Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[CH3:5])=[N+]=[N-].[H][H]>[Pd].CO>[F:13][C:12]([F:14])([F:15])[C:10]1[CH:11]=[C:6]([CH:4]([NH2:1])[CH3:5])[CH:7]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: [H][H]
Reactant: CC(N=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
The crude product of 1-azido-[3,5-bis(trifluoromethyl)phenyl]ethane obtained in Example 2-5 was added with palladium-fibroin (18 mg) and methanol (6 mL), and after the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature. After stirring over 1 hour, the reaction mixture was filtered through Celite, and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 5:1) to obtain 77.6 mg of α-[3,5-bis(trifluoromethyl)phenyl]ethylamine as colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([N:19]2[CH:23]=[CH:22][CH:21]=[CH:20]2)=[CH:10][C:9]2[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[C:35]#[N:36])=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc2c(cc1-n1cccc1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-5-(2-methoxy-ethoxy)-4-pyrrol-1-yl-phenyl]-carbamic acid tert.-butyl ester (Example M10) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (22 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl[CH2:32][CH2:33][CH2:34]C(Cl)=O.[OH-].[Na+]>C(#N)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]3[CH2:34][CH2:33][CH2:32][C:16]3=[O:22])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Nc1ccc(N2CC[C@@H](N3CCCC3=O)C2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[O:11])[CH2:6]1>>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:7]3[CH2:8][CH2:9][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6]3)=[O:11])[S:20][C:19]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@H](O)C1
Reactant: CCI
Product: CCO[C@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from iodoethane and (3S)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 311.2/313.2 (MH+); HPLC Rf: 4.692 min.; HPLC purity: 96%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:9]=2)[N:3]=1.[NH2:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]1>CS(C)=O>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:27])=[O:26])[CH:9]=[C:8]2[C:4]1[N:3]=[C:2]([NH:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(4-chloropyrimidin-2-yl)-5-(2,6-difluorophenyl)-1-tosyl-1H-indole (500 mg, 10 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (404 mg, 2.02 mmol) in DMSO (10 mL) was heated at 110° C. for 12 h. The resulting mixture was cooled to at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to the title compound (500 mg, 75%). MS (ESI, pos. ion) m/z: 660 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH3:24]>CN(C=O)C>[CH3:1][C:2]1[N:7]([CH2:23][CH3:24])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCI
Reactant: CCCn1c(=O)[nH]c(C)c([N+](=O)[O-])c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c([N+](=O)[O-])c(C)n(CC)c1=O
Temperature: 80 °C

Procedure:
To a mixture of the nitro derivative, 6-methyl-5-nitro-3-propyl-1,3-dihydropyrimidine-2,4-dione prepared in Example 5 (1.56 g) and K2CO3 (3.0 g) in DMF was added iodoethane. The reaction mixture was heated at 80° C. for 3 h. After completion of the starting material, K2CO3 was filtered and DMF was distilled off. The residue was dissolved in ethyl acetate, washed with water, brine and dried over Na2SO4 Removal of solvent furnished the product as yellow oil, which was purified using flash chromatography. Elution with 30% ethyl acetate/hexane furnished the material as white solid, which was characterized by using NMR and mass.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][C:7]1([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]1)[C:6]2=[N:20]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:6]2=[NH:20])=[CH:10][C:11]=1[F:12]
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=N
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
HCl (4 M in 1,4-dioxane) (7.84 mL, 31.4 mmol) was added to a solution of N-(5′-bromo-6′-fluoro-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 12, 1.35 g, 3.14 mmol) in anhydrous 1,4-dioxane (23 mL) and the resulting mixture was stirred under an argon atmosphere for 15 min. Et2O (60 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM and saturated aqueous NaHCO3. The phases were separated, the organic phase dried over sodium sulfate and concentrated to give the title compound (0.95 g, 93% yield) that was used without further purification. MS (ES+) m/z 326, 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:27])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NC(C)=O
Yield: 39.7 %

