cc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(C2Cc3ccc([N+](=O)[O-])cc3C2=O)CC1
Yield: 97.4 %

Procedure:
A solution of 4.42 g of 6-nitro-2-(1-methyl-4-piperidyl)-1-oxo-2-indanecarboxamide in 60 mL of 6N hydrochloric acid was stirred and refluxed for one hour. The solution was cooled in an ice bath and made basic by the addition of 20% aqueous sodium hydroxide. The mixture was extracted with three 100 mL portions of ether. The combined extracts were dried over magnesium sulfate, filtered, and the ether was removed under reduced pressure to give 3.72 g (97%) of 6-nitro-2-(1-methyl-4-piperdyl)-indan-1-one as a low melting crystalline solid.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:40])[C:29]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:30]=3[N:31]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:40])[C:29]3[CH:39]=[C:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCCC3
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 13 %

Procedure:
H2O2 (70%, 0.36 mL, ca. 6.0 mmol) was added dropwise to a stirred solution of TFAA (0.96 mL, 6.0 mmol) in DCM (5 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then added to a stirred solution of 1-oxide 179 (204 mg, 0.60 mmol) and TFA (0.24 mL, 3.0 mmol) in DCM (5 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1,4-dioxide 180 (28 mg, 13%) as a red solid which was converted to the hydrochloride salt: mp (MeOH/DCM) 182-185° C.; 1H NMR [(CD3)2SO] δ 10.29 (s, 1H, HCl), 8.35 (br s, 1H, NH), 7.95 (s, 1H, H-10), 7.87 (s, 1H, H-5), 3.92-4.01 (m, 2H, CH2O), 3.37 (m, 4H, CH2N, CH2O), 2.88-3.22 (m, 8H, 2×CH2N, H-6, H-9), 2.53 (t, J=5.6 Hz, 2H, CH2N), 2.00-2.09 (m, 2H, CH2N), 1.74-1.83 (m, 4H, H-7, H-8); 13C NMR [(CD3)2SO] δ 149.2, 147.8, 138.0, 136.1, 128.5, 119.4, 115.0, 63.0 (2), 53.5, 50.9 (2), 37.9, 29.4, 28.5, 22.7, 21.7, 21.6. Anal. calcd for C18H25N5O3.2HCl.2H2O: C, 46.2; H, 6.7; N, 15.0. Found: C, 46.3; H, 6.4; N, 15.0%.
Reaction SMILES: C([NH:4][CH:5]([CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.[ClH:22]>>[ClH:22].[NH2:4][CH:5]([CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: NC(C(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
A solution (21 mL) of 2-acetylamino-3,3-diphenylpropanoic acid (2.83 g, 10 mmol) in concentrated hydrochloric acid was stirred at 90° C. for 5 hrs, and the reaction mixture was cooled in an ice bath to allow solid precipitation. The solid was collected by filtration and dried to give the title compound (2.65 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)=[N:6][CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Ic1ccc(NCCN2CCCCC2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(NCCN4CCCCC4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from (5-iodo-pyridin-2-yl)-(2-piperidin-1-yl-ethyl)-amine (397 mg, 1.20 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (256 mg, 1.20 mmol).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][CH3:4].Cl[C:7]1[N:12]=[N:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:14]>O>[CH3:14][C:8]1[CH:9]=[C:10]([NH2:13])[N:11]=[N:12][C:7]=1[O:5][CH2:2][CH2:3][CH3:4]
Reactant: CCCO
Reactant: Cc1cc(N)nnc1Cl
Agent: [Na]
Solvent: O
Product: CCCOc1nnc(N)cc1C
Reaction time: 24 h

Procedure:
Sodium (40 mg) was added to stirred propanol (4 g). After the sodium had dissolved, 6-chloro-5-methylpyridazin-3-amine (200 mg) was added and the mixture was heated to 155° in a glass pressure vessel with magnetic stirring for 24 h. The cooled reaction mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried (sodium sulfate) and evaporated to afford crude 5-methyl-6-propyoxypyridazin-3-amine.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCO>[CH3:16][S:13]([C:10]1[CH:11]=[CH:12][C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:8][C:7]=2[CH:9]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Reactant: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)OC2
Temperature: 130 °C
Yield: 43.7 %

