Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15]OS(C)(=O)=O)[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[CH:28]=[N:27][NH:26][N:25]=1)([O-:23])=[O:22].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:26]3[N:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:28]=[N:27]3)[N:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2cccc(COS(C)(=O)=O)n2)OCCO1
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2cccc(Cn3ncc([N+](=O)[O-])n3)n2)OCCO1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester (164 mg, 0.6 mmol) in DMF (2.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (57 mg, 0.5 mmol) in DMF (1.0 mL) pre-treated for 30 min with DIPEA (0.20 mL, 1.17 mmol) and the reaction mixture was stirred for 48 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:1 to 1:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=0.90 min, [M+H]+=292.35.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a Schlenk tube charged with a solution of 200 mg (1.0 mmol) of 2-acetyl-6-bromopyridine and 23 mg (0.02 mmol) of (Ph3P)4Pd in 10 mL of degassed toluene was added a solution of 150 mg (1.2 mmol) phenylboronic acid and 270 mg (2.5 mmol) Na2CO3 in 8 mL of degassed 4:1 H2O/MeOH. The biphasic mixture was heated to 80° C. with rapid stirring for 1 h. On cooling to RT, Et2O (50 mL) was added and the layers were separated. The organic layer was dried over Na2SO4 and the volatiles were removed by rotary evaporation. The resulting oil was chromatographed on silica with 10-50% CH2Cl2/hexanes eluent to provide 176 mg (89%) of 2-acetyl-6-phenylpyridine as a white powder. 1H NMR (CDCl3); δ 2.84 (s, 3H); 7.43-7.62 (m, 3 H); 7.91-8.08 (m, 3 H); 8.18 (d, J=6.6 Hz, 2H). Mass Spec.: m/e 197.
Reaction SMILES: [CH:1](OCC#N)=[O:2].[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1>CN(C=O)C.C(OCC)(=O)C>[CH:7]1([NH:10][C:11]([C:13]2[C:21]3[CH:20]=[C:19]([C:22]4[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]5[CH2:34][CH2:35][N:36]([CH:1]=[O:2])[CH2:37][CH2:38]5)[N:23]=4)[S:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:8][CH2:9]1
Reactant: N#CCOC=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=CN1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
Cyanomethyl formate (10 mg, 0.11 mmol) is added to a stirred suspension of 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (50 mg, 0.11 mmol) in DMF (1 mL) and stirred for 18 hours to form a thick suspension. The mixture is diluted with ethyl acetate (1 mL) then filtered to give the title compound as a solid (41 mg). ES+(m/z) 498 (35Cl) and 500 (37Cl) [M+H].
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(N(C(C)C)CC)(C)C.[NH2:55][CH2:56][CH2:57][CH2:58][OH:59]>C(O)(C)C>[OH:44][C@H:43]([CH2:45][NH:55][CH2:56][CH2:57][CH2:58][OH:59])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:37])[CH3:39])[NH:13]2)=[O:11])=[N:5]1
Reactant: NCCCO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H](O)CNCCCO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 20.8 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (43.6 mg, 0.066 mmol), isopropyl alcohol (2 mL), diisopropylethyl amine (0.1 mL, 0.56 mmol) and 3-amino-1-propanol (0.1 mL, 1.3 mmol) was microwaved at 130° C. for 15 min. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (1-{2-[(R)-2-hydroxy-3-(3-hydroxy-propylamino)-propoxy]-2-methyl-propyl}-1H-pyrazol-3-yl)-amide (10.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C36H46Cl2F2N6O4S+H [(M+H)+]: 735.2999. found: 735.2998.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8]>[Cu+2]>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:9])[CH3:8]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Agent: [Cu+2]
Product: CC(=O)OC1C=CCCC1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 0.3 g of di-L-prolinato Copper (II), 15 ml of cyclohexene, 20 ml of acetic acid and 5 ml of t-butyl peroxybehzoate was heated with stirring at 90° C for 5 hours in a nitogen atmosphere. After cooling, the reaction mixture was treated in the same manner as in Example 1 to obtain 2.50 g of 2-cyclohexenyl acetate.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH2:19][CH2:20][CH3:21])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCCc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 140 °C