Procedure:
N-[2-(4-Amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (0.72 g, 1.56 mmol) was dissolved in 200 mL of warm ethanol. 10% Palladium on carbon (0.33 g) was added and the mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filtrate was removed under reduced pressure. The resulting brown solid was purified by flash column chromatography on silica gel, eluting with 14% methanol in dichloromethane. The fractions containing the desired product were combined and further purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used with the eluent being a gradient of 30-50% CMA in chloroform. The clean fractions were combined and concentrated under reduced pressure to provide 0.23 g of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as an off-white solid, m.p. 140° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:20]=[N+:21]=[N-:22])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: 65 °C

Procedure:
A solution of methanesulfonic acid trans-4-tert-butoxycarbonylamino-cyclohexyl ester (21 g, 72 mmol) in DMSO (350 mL) was charged with sodium azide (14 g, 216 mmol) and heated at 65° C. for 14 h. After cooling to RT, the solution was diluted with EtOAc and washed successively with water, 5% aq. NaHCO3, water, and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo, and the resulting residue was purified via flash chromatography to afford (cis-4-azido-cyclohexyl)-carbamic acid tert-butyl ester (16 g, 92% yield). MS found: (M+H)+=241.7.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH3:28])[C:8]1[C:13]([N:14](CC3C=CC(OC)=CC=3)[C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH2:1]([O:3][C:4]([C:6]12[CH2:27][C:7]1([CH3:28])[C:8]1[C:13]([NH:14][C:15]2=[O:16])=[CH:12][CH:11]=[C:10]([Cl:26])[CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1N(Cc1ccc(OC)cc1)C2=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C12CC1(C)c1cc(Cl)ccc1NC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
A solution of 4 (20.0 mg, 0.050 mmol) in acetonitrile/H2O (9:1, 0.300 mL) was cooled to 0° C. in an ice-water bath and treated with CAN (82.0 mg, 0.150 mmol). The reaction mixture was stirred at ambient temperature for 12 h and quenched with Na2S2O5 to remove anisaldehyde. The resulting suspension was diluted with H2O, extracted with CH2Cl2, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography afforded 5 (12.0 mg, 86%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.55 (br s, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.15 (dd, J=2.2, 9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 4.31 (m, 2H), 2.12 (d, J=6.6 Hz, 1H), 1.55 (s, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[CH:13]=3)[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:32][S+:33](C)SC.F[B-](F)(F)F.[H+].C(=O)(O)[O-]>C1COCC1.C(Cl)Cl>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[C:13]=3[S:33][CH3:32])[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Reactant: CS[S+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(SC)n4C)C[C@H]2N(C)C1
Reaction time: 0.5 h

Procedure:
A solution is prepared from 354 mg of 1,1-diethyl-3-(1,6-dimethyl-8α-ergolinyl)urea (1 mmol) in 20 ml of THF and, at room temperature under nitrogen, 392 mg of dimethylmethylthiosulfonium tetrafluoroborate (2 mmol) and 0.24 ml of 50% strength tetrafluoroboric acid are added thereto. After 30 minutes of agitation at room temperature, the mixture is distributed between methylene chloride and bicarbonate solution, the organic phases are combined, dried with sodium sulfate, and evaporated. The crude product is chromatographed with methylene chloride on silica gel yielding, after crystallization, 276 mg (69% of theory). [α]D =+11° (0.5% in chloroform).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][C:25]([OH:27])([CH3:28])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: CC(C)(O)CN
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 6 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of rac-2-amino-1-propanol, to the title compound (10 mg, 6%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=362.3 [M+H]+.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CN(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Reaction time: 20 h
Yield: 63.7 %