Procedure:
A mixture of 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (0.70 g, 2.28 mmol), piperidine (2.0 ml, 20.2 mmol) and EtOH (4.0 ml) was heated under microwave irradiation at 130° C. for 30 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the pure title compound (0.31 g, 49%). The amine was converted into HCl salt and crystallized from MeOH/DEE (0.33 g). M.p. 217° C. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J1 8.0 Hz, J22.0 Hz), δ 7.39 (1H, d, J 1.6 Hz), δ 7.31 (1H, d, J 8.0 Hz), δ 5.31 (1H, t, J 5.2 Hz), δ 5.02 (2H, dd, J1 60.4 Hz, J2 15.6 Hz), δ 3.10 (3H, s), δ 2.77 (2H, m), δ 2.60 (4H, s, broad), δ 1.63 (4H, m), δ 1.49 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:17](SCCC)[C:18]([NH2:20])=[O:19]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH2:20])=[O:19]
Reactant: CCCSC(C(N)=O)c1cccc(C(=O)c2ccc(F)cc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(=O)Cc1cccc(C(=O)c2ccc(F)cc2)c1N
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A solution of 24.2 g (0.07 mole) of 2-amino-3-(4-fluorobenzoyl)-α-(n-propylthio)phenylacetamide in 300 ml of tetrahydrofuran was treated with 250 g of wet Raney nickel (washed 3 times with water and 3 times with tetrahydrofuran). The mixture was stirred for one hour and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from 95% ethyl alcohol to give 14.8 g (78%) of yellow needles melting at 184°-186° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[O:7]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:23]=[CH:22][C:12]([CH2:13][O:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][Br:20])=[CH:11][CH:10]=1
Reactant: O=C(CCCCBr)Nc1ccc(COC(=O)CCCCBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCCCBr)OCc1ccc(N2CCCCC2=O)cc1

Procedure:
The ester from Step 1 (1 g, 2.22 mmol) was dissolved in DMF. Cs2CO3 (725 mg , 2.22 mmol) was added and the reaction mixture was heated to 50° for 18 hours. TLC shows ~50% starting material remaining. Additional Cs2CO3 (2.22 mmol) was added the reaction mixture was heated at 50° for and additional 8 hours. The mixture was dissolved in 10% citric acid and extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried (MgSO4) filtered and concentrated to yield a yellow oil. Flash chromatography (EtOAc) yielded the title compound as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:42][O:43][CH2:44][C:45]([O:47]C(C)(C)C)=[O:46])[C:17]([NH:19][CH:20]2[C:40](=[O:41])[N:22]3[C:23]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=[O:9]>C1(OC)C=CC=CC=1>[CH:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:42][O:43][CH2:44][C:45]([OH:47])=[O:46])[C:17]([NH:19][CH:20]2[C:40](=[O:41])[N:22]3[C:23]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])=[CH:24][CH2:25][S:26][C@H:21]23)=[O:18])[N:15]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=CNc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.8 %

Procedure:
Trifluoroacetic acid (40 ml.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 10 g.) in anisole (10 ml.) at 5° C., and stirred at room temperature for 70 minutes. After evaporating the solvent from the resultant mixture in vacuo, the residue was triturated with diethyl ether. The precipitates were collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 8.2 g.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:19]1[CH:20]=[C:21]([C:27]#[N:28])[C:22](=[CH:25][CH:26]=1)[C:23]#[N:24])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:19]2[CH:20]=[C:21]([C:27]#[N:28])[C:22](=[CH:25][CH:26]=2)[C:23]#[N:24])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1C#N
Yield: 111.9 %

