Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=3)[C:15](=[O:26])[N:14]([CH3:27])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:28]1[N:37]=[CH:36][C:35]2[C:30](=[C:31]([F:42])[CH:32]=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:34]=2)[C:29]1=[O:43])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:38]([C:33]1[CH:34]=[C:35]2[C:30](=[C:31]([F:42])[CH:32]=1)[C:29](=[O:43])[N:28]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[N:21]([CH3:25])[N:20]=4)[C:15](=[O:26])[N:14]([CH3:27])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:37]=[CH:36]2)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nn1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (186 mg, 318 μmol, Eq: 1.00) in MeOH (15.0 ml) was added potassium carbonate (87.8 mg, 635 μmol, Eq: 2.0). The reaction mixture stirred at 40° C. for 2 h. The solution was cooled to room temperature. Concentrated in vacuo. The residue was taken up in DCM/water. The layers were separated. The aqueous layer was extracted once with DCM. The organic layers were combined, and then dried over Na2SO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 35% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give 6-tert-butyl-2-{3-[5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-hydroxymethyl-phenyl}-8-fluoro-2H-phthalazin-1-one (75 mg, 44%). LC/MS-ESI observed [M+H]+ 544. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 2.28 (s, 3H) 3.75 (s, 3H) 3.88 (s, 3H) 4.40 (s, 2H) 5.92 (s, 1H) 7.41-7.60 (m, 4H) 7.62-7.69 (m, 1H) 7.78 (s, 1H) 7.96 (s, 1H) 8.29 (d, J=2.64 Hz, 1H)
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][Si:21]([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCC(OCc2ccccc2)CC1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(OCc2ccccc2)CC1F

Procedure:
To a stirred solution of 4-(benzyloxy)-2-fluorocyclohexanol (3.9 g, 17.4 mmol) in DMF (50 mL) were added TBSCl (3.93 g, 26.1 mmol) and imidazole (1.78 g, 26.1 mmol). The reaction was monitored by TLC. After completion of the reaction, the mixture was treated with sodium bicarbonate solution, and extracted with EtOAc. The combined organics were dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[S:5][CH:6]=1.[CH3:29][O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:29][O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([C:7]3[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=3)[S:5][CH:6]=2)[CH:38]=1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2cc(Br)cs2)n(Cc2ccc(F)cc2F)c1=O
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2csc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
6-(4-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile 620 mg, 1.3 mmoles), [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (520 mg, 1.95 mmoles), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (1:1) (32 mg, 0.39 mmoles), and K2CO3 (540 mg, 3.91 mmoles) were combined in 6 ml of DME/H2O (9:1, degassed), and were stirred at 85° C. for 5 hours. After this period the reaction mix was evaporated and purified using flash silica chromatography (0-30% EtOAc/Hexane) to yield (3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic acid methyl ester (365 mg, 52%) as a yellow solid. 1H-NMR (CDCl3): δ 7.64 (br d, J=1.3 Hz, 1H), 7.39-7.35 (m, 2H), 7.33 (br d, J=1.3 Hz, 1H), 7.14-7.07 (m, 1H), 6.92-6.85 (m, 1H), 6.84-6.77 (m, 1H), 6.65 (s, 1H), 5.44 (s, 2H), 3.72 (s, 3H), 3.67 (s, 2H). MS(ES+): 545.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:16]1([CH2:22][O:23][CH2:24][CH2:25][C@@H:26]2[CH2:28][O:27]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:28][C@H:26]([OH:27])[CH2:25][CH2:24][O:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCC[C@@H]2CO2)cc1
Reactant: N#CCc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CC(C[C@H](O)CCOCc1ccccc1)c1cccc(Cl)c1
Temperature: -78 °C
Yield: 59.7 %

