Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH3:11])=[CH:4][N:3]=1.[O:12]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:11][O:10][C:5]1[C:6](=[O:9])[N:7]([CH3:8])[C:2]([C:22]2[CH:23]=[CH:24][C:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1cnc(Cl)n(C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Temperature: 120 °C
Yield: 100.3 %

Procedure:
To a solution of 750 mg (4.30 mmol) 2-chloro-5-methoxy-3-methylpyrimidin-4(3H)-one in 20 ml THF was added 314 mg (0.430 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 1.83 g (8.59 mmol) 4-phenoxyphenylboronic acid, and 4.30 ml (4.30 mmol) M aq Cs2CO3. The reaction mixture was heated to 120° C. for 15 min in the microwave, then diluted with 10 ml water, extracted with 50 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo to give 1.33 g (100% yield) of crude 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.O[C@@H]1CCNC1.[CH3:56][C:57]([OH:61])([C:59]#[CH:60])[CH3:58]>>[OH:61][C:57]([CH3:58])([CH3:56])[C:59]#[C:60][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: NC(=O)c1nc2n(c1CN1CC[C@@H](O)C1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Agent: O[C@@H]1CCNC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CC[C@@H](O)C3)n1CCO2
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, (R)-10-bromo-3((3-hydroxypyrrolidin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with (R)-3-hydroxypyrrolidine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a white solid (11 mg, 14%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[S:4]([C:7]1[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].C(N=[C:24]=[O:25])CCC.C(Cl)(Cl)=O>>[CH2:17]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:24]=[O:25])(=[O:14])=[O:15])(=[O:6])=[O:5])[CH3:18]
Reactant: CCCCN=C=O
Reactant: CCN(CC)S(=O)(=O)c1ccccc1S(N)(=O)=O
Agent: O=C(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reaction time: 0.5 h

Procedure:
A solution of 13.2 g of N,N-diethyl-1,2-benzenedisulfonamide, 4.5 g of n-butylisocyanate, and 0.2 g of 1,4-diaza[2,2,2]bicyclooctane (DABCO) in 90 ml of mixed xylenes was heated to 135°. To this solution ws added 3.3 ml of liquid phosgene at such a rate that the temperature was maintained between 125° and 135° (about 2 hours). The temperature was kept at 130° for 1/2 hour after the addition. The solution was cooled and filtered to remove a small amount of insoluble solid then concentrated at 60°-70° in-vacuo. The residue of o-N,N-diethylsulfamoylbenzenesulfonyl isocyanate was an oil weighing 16.8 g and was sufficiently pure for further reaction.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8])=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C.O>[Cl:1][CH2:2][C:3]1[O:8][C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[N:6][N:5]=1
Reactant: O=C(CCl)NNC(=O)C1CCN(c2ccccn2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: ClCc1nnc(C2CCN(c3ccccn3)CC2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The hydrazide of Preparation 3 (50.0 g, 169 mmol) was suspended in acetonitrile (250 ml) and cooled using an ice bath. Trifluoromethanesulfonic anhydride (29.9 ml, 177 mmol) was added dropwise at T<15° C. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was cooled using an ice bath and a solution of sodium hydrogen carbonate (29.8 g, 354 mmol) in water (250 ml) was added dropwise. Dichloromethane (250 ml) was added and the phases were separated. The organic containing product phase was used in preparation 14b.
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:8]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([N:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]4)[C:10]=3[C:9]=2[CH:11]=1)#[N:16]
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (100 mg, 0.3 mmol) and (S)-tert-butyl piperidin-3-ylcarbamate (167 mg, 0.9 mmol) in N,N-dimethylacetamide (1.3 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (130 mg, 90%).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:6])(=[S:5])[CH3:4].[C:7]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH2:8][CH3:9]>CO>[C:7]([NH:11][C:12](=[O:15])[CH2:13][S:5][C:3](=[O:6])[CH3:4])(=[O:10])[CH2:8][CH3:9]
Reactant: CCC(=O)NC(=O)CCl
Reactant: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)NC(=O)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nitrogen was bubbled through 4.0 g. (0.1 mole) of sodium hydroxide in 200 ml. of methanol and to this there was added 7.1 ml. (0.1 mole) of thioacetic acid and then 16.0 g. (0.1 mole) of N-propionyl-2-chloroacetamide. The reaction mixture was stirred at ambient temperature for 2 hours and then stripped in vacuo and filtered. The product was dissolved in boiling water, treated with characoal, filtered and dried in vacuo. A yield of 6.0 g. of white crystalline product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:40])=[C:4]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:41][N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN.Cl>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:40])=[C:4]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH:42][CH3:41])=[O:28])[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cccc(Cl)c1F)C2=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CNC(=O)Cc1cnc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cccc(Cl)c2F)C3=O)c1

