Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:26])([F:25])[S:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:21]/[C:20]1[CH:23]=[CH:24][C:17]([S:16][C:15]([F:26])([F:14])[F:25])=[CH:18][CH:19]=1)/[CH2:5]2
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: COc1cc2c(cc1Br)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 5-bromo-6-methoxy-2, 3-dihydro-1H-inden-1-one 11 (250 mg, 0.1037 mmol) in benzene was added 4-((trifluoromethyl)thio)benzaldehyde 72 (213 mg, 0.103 mmol). PTSA (395 mg, 0.207 mmol) was added, the reaction mass was stirred at 120° C. for 6 h, then diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 104 and was purified through flash chromatography by using 100-200 mesh silica gel. The compound 104 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:2].CS(O[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([O:37]COC)[C:28]=1[CH:41](OC)[O:42]C)(=O)=O>>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[C:29]([OH:37])[C:28]=2[CH:41]=[O:42])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCc1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Reactant: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Product: CCc1cc(CC(=O)OC)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C=O)cc1
Yield: 79 %

Procedure:
According to a method similar to Example (40-2) and Example (8-3), from methyl (2-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (4.90 g, 18.1 mmol) obtained in Example (26-4) and 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate (8.35 g, 21.5 mmol) obtained in Example (26-5), methyl (2-ethyl-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate was obtained as a colorless solid (6.77 g, two-step total yield: 79%).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:25][C:26]([OH:28])=O.[CH3:29][N:30]([CH2:32][C:33]1[N:34]=[C:35]([NH2:42])[S:36][C:37]=1[C:38]1([CH3:41])[CH2:40][CH2:39]1)[CH3:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH3:31][N:30]([CH2:32][C:33]1[N:34]=[C:35]([NH:42][C:26](=[O:28])[CH2:25][C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]4[CH:15]=[CH:16][C:17]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)=[CH:18][C:13]4=[N:12][CH:11]=3)=[CH:9][C:4]=2[F:3])[S:36][C:37]=1[C:38]1([CH3:41])[CH2:40][CH2:39]1)[CH3:29]
Reactant: CN(C)Cc1nc(N)sc1C1(C)CC1
Reactant: O=C(O)Cc1ccc(-c2cnc3cc(-c4ccccn4)ccn23)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1nc(NC(=O)Cc2ccc(-c3cnc4cc(-c5ccccn5)ccn34)cc2F)sc1C1(C)CC1
Reaction time: 14 h