Procedure:
(3-Chlorophenyl)acetonitrile (8.62 mL, 72.9 mmol) in 100 ml of THF was cooled to −78° C. Butyllithium (35.1 mL, 56.1 mmol, 1.6 M in THF) was added over 20 minutes and stirred for an additional 15 min at −78° C. (2R)-2-{2-[(phenylmethyl)oxy]ethyl}oxirane (10.0 g, 56.1 mmol, Synthesis 1992, 7, 621-623) in 20 mL of THF was added over 30 minutes and stirred for an additional hour at −78° C. After warming to room temperature the solvent was evaporated and the orange red oil was chromatographed on silica gel with 20-25% EtOAc in Hexanes to give the title compound (11.05 g, 58%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.8 (m, 3H) 3.6 (m, 1H) 3.7 (m, 2H) 4.1 (m, 2H) 4.5 (m, 2H) 7.3 (m, 9H).
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.O>ClCCl>[Cl:7][C:8]1[C:9]([F:16])=[C:10](/[CH:11]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)CN
Reactant: O=Cc1cccc(Cl)c1F
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (50 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (1.6 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (2.4 g, 99%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[OH:11][CH:12]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH2:13][N:14]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[C:36]1[CH:41]=[C:40]([CH:42]([CH3:44])[CH3:43])[CH:39]=[CH:38][C:37]=1[O:45][CH3:46])[C:15](=[O:24])OCC1C=CC=CC=1>C1(C)C=CC=CC=1.C1COCC1>[CH:42]([C:40]1[CH:39]=[CH:38][C:37]([O:45][CH3:46])=[C:36]([C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:35])[F:34])=[CH:31][C:26]=2[CH2:25][N:14]2[CH2:13][CH:12]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[O:11][C:15]2=[O:24])[CH:41]=1)([CH3:43])[CH3:44]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1ccccn1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccccn2)OC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide (464 μL of a 0.5M solution in toluene, 0.232 mmol) was added dropwise to a stirred solution of benzyl (2-hydroxy-2-pyridin-2-ylethyl){[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (134.3 mg, 0.232 mmol) in dry THF (10 mL) at room temperature under N2. After stirring at room temperature for 1 h, the reaction was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-70% EtOAc in hexanes gradient) to afford 3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-pyridin-2-yl-1,3-oxazolidin-2-one. Rf=0.58 (50% EtOAc/hexanes). LCMS calc.=471.19; found=471.2 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 91 %

Procedure:
A mixture of 4-bromo-2-methoxy-1-nitrobenzene, (I24) (2.364 g, 10.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (3.00 g, 9.70 mmol), potassium carbonate (4.02 g, 29.1 mmol) and DMF (60 mL) was degassed with three vacuum/nitrogen cycles then PdCl2(dppf)-DCM solvate (450 mg, 6 mol %) added under nitrogen in a Schlenk tube. A second tube was prepared in the same manner (i.e. a total of 6.00 g starting boronate), and both tubes were heated to 85° C. under nitrogen. After 17 hours both tubes were cooled under nitrogen and added to 5% w/v aqueous lithium chloride (600 mL). The resulting mixture was extracted with ether (300 mL) and ethyl acetate (3×300 mL). The combined organic extracts were washed with water (600 mL) and brine (600 mL), dried (sodium sulphate) then evaporated to dryness. The residue was chromatographed (120 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I25) (5.863 g, 91% yield) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.5 Hz, 1H), 7.04-6.97 (m, 2H), 6.17 (s, 1H), 4.12 (d, J=2.5 Hz, 2H), 3.98 (s, 3H), 3.65 (t, J=5.6 Hz, 2H), 2.52 (s, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.27 min; m/z 279.0 [M-tBu+2H]+, 235.1 [M-Boc+2H]+.
Reaction SMILES: Cl[C:2]1(Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[N:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3]1=[O:19]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:3](=[O:19])[CH2:2]2
Reactant: COC(=O)CN1C(=O)C(Cl)(Cl)c2cc([N+](=O)[O-])ccc21
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CN1C(=O)Cc2cc(N)ccc21
Reaction time: 2 h
Yield: 55.4 %

