Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:44]1[C:52]2[C:47](=[N:48][CH:49]=[N:50][C:51]=2[NH2:53])[NH:46][N:45]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:13]1([CH2:12][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:44]4[C:52]5[C:47](=[N:48][CH:49]=[N:50][C:51]=5[NH2:53])[NH:46][N:45]=4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnc2[nH]nc(Br)c12
Reactant: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncnc2[nH]nc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-bromo-1-(phenylacetyl)-2,3-dihydro-1H-indole (148 mg, 0.467 mmol),bis(pinacolato)diboron (125 mg, 0.491 mmol), and potassium acetate (138 mg, 1.402 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (19.08 mg, 0.023 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C into a sealed vessel. The reaction was cooled down to room temperature. 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.467 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (19.08 mg, 0.023 mmol) was added, the vessel was sealed, and the reaction mixture was stirred for 3 days at 100 C. The mixture was allowed to cool to room temperature and poured onto water (˜150 mL). The resulting mixture was filtered, and the resulting solid was triturated with EtOAc. To the dark solid in the filter was added a 80:20 mixture of CHCl3:CH3OH (˜7 mL), and the resulting mixture was filtered. The filtrate was injected into a 90 g SiO2 columns. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90:10:1 CHCl3:CH3OH:NH4OH) provided the title compound. Trituration with Et2O afforded the title compound 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (35 mg) as a grey solid. 1H NMR (400 MHz, DMSO-d6) 3.24 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.24 (t, J=8.46 Hz, 2H), 7.22-7.40 (m, 6H), 7.44 (d, J=8.34 Hz, 1H), 7.50 (s, 1H), 8.17-8.23 (m, 2H), 13.51 (s, 1H)
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[C:22]([NH:27][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]
Reactant: CCOc1cccnc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Product: CCOc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 3-ethoxypyridine-2-amine as the starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH:12]([S:15](Cl)(=[O:17])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>CN(C=O)C.[Cl-].[Na+].O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1cncc(Br)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)S(=O)(=O)NCc1cncc(Br)c1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 200 mg, 0.77 mmol) in DMF (8 mL) at 0° C. was added sodium hydride (60% oil dispersion, 150 mg, 3.8 mmol) followed by isopropylsulfonyl chloride (0.13 mL, 1.16 mmol). The reaction was stirred for 30 minutes and then diluted with brine and dichloromethane. The pH of the aqueous layer was adjusted to ca. 7 by the addition of acetic acid and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to provide propane-2-sulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide without the need for further purification; MS: (ES+) m/z 292.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:5]=[C:4]([NH2:18])[N:3]=1.CO.O1CCCC1.C(OCC)(=O)C>[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CCCCCC>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[CH:2][N:3]=[C:4]([NH2:18])[N:5]=2)=[CH:10][CH:11]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(N)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 340.9 %

Procedure:
After suspending 4-chloro-6-(4-nitrophenoxy)pyrimidin-2-ylamine (1.60 g, 1.32 mmol) in a methanol (30 ml)-tetrahydrofuran (30 ml) mixed solvent, palladium-carbon hydroxide (300 mg) was added and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The catalyst was filtered off by celite filtration, and after washing with ethanol, the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent-ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated to obtain the title compound (910 mg, 4.50 mmol, 75%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Cl.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][N:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=[CH:5]1
Reactant: N#Cc1nc[nH]c1C#N
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncn(Cc2ccc(Cl)c(Cl)c2)c1C#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
4,5-Dicyanoimidazole (93 g, described by Woodward, U.S. Pat. No. 2534331 (1950)) was dissolved in dry dimethylformamide (500 ml) with stirring. Sodium hydride (20 g) was added to the solution in portions at such a rate that the temperature after the addition was 90° C. When effervescence had ceased the solution was heated on a steam bath for 15 minutes and then allowed to cool to 60° C. 3,4-Dichlorobenzyl chloride (230 g, described by Beilstein & Kuhlberg, Ann., 146, 326 (1867)) was added over 30 minutes to the solution, which was heated on a steam bath for 6 hours and then at 150° C. for 10 minutes. The cooled reaction mixture was poured into water (2 liters) and a brown solid was filtered off and washed with water. The damp solid was recrystallised from ethanol (1 liter) to give 1-(3,4-dichlorobenzyl)-4,5-dicyanoimidazole, m.p. 132°-134° C., (114 g) as off-white crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:12]=1[CH3:13].CN(C)[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]=2[CH3:13])[CH:24]=[O:25])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cncc(Br)c2C)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cncc(C=O)c2C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
A n-butyllithium-1.58M n-hexane solution (3.9 ml, 6.13 mmol) was added dropwise to a solution of 3-bromo-5-(4-methoxyphenyl)-4-methylpyridine (1.55 g, 5.57 mmol) obtained in Example (76-1) in tetrahydrofuran (20 ml) at −78° C., and the mixture was stirred for 5 minutes. N,N-Dimethylformamide (0.87 ml, 11.2 mmol) was added dropwise thereto at the same temperature and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture and the temperature of the mixture was raised to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1-2/3) to give 5-(4-methoxyphenyl)-4-methylnicotinaldehyde (0.56 g, yield: 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCc1nc2ccc(C(=O)OC)cc2[nH]1
Temperature: 0 °C
Yield: 40.3 %