Procedure:
Combine [2-fluoro-4-(7-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-acetic acid, dihydrochloride (0.190 g, 0.452 mmol) and 4-Dimethylaminomethyl-5-(1-methyl-cyclopropyl)-thiazol-2-ylamine (0.105 g, 0.497 mmol) in DMF (4 mL). Add N,N-diisopropylethylamine (0.26 mL, 1.49 mmol), then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.190 g, 0.500 mmol). The reaction mixture is stirred for 14 hours under N2. Purify using an SCX cartridge (10 g VARIAN BondElut®), eluting with 1:1 methanol:dichloromethane, then 1:1 2 M NH3 in methanol:dichloromethane. Purify via reverse phase chromatography using a 25 cm by 50.8 mm (i.d.) column w/10 micron particles (MeCN/0.03% HCl H2O (5:95) to 100% MeCN; 30 min). Partition between ethyl acetate and 1 N NaOH. Wash the organic layer with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate to the title compound (0.054 g, 22%). MS (ES), n/z 541 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[CH:7]=O.[NH2:15][C:16]1[C:21]([NH2:22])=[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:19]([Cl:34])=[CH:18][N:17]=1.C([O-])(=O)C.[NH4+]>>[Cl:34][C:19]1[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[C:21]2[N:22]=[C:7]([C:6]3[S:5][C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)=[N:3][C:2]=3[Cl:1])[NH:15][C:16]2=[N:17][CH:18]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCOCC2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4sc(N5CCOCC5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 10.5 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-morpholin-4-yl-thiazole-5-carbaldehyde (65 mg, 0.28 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.26 mmol), and Ammonium acetate (98 mg, 1.3 mmol) were reacted to produce 13.87 mg (11%) of the title compound. (300 MHz, DMSO-d6) 12.79 (s, 1H), 7.95 (s, 1H), 7.77 (s, 2H), 7.25 (s, 2H), 6.40-6.30 (m, 2H), 4.98 (t, J=17 Hz, 8.5 Hz, 1H), 3.72 (m, 4H), 3.27 (m, 4H), 3.48 (m, 4H), 2.87 (s, 1H), 2.75 (s, 1H), 2.57 (d, J=8 Hz, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=507 (M+H), HPLC: 2.35 min. (G Method)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C#N)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a suspension of 3-(3-cyanopyridin-2-yl)aniline (195 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (332 mg) and diisopropylethylamine (0.401 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-cyanopyridin-2-yl)phenyl)guanidine (383 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1([CH:30]2[CH2:35][CH2:34][N:33]([C:6]3[N:5]=[C:4]4[N:11]([C:16]5[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=5[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]4=[C:2]([Cl:1])[N:7]=3)[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 115 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added 1,4′-bipiperidine (270 mg, 1.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (298 mg, 83%). LC-MS m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[N:10]=[CH:9]2)=[C:5]([CH3:16])[O:4][N:3]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[N:10]=[CH:9]2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1noc(C)c1Cn1cnc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1noc(C)c1Cn1cnc(N)c1
Yield: 92.5 %

Procedure:
3,5-dimethyl-4-((4-nitro-1H-imidazol-1-yl)methyl)isoxazole (example 10-40b) (1.0 g, 4.5 mmol) and 10% palladium on charcoal (200 mg) in methanol (40 mL) was shaken on a Parr shaker under a pressure of 2.5 bar hydrogen for 2 hours. Filtration through a plug of celite followed by rotary evaporation afforded 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-imidazol-4-amine as a yellowish-red solid (800 mg, 93% yield). MS M+H calculated 193. found 193.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([NH:15][C:16](=O)[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[O:14][C:16]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][C:10]=2[CH2:9]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(NC(=O)COc2ccccc2)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc(COc3ccccc3)nc2C1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
A suspension of 4-oxo-3-[(phenoxyacetyl)amino]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (0.36 g, 1.0 mmol) and Burgess reagent (0.30 g, 1.25 mmol) in THF (4 mL) was stirred at 120° C. for 10 minutes under microwave irradiation. Then additional Burgess reagent (0.30 g, 1.25 mmol) was added and the mixture stirred at 150° C. for a further 5 minutes under microwave irradiation. The mixture was diluted with a saturated solution of NaHCO3 and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 99/1 to 80/20). The desired fractions were collected and the solvents evaporated in vacuo to yield 6,7-dihydro-2-(phenoxymethyl)-oxazolo[4,5-c]pyridine-5(4H)-carboxylic acid 1,1-dimethylethyl ester (0.11 mg, 33% yield). C18H22N2O4 LCMS: Rt 2.87, m/z 331 [M+H]+ (using method, LC-MS Method 3).
Reaction SMILES: N([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:17]C(C)=O)=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)C(C)=O.[ClH:21]>CO>[ClH:21].[NH2:17][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[N+:14]([O-:16])=[O:15])[NH:5][CH2:6][CH2:7]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(NC(C)=O)CC2
Agent: Cl
Solvent: CO
Product: Nc1cc2c(cc1[N+](=O)[O-])NCC2
Yield: 82.5 %