Procedure:
To a suspension of methyl 2-(3,3-dichloro-5-nitro-2-oxoindolin-1-yl)acetate (0.314 g, 0.984 mmol) in acetic acid (10 ml), zinc powder (0.901 g, 13.78 mmol) was added potion wise at room temperature, and the mixture was stirred for 2 hours. Then the mixture was diluted with ethyl acetate, the solid was filtered off and washed with ethyl acetate and water. The filtrate was basified with solid K2CO3 (pH=8), and the phases were separated. The aqueous phase was extracted with DCM, and the combined organic layers were dried over sodium sulfate. The solvent was removed, and the crude was purified by filtration on silica gel cartridge (DCM:EtOAc from 80:20 to 50:50) affording methyl 2-(5-amino-2-oxoindolin-1-yl)acetate (0.120 g, 0.545 mmol, 55% yield). MS/ESI+ 220.9 [MH]+.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][C:4]2([CH2:9][C@@H:8]([C:10]([OH:12])=[O:11])[N:7]([C:13](=[O:23])[C@H:14]([CH:20]([CH3:22])[CH3:21])[NH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:6]2)[CH2:3]1.[CH3:25][O:26][C:27]([NH:29][C@H:30]([C:34]([N:36]1[CH2:62][CH2:61][CH2:60][C@H:37]1[C:38]([O:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([C:56](=[O:59])[CH2:57]Br)=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)=[O:43])=[O:39])=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28]>>[F:24][C:2]1([F:1])[CH2:5][C:4]2([CH2:9][C@@H:8]([C:10]([O:12][CH2:57][C:56]([C:53]3[CH:54]=[CH:55][C:50]([C:47]4[CH:46]=[CH:45][C:44]([C:42](=[O:43])[CH2:41][O:40][C:38]([C@@H:37]5[CH2:60][CH2:61][CH2:62][N:36]5[C:34](=[O:35])[C@@H:30]([NH:29][C:27]([O:26][CH3:25])=[O:28])[CH:31]([CH3:33])[CH3:32])=[O:39])=[CH:49][CH:48]=4)=[CH:51][CH:52]=3)=[O:59])=[O:11])[N:7]([C:13](=[O:23])[C@@H:14]([NH:15][C:16]([O:18][CH3:19])=[O:17])[CH:20]([CH3:21])[CH3:22])[CH2:6]2)[CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)CBr)cc2)cc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)O)CC(F)(F)C2)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc(-c2ccc(C(=O)COC(=O)[C@@H]3CC4(CN3C(=O)[C@@H](NC(=O)OC)C(C)C)CC(F)(F)C4)cc2)cc1)C(C)C
Yield: 76 %

Procedure:
This compound was prepared in an analogous fashion to 117 (Example 17) from (7S)-2,2-difluoro-6-{N-[(methyloxy)carbonyl]-L-valyl}-6-azaspiro[3.4]octane-7-carboxylic acid (156) (59 mg, 0.17 mmol) and 2-[4′-(bromoacetyl)-4-biphenylyl]-2-oxoethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate (70) (95 mg, 0.16 mmol) to afford the title compound as a white solid (104 mg, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][N:18]2[C:19](=[O:29])[CH2:20][C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:26][C:27]2=[O:28])[CH2:13][CH2:14]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Solvent: CO
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2cc(F)ccc2F)CC1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(2,5-difluorophenyl)piperazine (100 mg, 0.51 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione (100 mg, 0.44 mmol) was heated with stirring at 160° C. for 5 hours. The residue was dissolved in methanol, transferred to a preparative thin layer chromatographic plate (silica gel), and eluted with ethyl acetate/hexane (1:1). A band at Rf=0.7 was removed and rinsed with chloroform/methanol (4:1). The solvent was removed, giving the title compound as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ6.99-6.89 (11-line m, 1H), 6.65-6.52 (m, 2H), 3.95 (t, 2H, J=6.5 Hz), 3.03 (t, 4H, J=4.7 Hz), 2.66 (t, 4H, J=4.7 Hz), 2.60 (s, 4H), 2.54 (t, 2H, J=6.6 Hz), 1.74-1.69 (m, 4H), 1.55-1.51 (m, 4H); ESI-MS m/z 392 (MH+). The title compound was dissolved in ether and precipitated by addition of 1N HCl in ether, giving a white solid (64.9 mg, 0.15 mmol, 35%): mp 237-239° C., Anal. Calcd. for C21H27N3F2O2·HCl: C, 58.94; H, 6.59; N, 9.82; F, 8.88. Found: C, 58.70; H, 6.46; N, 9.68; F, 9.00.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH3:12].[Br:13]Br>C(O)(=O)C>[Br-:1].[Br-:13].[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH3:12]
Reactant: BrBr
Agent: Cc1nc2ccc(Cl)nn2c1Br
Solvent: CC(=O)O
Product: [Br-]