Procedure:
A mixture of {5-[5-(3-chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-6-methoxy-pyridin-3-yl}-acetic acid (Step 85.1) (0.054 mmol), HATU (0.161 mmol), NMM (0.215 mmol) and methylamine.HCl (0.081 mmol) in DMF (0.5 mL) at rt was stirred for 2 h. The reaction mixture was diluted with EtOAc and successively washed with a saturated aqueous solution of NaHCO3 (2×) and brine, dried (MgSO4), filtered and concentrated. The residue was purified using a silica gel column to afford the title compound as a white solid. tR: 4.96 min (HPLC 4); ESI-MS: tR=1.02 min, [M+H]+ 572/574 (LC-MS 1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH3:32])=[O:30].O>O1CCCC1>[CH3:32][O:31][C:29](=[O:30])[NH:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11](=[O:12])[C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of (4-amino-1H-pyrrolo[3,2-c]pyridin-1-yl)(2,6-dichlorophenyl)methanone (50 mg, 0.16 mmol) and triethylamine (0.013 mL, 0.18 mmol) in anhydrous tetrahydrofuran was cooled to 0° C. and treated drop wise with methyl chloroformate (0.05 mL, 0.33 mL) and stirred at room temperature for 2 hours. The reaction mixture was poured onto cold water and the precipitated solid was filtered off, washed with hexane and dried to afford methyl[1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]carbamate (35 mg, 60%).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([C:15]3[CH:28]=[CH:27][C:18]4[N:19]([CH2:22][CH2:23][N:24]=[N+]=[N-])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:3]1)[CH2:9]2>CO.[Pd]>[OH:1][C:2]12[CH2:3][CH:4]3[CH2:10][CH:8]([CH2:7][CH:6]([CH:5]3[NH:12][C:13]([C:15]3[CH:28]=[CH:27][C:18]4[N:19]([CH2:22][CH2:23][NH2:24])[CH:20]=[N:21][C:17]=4[CH:16]=3)=[O:14])[CH2:11]1)[CH2:9]2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Agent: [Pd]
Solvent: CO
Product: NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide (1.0 g, 0.00263 mol) in methanol (20 mL) was added 10% Pd/C (200 mg). The reaction mixture was hydrogenated at 3 kg pressure for 1 h. The catalyst was filtered over celite and the filtrate was concentrated to give 1-(2-aminoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide (0.7 g, 75%).
Reaction SMILES: NC1C=CC(C)=C(NC2O[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)C=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34](=[O:36])C)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.NC1C=CC(C)=C(NC(=O)C)C=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]2[O:36][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: CC(=O)Nc1cc(N)ccc1C
Product: COc1cc(Nc2ncc(-c3ccc(C#N)cc3)o2)cc(OC)c1
Yield: 85 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(3,5-dimethoxyphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=85%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[C:9]([O:16][CH3:17])[CH:8]=1.C(=O)=O.CO.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>CCCCCC.C1COCC1>[Cl:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]([B:23]([OH:28])[OH:24])=[CH:8][C:9]=1[O:16][CH3:17]
Reactant: COc1cc(Br)cc(OC)c1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(B(O)O)cc(OC)c1Cl
Reaction time: 0.33 h

