Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][C:19]1[C:23]2[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=2[S:21][C:20]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Ba+2].[OH-]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:20]3[S:21][C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=4[C:19]=3[CH3:18])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc2sc(B(O)O)c(C)c2c1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Ba+2]
Solvent: COCCOC
Solvent: O
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ccc(C)cc4c3C)c(C)nc12
Temperature: 90 °C
Yield: 90 %

Procedure:
A mixture of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.145 mmol), 3,5-dimethyl-benzothiophene-2-boronic acid (0.29 mmol), Pd2 dba3 (0.0072 mmol), triphenylphosphine (0.029 mmol), and barium hydroxide (0.435 mmol) in previously degassed mixture of DME/water [(2:1), 0.5 ml] is added to a pressure tube with a stirring bar. The mixture is degassed for 30 min. After heating for 16 h at 90° C., the reaction mixture is cooled, diluted with diethylether and washed with saturated aqueous ammonium chloride solution. The organic layer is dried over anhydrous magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is purified by silica gel column chromatography using mixtures of hexane-ethyl acetate as eluent to give the tile compound (90%). 1H-NMR (CDCl3): 7.68 (m, 1H); 7.40 (m, 1H); 7.15 (m, 1H); 6.62 (s, 1H); 3.25 (m, 1H); 2.45 (s, 3H); 2.43 (s, 3H); 2.42 (s, 3H); 2.19 (s, 3H); 1.73 (m, 4H); 0.74 (t, 6H) ppm. MS/ES+=378 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[CH:4][CH:3]=1>Cl.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]3[NH:29][C:28](=[O:30])[NH:27][N:26]=3)[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(F)cc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3ccc(F)cc3c(O[C@H]3CCNC3)n2)[nH]1

Procedure:
A solution of (S)-tert-butyl 3-((7-fluoro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (70 mg, 0.15 mmol) in HCl/EtOAc (5 mL) was stirred at RT for 30 minutes. The mixture was subsequently concentrated in vacuo to give the title compound, which was used in the next step without further purification (60 mg, 100%). ESI-MS m/z [M+H]+ 316.
Reaction SMILES: [CH:1]1([N:6]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][CH2:9][C@H:8]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:19][C@H:8]1[CH2:9][CH:10]=[CH:11][C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: N[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-[(3S,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (75 mg) in MeOH (3 ml), was added hydrazine hydrate (21 mg) at RT under N2. The mixture was allowed to stir overnight at RT. The reaction was evaporated and the residue was taken up in DCM and washed with water. The organics were dried (Na2SO4), filtered and evacuated to afford the title compound (40 mg, 79% crude yield) as a crude, yellow oil. This crude oil was not characterized or purified further before taken on to the coupling step.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[N:5]=1)(=[O:3])[CH3:2].CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][N:29]([CH3:31])[CH:30]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Solvent: CC#N
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)C=CN(C)C)n1

Procedure:
A mixture of 3-acetyl-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (264 mg), N,N-dimethylformamide dimethyl acetal (1.5 mL) and acetonitrile (1.5 mL) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound (274 mg).
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[C:17]([O:18]CC2C=CC=CC=2)=[C:16]([CH2:26][OH:27])[C:15]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[CH:14][N:13]=1)=[O:11])C1C=CC=CC=1>[Pd].CO>[OH:8][NH:9][C:10]([C:12]1[C:17]([OH:18])=[C:16]([CH2:26][OH:27])[C:15]([C:28]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[O:29])=[CH:14][N:13]=1)=[O:11]
Reactant: COc1ccc(CNC(=O)c2cnc(C(=O)NOCc3ccccc3)c(OCc3ccccc3)c2CO)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CNC(=O)c2cnc(C(=O)NO)c(O)c2CO)cc1
Yield: 90.9 %