Procedure:
To a mixture of Methyl 3,4-diaminobenzoate (1.91 g) and triethylamine (0.56 g) in N,N-dimethylformamide (20 ml) was added decanoyl chloride (2.31 g), and the mixture was stirred for an hour at 0° C. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml), and conc. sulfuric acid (0.05 ml) was added, and the mixture was stirred for 6 hours at 60° C. After cooling, the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with (n-hexane:ethyl acetate=3:1) gave 5-methoxycarbonyl-2-nonylbenzimidazole (1.40 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:15]1([N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]2)[CH2:17][CH2:16]1
Reactant: NC1CCN(C2CC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC2CCN(C3CC3)CC2)c([N+](=O)[O-])c1

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35 mg). The mixture was stirred at reflux overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCO3, water, and brine and dried over Na2SO4. After filtration and concentration, the residue was dissolved in dichloromethane and loaded on a column and eluted with dichloromethane (500 mL), 5% 7N NH3 in 10% methanol in dichloromethane (1.5 L) to give the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.CC[N:25](CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N.CO>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:25])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1
Reactant: O=C(O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 5-bromo-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-1H-indole-7-carboxylic acid (1.2 g, 3.22 mmol) in CH2Cl2 (100 mL) was added Et3N (650 mg, 6.44 mmol), TBTU (2.1 g, 6.44 mmol), and NH3/MeOH (10 mL). The mixture was stirred for 2 hours at room temperature. The reaction solution was washed with water, and the organic phase was dried (MgSO4), concentrated, and purified by column chromatography on silica gel, giving 770 mg (65%) of the title compound.
Reaction SMILES: O.O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3:11].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:20]([N:31]([CH2:36][C:37]([OH:39])=[O:38])[CH2:32][C:33]([OH:35])=[O:34])[CH2:21][N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25]>[OH-].[NH4+]>[Bi:11].[CH2:21]([N:22]([CH2:27][C:28]([OH:30])=[O:29])[CH2:23][C:24]([OH:26])=[O:25])[CH2:20][N:31]([CH2:36][C:37]([OH:39])=[O:38])[CH2:32][C:33]([OH:35])=[O:34]
Reactant: [Bi+3]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: [Bi]

Procedure:
A precursor solution is prepared by mixing 2.425 g of bismuth nitrate hexahydrate into 10 ml of 28% ammonium hydroxide solution containing 2 g of EDTA (ethylene diamine tetraacetic acid-sodium salt) under reflux until a clear solution results.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:18]3[C:13](=[C:14]([Cl:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:22]3[S:23][CH:24]=[C:25]([CH3:27])[N:26]=3)[CH:10]=2)=CC=1>FC(F)(F)C(O)=O>[Cl:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[CH:10]=[C:9]2[OH:8]
Reactant: COc1ccc(COc2cc(-c3nc(C)cs3)nc3c(Cl)c(OC)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(O)cc(-c3nc(C)cs3)nc2c1Cl