Procedure:
21.4 g of 1,5-diacetamino-6-nitro-indoline were dissolved in 2.5 l of methanol, boiled under reflux overnight with 750 ml of 4 N hydrochloric acid in methanol and then evaporated. There were obtained 14.2 g (82.5% of theory) of 5-amino-6-nitro-indoline hydrochloride of melting point 259° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][C@@H:29]1[O:31][CH2:30]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:10]([CH2:27][CH2:28][C@H:29]2[CH2:30][O:31]2)[S:9]1(=[O:19])=[O:18]
Reactant: BrCC[C@H]1CO1
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2ccccc2N1c1ccccc1F
Temperature: 40 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.20 g, 0.72 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.15 mL, 1.46 mmol) and was heated to 40° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with 2 N sodium hydroxide (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.22 g, 86%) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>ClCCl>[O:6]=[C:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 25 gm (220 mMol) glutaric anhydride in dichloromethane (250 ml) was added a solution of 26.4 ml (242 mMol) benzylamine in dichloromethane (50 ml) dropwise. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then poured into diethyl ether (500 ml) and the resulting solid was filtered. The filter cake was washed with diethyl ether, dried under vacuum and then recrystallized from ethyl acetate to give 24.8 gm (51%) 5-oxo-5-(phenylmethylamino)pentanoic acid as a crystalline solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH:8]1[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]1
Reactant: C1CCN(C2CCC3(CC2)OCCO3)OC1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(1,4-dioxaspiro[4.5]decan-8-yl)-1,2-oxazinane (350 mg, 1.54 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (x4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]#[N:30])[CH:21]=[CH:20]3)=[CH:15][N:16]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]1[O:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([O:27][CH2:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3cnc(Cc4ccc5ccccc5c4)o3)ccc2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2cc(Cc3ncc(-c4ccc5cc(OCc6nnn[nH]6)ccc5c4)o3)ccc2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of ({6-[2-(2-naphthylmethyl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (99 mg, 0.252 mmol), prepared in the previous step, sodium azide (50.2 mg, 0.772 mmol) and ammonium chloride (40.7 mg, 0.761 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for three hours. Following the reaction by MS, starting material remained. Additional sodium azide (51.1 mg, 0.75 mmol) and of ammonium chloride (45.7 mg, 0.85 mmol) were added and the reaction stirred at 100° C. for two more hours. This procedure was repeated two additional times until the MS showed that the reaction went to completion. The reaction was filtered, acidified with 5 mL of 1N HC1 and then diluted with 10 mL of H2O. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (75.4 mg, 69%) as a tan solid, mp 179-182° C. Elemental Analysis for C26H19N5O2+0.31 mol H2O Calc'd: C, 71.13; H, 4.50; N, 15.95. Found: C, 70.44; H, 4.51; N, 14.98.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>O1CCCC1>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH3:9])=[O:41])[CH:30]=[C:29]([C:28]([F:27])([F:45])[F:46])[CH:34]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
To a solution of 180 mg (0.711 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine in 7 ml dry tetrahydrofuran 0.86 ml of a 0.91 M solution (0.78 mmol) of potassium hexamethyldisilazide in tetrahydrofuran was added at room temperature under an atmosphere of argon. After 45 min 295 mg (0.924 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added. The reaction mixture was stirred at room temperature for 3 h. Quenching with water was followed by dilution with tert-butyl methyl ether and washing with 2 M aqueous sodium carbonate solution and brine. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated. Flash chromatography gave 254 mg (67%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])C=O.CO[CH:17]([O:20][CH3:21])[O:18][CH3:19].C[O-].[Na+]>CO.Cl>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(OC)OC)cc(OC)c1OC
Yield: 100.3 %