Procedure:
Under an argon atomsphere, to dry THF (2 mL) stirred in a dry ice-methanol bath was gradually added a 1.57 M solution of n-butyllithium in hexane (0.8 mL), followed by the dropwise addition of a solution of 1-bromo-4-chloro-3,5-dimethoxybenzene (160 mg) in dry THF (2 mL). After the mixture was stirred for 20 minutes in the dry ice-methanol bath, triisopropyl borate (0.18 mL) was added and the mixture was additionally stirred for 20 minutes. The reaction mixture was then stirred at room temperature for 1 hour and pH of the mixture was adjusted at 3 using 4 M hydrochloric acid. The mixture was stirred at 0° C. for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate-hexane giving the title compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][C:49]([CH3:51])=[CH2:50])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.CCOC(C)=O>ClC(Cl)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:10][C@:9]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[C:3]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)[CH:4]=1)[O:8][C:49]([CH3:51])([CH3:50])[CH2:48]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(C)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A mixture of 25 (48 mg, 58 μmol) and silver triflate (15 mg, 58 μmol) in dichloroethane (1 mL) was heated to 70° C. for 2 h. LC/MS indicated that the conversion was complete to give a new and less polar component. After cooling, the mixture was loaded onto a TLC plate and developed using 10% EtOAc in petroleum ether to give 56 (19 mg, 40%). LC/MS m/z 846 (M+Na), 824 (M+1).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)[C:4]=2[O:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][NH2:35]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:34]([C:28]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=5[F:26])[N:35]=[CH:20][CH:19]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2cccc3c2OC(F)(F)O3)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=431.2 (M+H)+
Reaction SMILES: C(O[C:4]([N:6]1[CH2:12][CH2:11][C:10](=[O:13])[C:9]2[CH:14]=[CH:15][O:16][C:8]=2[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:4][N:6]1[CH2:12][CH2:11][CH:10]([OH:13])[C:9]2[CH:14]=[CH:15][O:16][C:8]=2[CH2:7]1
Reactant: CCOC(=O)N1CCC(=O)c2ccoc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(O)c2ccoc2C1
Temperature: 0 °C
Yield: 43.5 %

Procedure:
A solution of 1.38 g of 7-ethoxycarbonyl-5,6,7,8-tetrahydrofuro[2,3-c]azepin-4-one prepared in the step 5 in 30 mL of dry THF was slowly added by dropping into an ice-cooled solution of 0.29 g of lithium aluminum hydride in 20 mL of dry THF. The reaction solution was gradually heated followed by heating to reflux for 30 minutes. The reaction solution was cooled, an excess of lithium aluminum hydride was decomposed by gradual addition of ice thereto and the reaction solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.45 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:41][CH:42](Cl)[CH:43]([CH3:45])[CH3:44])(=[O:40])[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[C:36]([O:41][CH:42]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH:43]([CH3:45])[CH3:44])(=[O:40])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C(=O)OC(Cl)C(C)C
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(OC(=O)C(C)C)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Yield: 12.2 %

Procedure:
The title compound was prepared according to the procedure as described in Example 14 Step 2 using N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL), KOH (69 mg, 1.23 mmol) and a solution of 1-chloro-2-methylpropyl isobutyrate (108 mg, 0.61 mmol) in anhydrous DMF (0.5 mL). The crude product was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1), and recrystallized in methanol to afford the title compound as a white solid (47 mg, 13.4%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.ClC1C=CC=C(C(OO)=[O:30])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirred solution of 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylthio)benzo[d]thiazole (350 mg, 1.1 mmol) from the previous step in DCM (30 mL) at 0° C. was added meta-chloroperbenzoic acid (194 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 2 h. To the mixture was added saturated aq Na2S2O3 (15 mL) and the mixture was stirred for a further 0.5 h. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 5% MeOH in DCM to afford 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (320 mg, 87%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J=4.5, 1.5 Hz, 1H), 7.91-8.00 (m, 3H), 7.62 (s, 1H), 7.54 (dd, J=8.4, 1.8 Hz, 1H), 7.03 (m, 1H), 4.52 (s, 2H), 3.05 (s, 3H); LCMS (ESI) m/z 329 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.Br[C:38]1[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=3)[C:43]([N:45]([CH3:46])[CH3:47])=[O:44])[CH:16]=2)[NH:11][CH:10]=1
Reactant: CN(C)C(=O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)N(C)C)c3)cc12
Yield: 56.7 %

Procedure:
Into a 5 ml. Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.136 g, 0.270 mmol), 5-Bromo-N,N-dimethyl-nicotinamide (6.0756 g, 0.332 mmol; preparation described below), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (16.2 mg, 0.01 mmol), acetonitrile (2 mL) and saturated aqueous NaHCO3 (2 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 3:1 MeOH/acetone (4 mL total) and treated with 500 μL of 50% w/w KOH(aq) for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was partitioned between EtOAc and water, then the layers were separated, and the organic phase was washed 2× with water. The organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a tan powder (57 mg, 57%), 1H-NMR (500 MHz, d6-DMSO) δ=11.96 (br. s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H), 7.59 (dd, J=2.0, 5.5 Hz, 1H), 7.25 (dd, J=1, 7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 3H), 2.92 (8, 3H): MS: m/z 373.1 [MH+].