Procedure:
A mixture of 4-benzyloxyphenol (14.53 g, 72.6 mmol), 4-nitrophthalonitrile (10.47 g, 60.5 mmol), potassium carbonate (16.69 g, 120.9 mmol), and acetone (170 mL) was refluxed overnight; the reaction mixture was cooled, and the solids were filtered off and rinsed with EtOAc. All liquids were combined and concentrated in vacuo. The resulting residue was partitioned between EtOAc and 2 M NaOH solution in a 500-mL separation funnel. The organic phase was subsequently washed with 1 M HCl, saturated NaCl solution, dried over sodium sulfate, and concentrated in vacuo to give the crude title compound (22.1 g) that was used in the next step without further purification. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.7-6.6 (m, 12H), 5.08 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[N:16]=[C:15]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=3)[CH:14]=2)=[O:12])=[CH:6][CH:5]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:58][C:59]1[NH:63][N:62]=[N:61][N:60]=1.C(Cl)CCl>CN(C=O)C.C(OCC)(=O)C>[NH:60]1[C:59]([NH:58][C:23]([C:22]2[CH:26]=[CH:27][C:19]([CH2:18][N:17]3[C:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:38])([F:1])[F:37])=[CH:5][CH:6]=4)=[O:12])=[CH:14][C:15]([C:28]4[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=4)=[N:16]3)=[CH:20][CH:21]=2)=[O:24])=[N:63][N:62]=[N:61]1
Reactant: O=C(O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step B (45 mg, 0.84 mmol) in DMF was added HOAt (17 mg, 0.126 mmol), DIEA (44 μL, 0.252 mmol), amino tetrazole (22 mg, 0.252 mmol) and EDC (24 mg, 0.126 mmol). The resulting solution was left stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with 1N HCl. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified on the Gilson reverse phase HPLC to give the title compound. 1H NMR (DMSO, 500 MHz): 8.04 (d, J=8.3 Hz, 2H), 7.82 (d, J=9.2 Hz, 2H), 7.74 (dd, J=6.9, 8.7 Hz, 2H), 7.64 (s, 1H), 7.38 (d, J=7.9 Hz, 2H), 5.85 (s, 2H). LC-MS: 2.56 min; (M+H)=603.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.Cl[C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)OCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 65.7 %

Procedure:
At room temperature, under N2, a solution of 20 mg (0.031 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 3.8 mg (0.031 mmole) of DMAP, 18.9 mg (0.154 mmole) of propyl chloroformate, and 1 mL pyridine was stirred overnight. After quenching with methanol and water, the organic material was extracted with EtOAc, washed with water and brine, and dried over sodium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica gel (gradient elution with 0.5-5% MeOH/CH2Cl2) to give 15 mg (65%) of the desired compound as a white solid, mp >119° C. (gradual), homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 736 (M+1)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[Br:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl>[Br:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1

Procedure:
Diazomethane was added slowly to a suspension of 10 g of 4-(bromomethyl)-benzoic acid in 50 ml of methylene chloride until a persistent yellow coloring of the medium was obtained and excess diazomethane was destroyed by the addition of acetic acid. The mixture was evaporated to dryness and the residue was washed with water and dried under reduced pressure at ambient temperature to obtain 9.25 g of the desired product melting at 54° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.[Cl:8][C:9]1[CH:10]=[C:11](Cl)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:9]1[CH:10]=[C:11]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Cl)cc(Cl)nn12
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccncn3)cc(Cl)nn12
Temperature: 100 °C
Yield: 10.1 %

Procedure:
A solution of pyrimidin-4-amine (37.0 mg, 0.389 mmol) in degassed dioxane (4 mL) was treated with 6,8-dichloro-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.325 mmol), Pd2(dba)3 (14.86 mg, 0.016 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (9.39 mg, 0.016 mmol), and Cs2CO3 (211 mg, 0.649 mmol). The reaction was purged with argon and heated to 100° C. for 4 hours. The reaction was then cooled to room temperature and concentrated. The crude reaction product was dissolved in a small amount of MeOH, filtered and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=22.555 minutes) was isolated and lyophilized to dryness to afford 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 10.08%). HPLC Rt=2.463 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=367.0.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH2:28][C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].C([O-])(=[O:32])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)(=O)C>[C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH:28]([OH:32])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2]
Reactant: CC(=O)[O-]
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)CNC3=O
Agent: [Pb+4]
Solvent: CC(=O)O
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)C(O)NC3=O

Procedure:
140 mg (0.37 mmole) 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3a]pyrrolo[3,4-c]carbazole (Example 2) are stirred for 2 days at 20° C. in 20 mL glacial acetic acid with 197 mg (0.44 mole) lead tetraacetate. The solvent is evaporated in a vacuum and the residue partitioned between 50 mL tetrahydrofuran and 50 mL of saturated sodium hydrogencarbonate solution. The tetrahydrofuran phase is separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. The residue is chromatographed on silica gel with toluene/ethyl acetate 95:5 (v/v) and dichloromethan/methanol 98:2 (v/v). The fraction with an Rf of 0.1 in toluene/ethyl acetate 3:1 (v/v) is isolated. 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-7-hydroxy-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of beige crystals which decompose above about 220° C.