Yield: 42.9 %

Procedure:
To a solution of 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (134 mg, 438 μmol) in NMP (1.5 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (376 mg, 1.75 mmol) in 3 portions approximately every 12 h over 36 h, with heating at 140° C. in the periods between additions. The mixture was then diluted with ethyl acetate and brine. The phases were separated and the organic phase washed twice with brine. The organic phase was concentrated in vacuo and then purified by chromatography (silica, 30 to 100% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (91 mg, 188 μmol, 43%) as a light brown solid. MS (EI/CI) m/z: 484.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([OH:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17](=[O:23])[C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CC(O)c2cccs2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ncccc1CN1CCC(CC(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
12.0 g of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-hydroxy-2-(2-thienyl)ethyl]piperidine and 30.2 ml of triethylamine were dissolved in 72 ml of dimethyl sulfoxide, and a mix solution of 17.2 g of sulfur trioxide-pyridine complex and 90 ml of dimethyl sulfoxide was added dropwise thereinto under ice-cooling. After completion of the dropwise addition, the mixture was further stirred at room temperature for 30 minutes. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), to give 9.6 g of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]1[CH2:18][C:19]3([CH2:29][C:13]=1[CH:12]=2)[C:27]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[NH:21][C:20]3=[O:28].CN1CCOCC1.[CH3:41][C:42]([CH3:47])([CH3:46])[C:43](Cl)=[O:44]>C(Cl)Cl.CN1CCOCC1>[F:33][C:31]1[CH:30]=[C:4]([CH:3]=[C:2]([F:1])[CH:32]=1)[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]1[CH2:18][C:19]3([CH2:29][C:13]=1[CH:12]=2)[C:27]1[C:22](=[N:23][CH:24]=[CH:25][CH:26]=1)[NH:21][C:20]3=[O:28])[C:43](=[O:44])[C:42]([CH3:47])([CH3:46])[CH3:41]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1Nc2ncccc2C12Cc1cc3cc(CNCc4cc(F)cc(F)c4)cnc3cc1C2
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)C(=O)N(Cc1cc(F)cc(F)c1)Cc1cnc2cc3c(cc2c1)CC1(C3)C(=O)Nc2ncccc21
Temperature: 0 °C
Reaction time: 23 h

Procedure:
To a suspension of (±)-3-{[(3,5-difluorobenzyl)amino]methyl}-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (47.0 mg, 0.106 mmol) in DCM (1.5 mL) was added 4-methylmorpholine (32.2 mg, 0.320 mmol). This mixture was sonicated to provided a finely powdered suspension. After cooling to 0° C., trimethylacetyl chloride (23.0 mg, 0.190 mmol) was added and the cooling bath was removed. After 23 hours, additional 4methylmorpholine (2 drops) and trimethylacetyl chloride (23.0 mg, 0.190 mmol) were added. After 7 hours, the reaction was quenched by the addition of one drop of methanol. This reaction mixture was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—100:1 to 94:6, to give the title compound as a white solid. MS: m/z=527 (M+1). HRMS: m/z=527.2253; calculated m/z=527.2253 for C31H29F2N4O2.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH3:27])=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]([CH3:27])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:29][CH:30]=1
