Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=[CH:22][C:9]=1[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33]Br)[CH3:30]>O>[CH2:29]([O:31][CH:32]([O:35][CH2:36][CH3:37])[CH2:33][N:11]([CH2:10][C:9]1[CH:22]=[CH:23][C:24]2[O:28][CH2:27][O:26][C:25]=2[C:8]=1[O:7][CH3:6])[S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:30]
Reactant: COc1c(CNS(=O)(=O)c2ccc(C)cc2)ccc2c1OCO2
Reactant: CCOC(CBr)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 100 °C
Reaction time: 10 h
Yield: 79.3 %

Procedure:
44 mg (1.1 mmol) of 60% oil dispersion of sodium hydride was washed twice with 2 ml of dry hexane to eliminate oil. 2 ml of dry N,N-dimethylformamide, 335 mg (1 mmol) of N-(2-methoxy-3,4-methylenedioxybenzyl)-p-toluenesulfonamide (1) and 0.18 ml (1.1 mmol) of bromoacetaldehyde diethylacetal (purity 95%) were added in order. The resulting mixture was stirred at 100° C. for 10 hours. On cooling, to this 5 ml of water was added and the reaction mixture was extracted with 8 ml and then 2 ml of methylene chloride successively. The liquid extract was washed with 5 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluate: ethylacetate/n-hexane=1/4) to obtain 358 mg of N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (2) as an oil. Yield 79%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: [N-]=[N+]=NCc1cnc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cnc2ccccc2c1
Yield: 48.3 %

Procedure:
3(azidomethyl)quinoline (250 mg, 1.36 mmol) and triphenylphosphine (880 mg, 3.36 mmol, 2.5 equiv) were dissolved in 10 mL THF. The reaction mixture was treated with 0.5 mL of H2O and refluxed for 6 hours. The reaction mixture was cooled and partitioned between Et2O and 1N HCl. The aqueous portion was then treated with 1N NaOH until basic and extracted into EtOAc. The organic portion was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (104 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.[NH2:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]2)=[C:23]2[CH2:29][CH2:28][O:27][C:24]2=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:3]([C:17]([NH:20][C:21]2[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][C@H:32]([NH2:36])[CH2:31]3)=[C:23]3[CH2:29][CH2:28][O:27][C:24]3=[N:25][CH:26]=2)=[O:19])=[N:4][C:5]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
To a mixture of 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.9 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.8 mg, 0.0592 mmol) and HATU (72.9 mg, 0.192 mmol) DMF (1.50 mL) was added, followed by DIPEA (84.1 mg, 0.651 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (4.9 mg, 17%). LCMS calc. for C24H24F3N6O2 (M+H)+: m/z=485.2. found 485.2. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (br s, 1H), 8.86 (s, 1H), 7.60 (tt, J=8.3, 6.8 Hz, 1H), 7.40 (br s, 2H), 7.26 (t, J=8.2 Hz, 2H), 7.21 (d, J=11.5 Hz, 1H), 4.47 (t, J=9.0 Hz, 2H), 3.34 (t, J=8.5 Hz, 2H), 3.04-2.93 (m, 1H), 2.88-2.78 (m, 1H), 2.69-2.57 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.37 (m, 1H), 1.50-1.17 (m, 3H), 0.95-0.78 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]([NH:32][OH:33])=[NH:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34].N1C=CC=CC=1.Cl[C:42](OCC(CC)CCCC)=[O:43]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:31][C:42](=[O:43])[O:33][N:32]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:34]
Reactant: CCCCC(CC)COC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1nc(NCCC(=N)NO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(F)ccc1-c1nc(NCCc2noc(=O)[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
Under Ar, to a soln of the product of Example 242, 3-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-N-hydroxy-propionamidine (100 mg, 0.20 mmol), and pyridine (0.048 mL, 0.6 mmol), was added 2-ethylhexyl chloroformate (0.039 mL, 0.2 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was diluted with xylene (10 mL) and heated to reflux for 18 h to give the crude material, which was purified by preparative hplc to give the desired product 28 mg (28%). LC-MS: 495.0 (MH+, m/z), 1.96 (Rt, min).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:16]([O-:18])=[O:17])=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH3:13])([CH3:12])[CH:3]1[CH3:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)C2(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(C)C2(C)C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condensor, addition funnel and cooling bath is placed 51 grams of 1,1,2,3,3,6-hexamethyl indane having the structure: ##STR40## (51 grams) in admixture with 100 grams of acetic acid. The resulting mixture is cooled to 10° C. Over a period of 0.5 hours, 40 grams of fuming nitric acid is added to the reaction mass, while maintaining the reaction mass at 10° C. Over a period of 10 minutes, 10 grams of concentrated sulfuric acid is then added to the reaction mass. The reaction mass is then heated to 25° C. and maintained at 25° C. for a period of 3.5 hours. At the end of the 3.5 hour period, the reaction mass is quenched with ice water (500 ml) and crystals are formed. The crystals are then re-crystallized from water. The melting point of the resulting crystals is 115.7° C. NMR, IR and mass spectral anaylses yield the information that the compound has the structure: ##STR41##
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([F:8])=[N:6][CH:7]=1.C(O)C.Cl>[Fe].O>[I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cnc1F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cnc1F
Temperature: 80 °C
Yield: 53.2 %