Procedure:
The product of example 5 (0.010 g, 0.019 mmol, 1 eq) and 10% Pd/C catalyst (5 mg) were stirred in 4.0 mL of methanol under an atmosphere of hydrogen for 1 hour. The catalyst was filtered and reaction mixture was concentrated under vacuum yielding 0.006 g of N2,3-dihydroxy-4-(hydroxymethyl)-N5-(4-methoxybenzyl)pyridine-2,5-dicarboxamide (85% yield) as a white solid; MS-ESI m/z 348 [MH]+.
Reaction SMILES: [H-].[Na+].CI.C(O[C:10]([NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O)(C)(C)C>C1COCC1>[CH3:10][NH:12][CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CNCc1ccc(C(=O)OC)cc1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
1.13 g of NaH at 60% in oil, and then 2.35 ml of methyl iodide are added to a solution of 5 g of methyl 4-[[(tert-butoxycarbonyl)amino]methyl]benzoate in 150 ml of THF and the mixture is left to stir at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with a water/ice mixture, the mixture is extracted with EtOAc, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is taken up with 80 ml of 2N hydrochloric ether, 1 ml of water is added, and the mixture is left to stir at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up with a 5% NaHCO3 solution, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 2.2 g of the expected compound are obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:16][CH:17]=2)=[CH2:11])=[CH:2]1>O1CCCC1.CO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=3)=[N:16][CH:17]=2)[CH3:11])=[CH:2]1
Reactant: C=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Reaction time: 8 h
Yield: 4.8 %

Procedure:
5-[1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)-amine (623, 0.043 g, 0.00011 mol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction was shaken under an atmosphere of hydrogen (30 psi) overnight. The reaction was filtered through Celite and the filtrate adsorbed onto silica and purified by silica gel column chromatography (ethyl acetate:hexanes) to provide the desired compound as a white solid (P-0388, 2.1 mg, 5%), consistent with compound structure by 1H-NMR and MS (ESI): [M+H+]+=397.6.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:25]>>[NH2:25]/[C:7](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[C:6]1\[C:2](=[O:1])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[S:5]\1
Reactant: O=C(c1ccccn1)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccn1
Yield: 27 %

Procedure:
Prepared as in Example 1 from (3-hydroxybenzo-[b]thien-2-yl)-2-pyridinyl-methanone, phosphorus(V) chloride and concentrated ammonia with a yield of 27% of theory. M.p. 128°-130° C. (ethyl acetate) C14H10N2OS (254.30): Calc.: C-66.12%; H-3.96%; N-11.02%; S-12.61%; Found: C-66.34%; H-4.09%; N-11.45%; S-12.70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:25])[NH:11][N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1.N>O>[F:33][C:30]1[CH:31]=[C:32]([N:11]2[C:10](=[O:25])[C:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:13]=[N:12]2)[CH:27]=[CH:28][C:29]=1[F:34]
Reactant: Fc1ccc(Br)cc1F
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2Cc2ccc(F)cc2)cc1
Agent: N
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2Cc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 62 substituting 4-(4-fluorophenylmethyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3,4-difluorobenzene in place of 4-iodo-1-fluorobenzene (yield: 0.085 g, 54%). mp 157-159° C. 1H NMR (300 MHz, DMSO d6) δ 3.30 (s, 3H), 3.88 (bs, 2H), 7.04 (m, 4H), 7.49-7.66 (m, 2H), 7.70 (m, 2H), 7.81 (m, 1H), 8.12 (s, 1H). MS (DCI/NH3) m/z 471 (M+H)+, 488 (M+NH4)+. Anal. calc. for C24H17F3N2O3S.0.25 H2O: C, 60.69; H, 3.71; N, 5.84. Found: C, 6.39; H, 3.76; N, 5.81.
Reaction SMILES: [I:1]I.[C:3]1([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[C:11]3[CH:17]=[N:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOCC>[I:1][C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[NH:15][N:16]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Yield: 95.4 %