Procedure:
Compound 275 (750 mg, 1 eq.) in trifluoroacetic acid (5 mL) was stirred at room temperature for 10 min. Then, the acid was evaporated, ethyl acetate added and concentrated again in diminished pressure. The residue was triturated in diethyl ether to give the compound 276 as a white solid in quantitative yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.59 (d, J=0.81 Hz, 3H), 4.10 (s, 3H). 7.19 (d, J=9.25 Hz, 1H), 7.22 (d, J=0.81 Hz, 1H), 7.25 (s, 1H), 8.36 (d, J=9.25 Hz, 1H), 10.51 (br s, 1H); MS (ESI, EI+): m/z=306.93 (MH+).
Reaction SMILES: Cl.C1(N2CCN(CC[CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[CH:29]=[CH:30][CH:31]=[C:24]5[C:25]=4[C:20](=[CH:21][CH:22]=[CH:23]5)[C:19]3=[O:32])CC2)C=CC=CC=1.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:16][CH2:17][N:18]1[C:19](=[O:32])[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25]=2[C:26](=[CH:29][CH:30]=[CH:31]3)[C:27]1=[O:28]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccc2)CC1
Reactant: BrCCCCBr
Agent: Cl
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 34 but substituting 1,6 -dibromohexane for 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>CCOCC.Cl[Ni](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>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: CC1=Cc2c(Br)cccc2C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
4-Bromo-2-methylindene (10.7 g, 51 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-bis(trifluoromethyl)phenylmagnesium bromide (51 mmol) as a Et2O solution was added under vigorous stirring and the reaction stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 2.2 g (13%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27]([OH:29])=[O:28])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)OCc4ccccc4)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)O)cc3)cc2)CC1
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
The benzyl ester from Step 8 (1 g, 2.1 mmol) in ethyl acetate (10 mL) was degassed with nitrogen for 10 minutes. 10% Palladium on activated carbon (0.2 g, 0.2 mmol) was added and the solution was sparged with hydrogen via balloon. The balloon of hydrogen was maintained on the head space and the solution stirred for 1.5 hours. The reaction was diluted with ethanol and actone (to solublize the product), filtered through celite and evaporated to yield 700 mg product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: Cc1nc(N)sc1C
Reactant: CCOC(=O)CC(=O)CCl
Product: Cc1sc2nc(CCl)cc(=O)n2c1C
Yield: 144 %

Procedure:
This compound was synthesized from 2-amino-4,5-dimethylthiazole (5.0 g, 30.365 mmol) and ethyl chloroacetoacetate (6.519 g, 42.511 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 10.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 229.60 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([Cl:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:28])[C:21]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:14][C:11]([F:13])([F:12])[C:8]1[N:6]2[N:7]=[C:2]([N:25]3[CH2:26][CH2:27][N:22]([C:21]4[C:20]([Cl:28])=[CH:19][N:18]=[CH:17][C:16]=4[Cl:15])[CH2:23][CH2:24]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(Cl)c1nnc2ccc(N3CCN(c4c(Cl)cncc4Cl)CC3)nn12
Temperature: 70 °C
Yield: 29.3 %

Procedure:
A solution of 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Examples 335-338, preparation of starting materials) (53 mg, 0.22 mmol) in ethanol (1 mL) was added to 1-(3,5-dichloropyridin-4-yl)piperazine (77 mg, 0.33 mmol). The reaction mixture was treated with DIPEA (43 mg, 0.33 mmol) and the mixture was heated at 70° C. for 4 hours. The reaction mixture was evaporated to leave an involatile residue that was purified by preparative reverse phase chromatography to give 3-[chloro(difluoro)methyl]-6-[4-(3,5-dichloropyridin-4-yl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (28 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.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>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc2n1-c1ccc(-c3cn[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
To a solution of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (100 mg, 0.26 mmol) in DME/H2O (3:1, 2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.36 mmol), cesium carbonate (164 mg, 0.50 mmol) and Tetrakis(triphenylphosphine)palladium(0)(22 mg, 0.02 mmol). The mixture was stirred in the microwave at 130° C. for 20 min. The reaction mixture was concentrated and purified by prep-TLC (elute: DCM:MeOH=15:1) to give (R)-4-(1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (15 mg, 15%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[N:16][C:17]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution containing 1-Boc-piperidine-4-carboxaldehyde (3.0 g, ca. 14 mmol), 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (3.7 g, 14 mmol), and pyridinium p-toluenesulfonate (0.3 g, 1.4 mmol) in benzene (250 mL) was heated at reflux for 24 h with azeotropic removal of water. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL) and then brine (150 mL); then dried with MgSO4, filtered and concentrated in vacuo to give 6.0 g (93%) of the title compound as an orange foam which was used directly in the next step without further purification.