Procedure:
5-Iodo-3-nitro-2-fluoropyridine (1.739 g, 6.49 mmol), ethanol (13 mL), water (2 mL), and concentrated HCl (0.20 mL) were added to a 25 mL round bottom flask and allowed to stir. Iron (3.6 g, 64.4 mmol) was added in portions to the reaction followed by heating at 80° C. for 30 min. The iron was then removed and washed with ethanol over a fritted filter while the ethanol washings were concentrated under reduced pressure. The residue was purified by flash chromatography using 1:2 hexane:ethyl acetate as eluent to give 5-Iodo-2-fluoro-3-aminopyridine as a colorless solid (53%, 0.821 g).
Reaction SMILES: [F:1][C:2]1([F:21])[O:6][C:5]2[C:7]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[O:3]1.[CH2:22](OCC)C.C[Si](C=[N+]=[N-])(C)C>CO>[CH3:22][O:12][C:11]([C:9]1[CH:8]=[C:7]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[C:5]2[O:6][C:2]([F:1])([F:21])[O:3][C:4]=2[CH:10]=1)=[O:13]
Reactant: CC[Si](CC)(CC)c1cc(C(=O)O)cc2c1OC(F)(F)O2
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CC[Si](CC)(CC)c1cc(C(=O)OC)cc2c1OC(F)(F)O2
Reaction time: 1 h

Procedure:
22.0 g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid were dissolved using 200 ml of diethyl ether and 100 ml of methanol. Then, 35.0 ml of a 2M solution of trimethylsilyldiazomethane was added at 10° C.-20° C. Stirring was continued for 1 h at room temperature and the mixture then evaporated. Chromatography on silica gel using EA/HEP 1:10 yielded 17.0 g of the title compound, colorless oil. Rf (EA/HEP 1:20)=0.39
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[N:14][C:15]=2[NH:17][C@H:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=2)[CH2:19]O)[N:10]=[C:9]1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:36]>>[CH2:1]([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][N:14]3[C:13](=[O:36])[NH:12][C:11]=2[N:10]=[C:9]1[CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OC[C@@H](Cc1ccc(F)cc1)Nc1nc(Cl)nc2nc(C3CCCC3)n(Cc3ccccc3)c12
Product: O=C1Nc2nc(C3CCCC3)n(Cc3ccccc3)c2C2=N[C@H](Cc3ccccc3)CN12

Procedure:
To Compound C3 obtained in Reference Example 38 was added thionyl chloride, and a cyclized compound was obtained in a manner similar to that in Example 66. From the resulting cyclized compound, a hydrolyzed compound was obtained in a manner similar to the method by which Compound 77a was obtained from the Compound 66 in Example 77. From the resulting hydrolyzed compound (590 mg, 1.33 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (400 μL, 2.65 mmol, 2.0 equivalents), an adduct (0.56 g, 74%) was obtained in a manner similar to that in Example 79, and the residue was dissolved in methanol (10 mL). To the mixture was added p-toluenesulfonic acid monohydrate and the mixture was stirred with heating at 60° C. for 2 hours. The reaction solution was concentrated and directly purified by silica gel column chromatography (chloroform:methanol=98:2 to 97:3). Then, the title compound in the free form was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40. To the resulting free compound were added a 4 mol/L solution of hydrogen chloride in dioxane (2 mL) and methanol (2 mL), the mixture was concentrated, and the residue was crystallized from acetone and diethyl ether to obtain the title compound (210 mg, 49%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C@H:16]([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C@@H:16]([CH3:35])[NH2:12])=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[(1R)-2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 43, 282 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 min, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (173.8 mg).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH:4]([NH:7][NH2:8])[CH2:3]1.C[O-].[Na+].C(O[C:15](=[C:17]([C:20]#[N:21])[C:18]#[N:19])[CH3:16])C>C(O)C>[O:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]([NH2:21])=[C:17]([C:18]#[N:19])[C:15]([CH3:16])=[N:8]2)[CH2:3]1
Reactant: NNC1CCOC1
Reactant: CCOC(C)=C(C#N)C#N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C2CCOC2)c(N)c1C#N
Temperature: 25 °C
Reaction time: 21 h
Yield: 54.3 %