Procedure:
A mixture of 196.2 g of 3,4,5-trimethoxybenzaldehyde, 127.3 g of trimethoxymethane, 200 ml of methanol and 0.1 g of hydrochloric acid is refluxed for 3 hours. After cooling the reaction mixture, 0.2 g of a 24% sodium methoxide solution in methanol is added thereto and the mixture is evaporated under reduced pressure to remove solvent. 150 ml of tetrahydrofuran are added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. 243 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a pale yellow oil.
Reaction SMILES: CN(C)C=O.[CH:6]1([N:12]([CH2:30][CH2:31][OH:32])[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH2:33]=[C:34]1[O:38][C:36](=[O:37])[CH2:35]1>C(N(CC)CC)C>[C:36]([O:32][CH2:31][CH2:30][N:12]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:13](=[O:29])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH:22]=[CH:21]2)(=[O:37])[CH2:35][C:34]([CH3:33])=[O:38]
Reactant: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Reactant: C=C1CC(=O)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCCN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To 100 ml of dimethylformamide, there were added 7.45 g of N-cyclohexyl-N-(2-hydroxyethyl)-4-(6-carbostyriloxy)butyramide and 0.5 ml of triethylamine, then the whole mixture was heated at 80° to 90° C. on an oil bath. Next, 1.8 g of diketene were added dropwise to the reaction mixture, then the mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated then was purified by a silica gel column chromatography (eluant: chloroform/methanol=50/1), and the solvent was removed by distillation under reduced pressure to yield 6.33 g of N-(2-acetoacetoxyethyl)N-cyclohexyl-4-(6-carbostyriloxy)butyramide in the form of a brownish oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.I[Si](C)(C)C>C(#N)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][NH:13][CH2:12]3)=[C:8]([C:28]([NH2:29])=[O:30])[CH:7]=[N:6][N:5]2[CH:31]=1
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: C[Si](C)(C)I
Solvent: CCOCC
Solvent: CC#N
Product: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.1 %

Procedure:
A solution of (3R,4S)-benzyl 3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methoxypyrrolidine-1-carboxylate (300 mg, 0.61 mmol) in acetonitrile (5 mL), was added iodotrimethylsilane (123 mg, 0.614 mmol) at 0° C., the mixture was then stirred at rt for 2 h. The mixture was diluted with ether (30 mL), stirred for 1 h, filtered and rinsed with ether to give the hydroiodide salt of 6-bromo-4-(((3R,4S)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (292 mg, 99% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.07 (s, 1H), 4.97-4.88 (m, 2H), 4.56 (br. s., 1H), 4.16-4.09 (m, 1H), 3.67 (dd, J=11.4, 7.7 Hz, 1H), 3.53-3.50 (m, 3H), 3.50-3.45 (m, 1H), 3.40-3.34 (m, 1H), 3.11 (dd, J=11.6, 8.5 Hz, 1H); MS (ES+) m/z: 353.1, 354.0 (M+H); LC retention time: 2.01 min (analytical HPLC Method B).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:39])[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=2[F:29])[C:17]2[C:16](=[O:30])[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][C:12]=2[NH:11][C:10]=1[CH3:38])=[O:8]>CO>[ClH:1].[CH3:39][C:4]([O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:3])[CH2:5][O:6][C:7]([C:9]1[CH:18]([C:19]2[C:20]([F:29])=[C:21]([F:28])[C:22]([F:27])=[C:23]([F:26])[C:24]=2[F:25])[C:17]2[C:16](=[O:30])[CH2:15][NH:14][CH2:13][C:12]=2[NH:11][C:10]=1[CH3:38])=[O:8]
Reactant: CC1=C(C(=O)OCC(C)(C)Oc2ccccc2)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CN(Cc3ccccc3)CC2=O)N1
Agent: Cl
Solvent: CO
Product: CC1=C(C(=O)OCC(C)(C)Oc2ccccc2)C(c2c(F)c(F)c(F)c(F)c2F)C2=C(CNCC2=O)N1

Procedure:
The above hydrochloride (15 g), 400 ml of methanol, 10 ml of water, 8 ml of concentrated hydrochloric acid, and 1 g of 10% palladium on carbon were shaken with hydrogen (50 psig initial pressure) for 4.5 hours. The catalyst was separated and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in methylene chloride and shaken with saturated sodium carbonate solution. The methylene chloride solution was separated and a precipitate formed after 20 minutes. The mixture was filtered to obtain 6.5 g of solid, m.p. 170°-3° C. The solid was dissolved in methanol and treated with hydrogen chloride to obtain 4.9 g of the title compound as the hydrochloride.