Reactant: Cc1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Add N-(4-Fluoro-benzyl)-4-(3-methyl-indole-1-sulfonyl)-benzamide (0.106 g, 0.25 mmol) portionwise to a stirring mixture of NaCNBH3 (0.074 g, 1.2 mmol, in TFA (5.0 mL) at 0 to 5° C. under N2. Stir the mixture for 15 minutes at 0-5° C., allow to warm to ambient temperature and stir for 1 h. add NaCNBH3 (0.074 g, 1.2 mmol) and stir the reaction is for 2 h dilute with H2O (13.0 mL) and work up as described in the above example. Chromatograph and elute with EtOAc-hexane (0-50%) to give 0.075 g of the title compound: Mass spectrum (m/e) (M+H) 425.1335; found 425.1341.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 5.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine and 6.86 g. of ethyl carbazate in 80 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled in an ice bath and the resulting solid filtered, washed with n-butyl alcohol, water and dried. The product is recrystallized from ethanol to give crystalline material, m.p. 190°-192° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.[SH:38][CH2:39][CH2:40][OH:41]>CN(C)C=O.O>[CH2:29]([O:28][CH2:27][CH2:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][S:38][CH2:39][CH2:40][OH:41])=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20])[CH3:30]
Reactant: CCOCCN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: OCCS
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCCN(c1cccc2cc(-c3ncc(CSCCO)s3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 30.2 %

Procedure:
A solution (2 mL) of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-ethoxyethyl)thiophene-2-sulfonamide (18 mg) and triethylamine (14 mg), 2-mercaptoethanol (10 mg) in N,N-dimethylformamide was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was concentrated, and the residue was purified by preparative HPLC to give the title compound (5.9 mg, yield 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]1[NH:27]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O.C1CCCCC1>CN1CCCC1=O.ClCCl>[NH2:27][C@@H:22]1[C@H:21]([NH:20][C:2]2[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[N:13]=3)[CH:3]=2)[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1ccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.8 %

Procedure:
6-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (120 mg, 432 mmol) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (187 mg, 864 μmol) in N-methyl-2-pyrrolidinone (6 mL) was heated at 150° C. for 1.5 d. After solvent evaporation, the residue was dissolved in dichloromethane (2 mL) and TFA (370 mg, 250 μL, 3.24 mmol). The mixture was stirred at room temperature for 3 h, then the solvent was evaporated and the residue was purified by chromatography (spherical silica, 20-45 μm, 11 g, Versaflash from Supelco, 97:2.75:0.15 to 87:12.35:0.65 dichloromethane:MeOH:NH4OH, 20 min) to afford a brown solid. The brown solid was dissolved in dichloromethane and 10 mL of cyclohexane was added. After standing, a solid precipitate formed. The supernatant was decanted and the solid residue was dried under vacuum to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (18 mg, 12% over two steps) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.23 (br. s., 1H) 8.29 (s, 1H) 8.03 (br. s., 1H) 7.36 (d, J=8.08 Hz, 1H) 6.67 (d, J=8.08 Hz, 1H) 5.68-5.79 (m, 1H) 5.39 (br. s., 1H) 4.02 (d, J=7.33 Hz, 1H) 3.88 (d, J=11.12 Hz, 1H) 3.69 (d, J=11.62 Hz, 1H) 3.55 (t, J=11.49 Hz, 1H) 3.10 (br. s., 1H) 2.49 (s, 3H) 2.25 (s, 3H) 2.02 (d, J=12.38 Hz, 1H) 1.42-1.84 (m, 3H); LCMS (EI/CI) m/z: 358 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=1[O:14][CH2:15][CH3:16].C([Li])(C)(C)C.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:30]=1)[CH:28]=[O:29].[Cl-].[NH4+]>COCCOC>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([F:31])=[C:27]([CH:28]([C:2]2[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:3]=2[O:14][CH2:15][CH3:16])[OH:29])[CH:30]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOc1c(Br)cc(C(C)C)cc1C(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: COCCOC