Procedure:
I2 (0.421 g, 1.66 mmol) was added to a solution of tert-butyl 4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.63 g, 0.830 mmol) and KOH (0.140 g, 2.49 mmol) (crushed by mortar and pestle) in DMF (10 mL). The resulting mixture was heated to 60° C. for 3 hours. Ether (20 mL) and saturated Na2SO3 (10 mL) were added. The organic layer was separated, washed with brine, and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.40 g, 95%) as a solid. MS APCI (+) m/z 506.2 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.30 (s, 1H), 7.60 (m, 3H), 7.49 (m, 2H), 3.63 (m, 4H), 2.95 (m, 4H), 1.51 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].[C:17]1([S:23]([N:26]2[C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=3[CH:28]=[C:27]2[CH2:36]Br)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:36][C:27]2[N:26]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=3[CH:28]=2)[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: O=S(=O)(c1ccccc1)n1c(CBr)cc2c(Cl)nccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cc3c(Cl)nccc3n2S(=O)(=O)c2ccccc2)C1=O
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.081 g, 2.02 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.404 g, 2.02 mmol) in DMF (5 mL) at 0° C. The mixture is stirred for 10 minutes, then cannulated dropwise to a solution of 1-benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 1.92 mmol) in DMF (10 mL) at 0° C. The resulting yellow solution is stirred for 1 hour at 0° C. then quenched with saturated ammonium chloride solution and diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The solid product (0.94 g, 1.86 mmol) is used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15](=O)[CH3:16])[CH:11]=2)[CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(Br)[C:26]1[CH:31]=[CH:30]C=[CH:28][CH:27]=1>CO.[OH-].[Na+]>[CH2:15]([O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([CH2:4][C:3]([OH:2])=[O:18])[CH2:13]2)[C:16]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CC1Cc2ccc(OC(C)=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC1Cc2ccc(OCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
9.62 g (38.8 mmol) of methyl(5-acetoxyindan-2-yl)acetate was dissolved in 150 ml of methanol, to which was added 1.17 g (8.5 mmol) of potassium carbonate and stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 ml of acetone. 5.98 g (43.0 mmol) of potassium carbonate, 7.27 g (42.5 mmol) of benzylbromide were added thereto and refluxed for 5 hours. After cooling, the precipitates were filtrated and condensed under reduced pressure. The residue was dissolved in 100 ml of methanol, to which 12 ml of 20% sodium hydroxide were added and the mixture was heated at 50° C. for 1 hour. After cooling, methanol was removed, the residue was made acidic with conc. HCl, and the precipitates were extracted with chloroform. The organic phase was washed with water, dried and condensed under reduced pressure to obtain a pale brown solid. Recrystallization was carried out from a solvent mixture of isopropylether and ethyl acetate to obtain 5.97 g of colorless crystals. Yield: 68%
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7]C(=O)C)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=O)=O.[Mg+2].[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>O.CO>[N:1]([CH2:4][CH2:5][CH2:6][O:7][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[N+:2]=[N-:3]
Reactant: CC(=O)OCCCN=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
Acetic acid 3-azido-propyl ester (3.16 g, 22.1 mmol) was dissolved in water (25 mL) and methanol (25 mL). To the resulting mixture was then added potassium carbonate (3.81 g, 27.6 mmol) and the resulting solution was stirred for 2 hours at room temperature, reduced to a third of its volume, saturated with MgSO4, filtered and partitioned with water and dichloromethane. The organic layer was dried with magnesium sulfate, filtered and transferred into to dry round bottom flask. To the filtrate was then added (3.35 g, 33.1 mmol) and tosyl chloride (4.6 g, 24.3 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned with aqueous 1N HCl and dichloromethane. The organic layer was dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (10% ethyl acetate/hexanes) to yield the toluene-4-sulfonic acid 3-azido-propyl ester (2.03 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7](=[O:28])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:27])[C:16]([C:18]2[CH:23]=[C:22]([O:24]C)[N:21]=[N:20][C:19]=2[CH3:26])=[O:17])[N:13]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][NH:6][C:7](=[O:28])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]([CH3:27])[C:16]([C:18]2[CH:23]=[C:22]([OH:24])[N:21]=[N:20][C:19]=2[CH3:26])=[O:17])[N:13]=1
Reactant: COc1cc(C(=O)N(C)Cc2csc(NC(=O)NCc3cccc(F)c3)n2)c(C)nn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nnc(O)cc1C(=O)N(C)Cc1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
6-Methoxy-3-methyl-pyridazine-4-carboxylic acid {2-[3-(3-fluoro-benzyl)-ureido]-thiazol-4-ylmethyl}-methyl-amide was dissolved in DCM and treated with an excess of BBr3 at room temperature for a couple of hours. Column chromatography afforded the title product.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C:8]1[S:17][C:16]2[N:15]3[C:18]([CH3:21])=[N:19][N:20]=[C:14]3[CH:13]([CH3:22])[N:12]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[CH:9]=1)(=O)C.[OH-].[Na+]>CO>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:11]1[C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][OH:4])[S:17][C:16]=2[N:15]2[C:18]([CH3:21])=[N:19][N:20]=[C:14]2[CH:13]([CH3:22])[N:12]=1
Reactant: CC(=O)OCCCc1cc2c(s1)-n1c(C)nnc1C(C)N=C2c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnc2n1-c1sc(CCCO)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 2 g of compound obtained in Example 1 in 40 ml of methanol is added one equivalent of 2 normal sodium hydroxide solution and stirred at room temperature for 2 hours. The methanol is distilled off under reduced pressure and the residue is dissolved in 50 ml of chloroform. The solution is washed with water and then dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure to give 1.7 g of 4-(2-chlorophenyl)-2-(3-hydroxypropyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[N:7]=[C:6]([O:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(Cl)ncc1F
Temperature: -10 °C
Reaction time: 21 h
Yield: 7.4 %