Procedure:
A mixture of 3-tetrahydrofuranylhydrazine hydrochloride (6.2 g, 0.045 mol), sodium methoxide (2.4 g, 0.045 mol) and ethanol (70 ml) was refluxed under argon for 10 minutes. The reaction mixture was cooled to room temperature and 1-ethoxyethylidene malononitrile (6.1 g, 0.045 mol) was added. The reaction mixture was heated to reflux and stirred for 21 hours. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from water to afford 4.7 g (54%) of 1-(3-tetrahydrofuranyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as yellow crystals, m.p. 134°-135° C. when dried at 90° C. in high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:37]1C=CC(O)=C(C)C=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[CH:15][C:14]=1[CH3:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-2-methyl-phenol at Stage 6 of Scheme 2. m/z 504 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH:7]1(N)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N>>[CH:7]1([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(=O)CCO
Reactant: NC1CCCCC1
Agent: N
Product: C=CC(=O)NC1CCCCC1
Temperature: 164 °C

Procedure:
59 g of β-hydroxypropionamide and 69.4 g of cyclohexylamine were heated with 50 mg of 2,6-di-t-butyl-pcresol for 5 hours in a temperature range of 130°-170° C. until the evolution of ammonia was complete. After adding 2.5 g of polyphosphoric acid the reaction mixture was maintained at 164° C. for 1 hour and then distilled in a water jet vacuum. The main run was taken off between 140° and 160° C. at 11 bar and crystallized in the receiver.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[F:12][C:13]([F:42])([F:41])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]=[O:40])[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[F:41][C:13]([F:12])([F:42])[C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([O:32][C:33]4[CH:38]=[C:37]([CH:39]([OH:40])[C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)[N:36]=[CH:35][N:34]=4)=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: Cn1ccnc1
Reactant: O=Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-1H-imidazole (77 mg, 0.94 mmol) in 5 mL THF at −78° C. is added n-butyllithium (1.6 M in hexane, 0.44 mL). The solution is stirred at −78° C. for 1 h. Then, a solution of 5-(6-formyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (200 mg, 0.47 mmol) in THF (5 mL) is added. The reaction is allowed to warm up to rt and stir overnight. At that time the reaction is quenched with water and then extracted with EtOAc (3×25 mL). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue is then purified with semi-prep HPLC (C18; 30-100% I/H2O with 0.1% TFA) to give the title compound. The fractions are pololed and the pH is adjusted to 9 with sodium bicarbonate. The product is extracted with EtOAc. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to give the title compound. MS (ESI) m/z 509.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.59 (d, J=1.01 Hz, 1 H), 8.36 (d, J=9.09 Hz, 1 H), 8.06 (s, 1 H), 7.94 (d, J=3.79 Hz, 1 H), 7.90 (d, J=7.83 Hz, 1 H), 7.57 (m, 2 H), 7.46 (d, J=2.02 Hz, 1 H), 7.29 (s, 1 H), 7.16 (dd, J=8.97, 2.40 Hz, 1 H), 7.05 (d, J=1.26 Hz, 1 H), 6.85 (d, J=1.26 Hz, 1 H), 6.75 (d, J=3.54 Hz, 1 H), 5.91 (s, 1 H), 3.72 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](N2CCC(=C)CC2)[C:5]([N+]([O-])=O)=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1([C:40]#[N:41])[CH2:39][CH2:38][C:27]2([CH2:31][C:30]([C:32]#[C:33][Si](C)(C)C)=[N:29][O:28]2)[CH2:26][CH2:25]1>>[CH3:1][C:2]1[N:7]=[C:6]([C:33]#[C:32][C:30]2[CH2:31][C:27]3([CH2:38][CH2:39][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)([C:40]#[N:41])[CH2:25][CH2:26]3)[O:28][N:29]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: C[Si](C)(C)C#CC1=NOC2(CCC(C#N)(c3ccccn3)CC2)C1
Product: Cc1cccc(C#CC2=NOC3(CCC(C#N)(c4ccccn4)CC3)C2)n1