Procedure:
To 1 ml of pyridine were added 0.26 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.18 g of N,N-dimethylcarbamoyl chloride was added at room temperature. After stirring for 20 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.25 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-dimethyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (14)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([Br:1])[CH:3]=[C:4]([Br:11])[C:5]2=[N:10][CH:9]=1
Reactant: Brc1cc(Br)c2nccn2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Brc1cc(Br)c2ncc(Br)n2n1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a stirred suspension of 100.00 g (361.1 mmol) 6,8-dibromoimidazo[1,2-b]pyridazine, which was prepared according to intermediate example 96d, in 1.6 L acetic acid were added 69.2 g (433.3 mmol) bromine at it and the mixture was stirred for 1 h. The precipitate was filtered, washed with water and dissolved in 10 L DCM. The organic üphase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated to give 81.99 g (64%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.[NH2:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[CH3:33])[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[N:20]=1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:27]1([C:25]([NH:24][C:22]2[N:23]=[C:18]3[CH:17]=[CH:16][C:15]([O:14][C:13]4[CH:30]=[CH:31][C:32]([CH3:33])=[C:11]([NH:10][C:4](=[O:6])[C@@H:3]5[CH2:7][CH2:8][CH2:9][N:2]5[CH3:1])[CH:12]=4)=[N:20][N:19]3[CH:21]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.3 %

Procedure:
A mixture of 1-methyl-L-proline (170 mg, 1.3 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (210 mg, 0.65 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (490 mg, 1.3 mmol), N,N-diisopropylethylamine (330 mg, 2.6 mmol) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr, and then at 40° C. for 4 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (15 mg, 5%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:3]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=3)[C:7]=2[C:8]1=[O:22]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Yield: 74.2 %

Procedure:
A solution of cis-tert-butyl 2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (135.8 mg, 0.247 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (154 mg, 0.742 mmol) and bis(triphenylphosphine)palladium chloride (174 mg, 0.247 mmol) in dioxane (2 mL) and saturated aq Na2CO3 (2 mL) was heated at 120° C. for 30 min. After filtering out the solids, the solvent was removed and the residue was dissolved in MeOH and DCM and the mixture was purified by preparative HPLC. The fractions were collected and the solvent was stripped to dryness via rotary evaporation to give the title compound (109 mg, 74%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97-1.98 (m, 10H), 2.28-2.44 (m, 3H), 2.56-2.72 (m, 4H), 3.63-3.99 (m, 11H), 4.36 (d, J=18.06 Hz, 2H), 4.56 (br s, 2H), 6.50 (br s, 1H), 6.61 (br s, 1H), 6.65-6.81 (m, 1H), 7.08 (br s, 1H), 7.70 (br s, 1H), 8.30 (br s, 1H), 8.75-9.02 (m, 1H). [M+H] calc'd for C31H39FN6O5, 595. found, 595.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][CH2:11][C@@H:12]([N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1)[CH3:13]>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C@@H:12]([CH3:13])[CH2:11][NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
The title compound was prepared using the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (S)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. The crude product was purified by triturating in DCM at RT. 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, d), 2.27 (3H, s), 3.57 (1H, m), 3.67 (1H, m), 4.68 (1H, m), 6.96 (1H, d), 7.44 (1H, s), 7.89 (1H, d), 7.95-7.99 (3H, m), 8.12 (1H, s), 12.1 (1H, broad s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:22]([NH:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1)=[O:23])[CH:8]=[CH:7][CH:6]=2
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc2c(N)cccc2nn1
Product: Cc1cc2c(NC(=O)NCc3ccc(OC(F)(F)F)cc3)cccc2nn1

Procedure:
Prepared from 3-methylcinnolin-5-amine and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to the procedure of Description 61. m/z (ES+) 377 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][C:25]([NH:31][CH2:32][C:33]3[CH:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]5[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]5)[CH:40]=4)[CH:36]=[CH:37][CH:38]=3)=[O:27])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)NCc1cccc(-c2cccc(CC3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.3 %

Procedure:
To a solution of 5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoic acid (0.0807 g, 0.200 mmol) in DCM (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (0.0837 g, 0.220 mmol), HBTU (0.0910 g, 0.240 mmol), and TEA (0.0562 mL, 0.400 mmol), and was stirred at room temperature for 16 h. The reaction mixture was concentrated on a Glas-Col evaporator, purified using a Gilson HPLC and concentrated with Biotachi evaporator. The crude product was dissolved in DCM (0.6 mL), and TFA (0.2 mL) was added. The resultant mixture was left at room temperature for 1 h before being concentrated on a Glas-Col evaporator, purified using a Gilson HPLC (acidic conditions: with 0.1% TFA) and basified with an amine cartridge to afford the title compound 0.048 g (35%). LC-MS m/z 680.