Product: CCOc1c(C(C)C)cc(C(C)C)cc1C(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromo-2-ethoxy-3,5-diisopropyl-benzene (2.0 g, 7.01 mmol) was dissolved in ethylene glycol dimethyl ether (20 ml) and the mixture cooled to −78° C. t-Butyl lithium (8.66 ml, 1.7M, 14.7 mmol) dropwise to the mixture over 30 min., then the reaction was stirred for an additional 30 min. before 5-bromo-2-fluorobenzaldehyde (1.57 g, 7.71 mmol) was added in one portion. The reaction was allowed to warm to ambient temperature, then stirred overnight The mixture was poured into saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified flash column (5% ethyl acetate in hexanes) to give (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol, as a pale yellow oil (1.88 g, 66%). 1H NMR (250 MHz, CDCl3): δ 7.73 (dd, 1H, J=1.2, J=7.5), 7.42 (m, 1H), 7.11 (d, 1H, J=1.2), 6.95 (t, 1H, J=7.5), 6.85 (d, 1H, J=1.2), 6.35 (d, 1H, J=6.2), 3.84 (q, 2H, J=6.9), 3.30 (m, 1H), 3.07 (d, 1H, J=6.2), 2.85 (m, 1H), 1.47 (t, 3H, J=6.9), 1.25 (s, 6H), 1.20 (s, 6H). MS [EI+] 431, 433 (M+Na)+.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].CCN(CC)CC>CC#N>[C:17]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Yield: 77.6 %

Procedure:
1-(3,3-Diphenylpropyl)homopiperazine (2.0 g, 6.79 mmol) was dissolved in CH3CN (60 mL) and treated with methyl bromoacetate (1.56 g, 10.18 mmol) and Et3N (1.42 mL, 10.18 mmol). The mixture was refluxed for 18 h and subsequently concentrated in vacuo. The residue was subjected to flash silica gel column chromatography (eluent: CH2Cl2/MeOH, 96/4, v/v) to give Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (1.93 g) in 78% yield, TLC Rf=0.53 (10% CH3OH—CH2Cl2); RPLC tR=4.71 min (>85%), 220 nm (Method A); ESI/MS m/e 367.1 (M++H, C23H30N2O2).
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=O)[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH3:23])[CH:16]=[CH:15]2.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH:23]=[CH:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[CH:1]=[O:10])[CH:16]=[CH:15]2
Reactant: O=Cc1cccc(C=O)c1
Reactant: Cc1ccc2cc(F)c(F)cc2n1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Yield: 59429.1 %

Procedure:
A solution of isophthalaldehyde (312.4 g, 2.33 mmol), 6,7-difluoro-2-methylquinoline (278.4 g, 1.55 mmol) and acetic anhydride (416 mL) in 2 L of xylene was heated to reflux overnight. The solvent was evaporated and the product was swished in 2.5 L of EtOAc to yield the title compound (272 g, 56%). 1H NMR (CD3COCD3): δ 10.12 (1H, s), 8.4 (1H, d), 8.29 (1H, s), 8.1-7.85 (6H, m), 7.7-7.55 (2H, m).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1.[Cl-].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH:12]([N:10]1[CH:11]=[C:7]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:8]=[N:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)n1cc(Br)cn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
n-Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was added over 15 min to a solution of 4-bromo-1-isopropyl-1H-pyrazole (500 mg, 2.65 mmol) in diethyl ether (10 mL) at −78° C. After 30 min, a solution of tri-n-butylstannane chloride (920 μL, 3.45 mmol) in diethyl ether (1 mL) was added and the resultant reaction mixture was left to stir at −78° C. for 1 h, then allowed to warm to ambient temperature. The reaction mixture was diluted with diethyl ether (40 mL) and washed with water (20 mL), then brine (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title product as a colourless oil (98 mg, 94%) which was used without further purification. 1H NMR (CDCl3, 400 MHz): 7.46-7.42 (m, 1H); 7.28 (t, J=4.2 Hz, 1H); 4.59-4.43 (m, 1H); 1.58-1.42 (m, 12H); 1.39-1.24 (m, 6H); 1.02-0.77 (m, 15H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][OH:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: OCCOc1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-(Pyridin-2-yloxy)-ethanol (100 mg, 0.72 mmol) was dissolved in DCM (2 mL) and MsCl (72 μL, 0.94 mmol) and DIPEA (192 μL, 1.08 mmol) were added. The mixture was stirred at rt overnight, diluted with EtOAc, washed with water, sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 114 mg methanesulfonic acid 2-(pyridin-2-yloxy)-ethyl ester which was used without further purification for the next step.