Procedure:
The title compound was prepared following the method described for the compound of Example 3, replacing Compound 3c with Compound 48b. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum ether-EtOAc from 65:35 to 4:6) to give the title compound as yellow oil. Yield: 43.4%.
Reaction SMILES: [CH:1]1([CH:4]([NH2:6])[CH3:5])[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]2[C:15](Cl)=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1.CO>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:15]([NH:6][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])=[C:14]([C:17]([NH2:19])=[O:18])[CH:13]=[N:12][N:11]2[CH:20]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(N)C1CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Yield: 61.9 %

Procedure:
1-Cyclopropylethanamine (93 mg, 1.09 mmol) and 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 100 mg, 0.36 mmol) in NMP (0.5 mL) were heated in the CEM microwave at 120° C. for 10 min. The reaction was allowed to cool to room temperature before the addition of MeOH. The resulting precipitate was then filtered and air dried to afford the title compound (72 mg, 61%). HPLC (condition G): retention time=3.87 min. LCMS (condition B): m/z 323.0, 325.0. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.99 Hz), 8.40-8.49 (2 H, m), 8.32-8.40 (1 H, m), 8.28 (1 H, s), 7.76 (1 H, td, J=6.59, 1.25 Hz), 7.68 (1 H, d, J=1.94 Hz), 4.12 (1 H, quin, J=6.45 Hz), 1.52 (3 H, d, J=6.38 Hz), 1.14-1.29 (1 H, m), 0.58-0.75 (2 H, m), 0.35-0.51 (2 H, m).
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:5])=[O:4].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].C(Cl)(=O)C(Cl)=O>CN(C)C=O.C(Cl)Cl>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)[C:3]([Cl:5])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: O=C(Cl)C(Cl)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a methylene chloride (i000 mL) solution of 2-chloro-2-phenylacetyl chloride (50.0 grams, 0.26 mol) and concentrated sulfuric acid (100 mL) cooled in an ice bath was added dropwise fuming nitric acid (20.0 grams, 0.32 mol). The mixture was allowed to stir for two hours and then poured into ice (500 mL). The organic layer was washed with saturated sodium chloride solution (2×200 mL), dried with magnesium sulfate and filtered through a thin pad of silica gel. To this methylene chloride solution was added oxalyl chloride (13.2 grams, 0.52 mol) and N,N-dimethylformamide (9 drops). The mixture was stirred at room temperature for 1.5 hours, was heated under reflux for 20 minutes, and concentrated in a rotary evaporator to give the desired 2-chloro-2-(3-nitrophenyl)acetyl chloride (50.2 grams, 81% yield whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]([N:8]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)=O)[CH3:2].C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:31]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)N(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Yield: 8.8 %

Procedure:
1.2 g N-(4-fluoro-phenyl)-N-(2-(4-fluoro-phenyl)-2-oxo-ethyl)-malonamic acid ethyl ester and 1.8 g ammonium acetate in 20 mL concentrated acetic acid were refluxed 4 h. The reaction was evaporated. Water was added to the residue and the mixture was extracted with DCM. The organic layer was dried and evaporated. The residue was purified by chromatography on silica (100% dichlormethane) to yield 100 mg of the desired compound. Rt: 1.39 min (method B), (M+H)+: 343
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[C:11]([CH2:21][CH2:22][N:23]1[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]1)=[CH:12][N:13]2[CH2:19][CH3:20])C1C=CC=CC=1>CO.[Pd]>[CH2:19]([N:13]1[C:14]2[CH:15]=[C:16]([F:18])[CH:17]=[C:9]([OH:8])[C:10]=2[C:11]([CH2:21][CH2:22][N:23]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:31]2)=[CH:12]1)[CH3:20]
Reactant: CCn1cc(CCN2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Agent: [Pd]
Solvent: CO
Product: CCn1cc(CCN2Cc3ccccc3C2)c2c(O)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
To a solution of 31-3 (30 mg, 0.072 mmol) in methanol (10 mL) was added 10% Pd/C (20 mg) under hydrogen atmosphere. The reaction mixture was stirred at room temperature overnight and then filtered through a pad of celite. The filtrate was concentrated to give a pale yellow residue, which was purified on silica gel column chromatography eluting with dichloromethane/methanol (9:1) to give 31-4 (25 mg, 70%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ (ppm) 7.29 (d, J=2.4 Hz, 2H), 7.17 (d, J=3.2 Hz, 2H), 6.76 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 6.30 (d, J=10.8 Hz, 1H), 5.00-4.96 (br.s, 2H), 4.34-4.32 (br.s, 2H), 3.96 (q, 2H), 3.59-3.57 (br.s, 2H), 3.32-3.30 (br.s, 2H), 1.37 (t, J=7.6 Hz, 3H). LRMS: calc 324.2 and found: 325.1 [M+1].