Procedure:
2,4-Dichloro-5-fluoropyrimidine (515 mg, 3.08 mmol) was weighed into a 150 mL RBF, and was suspended in THF (5.0 mL). The stirring suspension was cooled to −10° C. NaOMe (250 mg, 4.63 mmol) was added in one portion at −10° C. An additional 0.5 eq of NaOMe were added and the suspension was stirred at RT for 21 h. The suspension was diluted with MeOH, and the solvents were removed in vacuo. The crude material was purified by flash chromatography (eluting with 100% DCM) to give 2-chloro-5-fluoro-4-methoxypyrimidine (37 mg, 0.228 mmol, 7.38%) as an amorphous white solid. MS (ESI, pos. ion) m/z: 162.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.60 (d, J=2.7 Hz, 1H), 4.04 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:27][C:28]3[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: Nc1cccc(O)c1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3cccc(O)c3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.45 g, 1.0 mmol), 3-Amino-phenol (0.27 g, 2.5 mmol), Cs2CO3 (2 M, 3.0 mL), Xantphos (58 mg, 0.1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in dioxane (5 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (33% EtOAc in hexane) to give 3-{4-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenylamino}-phenol as brown solid in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C=O)C>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]4[N:12]([CH:14]=[CH:15][N:16]=4)[CH:13]=3)[CH:3]=2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2cn3ccnc3c(Nc3ccccc3)n2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccccc4)n3)c2)cc1

Procedure:
A solution of [6-(3-amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-phenyl-amine (5) (50 mg), 4-tert-butyl-benzoyl chloride (0.83 mL of a 0.2M solution in toluene), and triethylamine (0.034 mL) in toluene (1 mL) and N,N,-dimethylformamide (1 mL) is stirred at room temperature for 16 hr. The mixture is purified by preparative thin layer chromatography over silica gel, eluting with diethyl ether/dichloromethane (1:1) to afford 4-tert-butyl-N-[3-(8-phenylamino-imidazo[1,2-a]pyrazin-6-yl)-phenyl]-benzamide (6) as a cream foam.