Procedure:
0.23 g (0.93 mMol) 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine obtained from Example 1 is dissolved in 2 ml concentrated acetic acid and treated with 1.39 mMol elemental bromine. From the reaction mixture crystallizes out after a little while 3-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine dibromide. This is filtered off and dried. Yield 0.38 g, (89.4%), M.pt 217°-220°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]([O:12][C:13]([NH:15][C:16](=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])SC)=[O:14])([CH3:11])([CH3:10])[CH3:9]>O1CCCC1.O>[C:23]([O:22][C:20]([N:19]=[C:16]([NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCCCC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N=C(NCCCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Aminobutyric acid (100 mg, 0.97 mmol) was dissolved in tetrahydrofuran (0.3 mL) and water (0.03 mL), combined with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (340 mg, 1.2 mmol) and stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was subjected to a column chromatography to obtain 4-(2,3-di-tert-butoxycarbonylguanidino)butyric acid (compound 8; yield: 181 mg).
Reaction SMILES: 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.Cl[C:44]1[C:45]2[C@H:52]([CH3:53])[CH2:51][CH2:50][C:46]=2[N:47]=[CH:48][N:49]=1.[CH2:54]([N:61]1[CH2:66][CH2:65][C:64]2([C:74]3[C:69](=[CH:70][CH:71]=[CH:72][C:73]=3[CH:75]([OH:77])[CH3:76])[NH:68][CH2:67]2)[CH2:63][CH2:62]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH2:54]([N:61]1[CH2:66][CH2:65][C:64]2([C:74]3[C:69](=[CH:70][CH:71]=[CH:72][C:73]=3[CH:75]([OH:77])[CH3:76])[N:68]([C:44]3[C:45]4[C@H:52]([CH3:53])[CH2:51][CH2:50][C:46]=4[N:47]=[CH:48][N:49]=3)[CH2:67]2)[CH2:63][CH2:62]1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(O)c1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)CC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
A flask was charged with Pd(OAc)2 (0.0027 g, 0.012 mmol) and Xantphos (0.010 g, 0.018 mmol) and purged with nitrogen. The flask was then charged with (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.022 g, 0.13 mmol), 1-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)ethanol (0.047 g, 0.12 mmol), Cs2CO3 (0.058 g, 0.18 mmol), and toluene (0.6 mL). The reaction was purged with nitrogen and heated to 100° C. for 3 hours. Additional (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine was added, and the reaction was heated at 100° C. for an additional 4 hours and then stirred at room temperature overnight. The reaction was filtered through GFF and concentrated under reduced pressure. The crude residue was purified by column chromatography (5% MeOH/DCM, then 5% 7N NH4 in MeOH/DCM) to yield 1-(1′-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)ethanol (0.017 g, 31%). LCMS (APCI+) m/z 455.2 [M+H]+; Rt=3.18 min.
Reaction SMILES: ClC1C2C(=CC(C)=CC=2)N=C(C(F)(F)C2C=CC(F)=CC=2)N=1.[F:23][C:24]([F:44])([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:25]1[N:34]=[C:33]([OH:35])[C:32]2[C:27](=[CH:28][C:29](C)=[CH:30][CH:31]=2)[N:26]=1>>[F:44][C:24]([F:23])([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:25]1[N:34]=[C:33]([OH:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1
Reactant: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Agent: Cc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Product: Oc1nc(C(F)(F)c2ccc(F)cc2)nc2ccccc12
Yield: 95 %

Procedure:
4-Chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline was obtained according to the procedure described in Example 26 for preparation of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazoline, substituting 2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazolin-4-ol in Example 26 with 2-(difluoro(4-fluorophenyl)methyl)quinazolin-4-ol (95% yield). LC-MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[S:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:72]>CO.O>[ClH:72].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[S:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-phenyl-4-thioxo-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and then chromatographed on a 5 g C18 cartridge {40 to 80% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a grey-green solid (17.2 mg, 64% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (br s, 3H), 8.53 (dd, J=8.3 and 1.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.61-7.57 (m, 1H), 7.48-7.39 (m, 5H), 7.34-7.26 (m, 4H), 2.57-2.49 (m, 4H), 2.23-2.13 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method E): RT=3.92 min, [M+H]+=384.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C.CO>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][OH:11])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a solution (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (26.1 g, 0.1 mol) in THF (500 mL), BH3.Me2S (80 mL, 0.8 mmol) was added dropwise at −78° C., then stirred at rt for 3 hrs. The reaction was stopped by careful addition of methanol. After evaporation and three distillations of methanol, the residue was dissolved in EtOAc, washed with 1 M NaHCO3, and brine. (S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (12 g, yield 49%) was obtained as an oil that was used in the next step without further purification.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[OH-].[Na+].[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1.O1CCOCC1>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:15]=[C:5]=[O:11])=[CH:17][C:18]=1[C:24]([F:25])([F:26])[F:27])#[N:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 1 h
Yield: 144.1 %

Procedure:
21.16 g of triphosgene are dissolved in 100 mL of anhydrous toluene in a 500 mL four-neck bottle equipped with a nitrogen intake, a magnetic stirrer, a condenser and a guard filled with 2 N sodium hydroxide. A solution of 20 g of 4-amino-2-trifluoromethylbenzonitrile in 125 mL of anhydrous dioxan is added dropwise at ambient temperature in 1 hour 30 min. The mixture is heated to 110° C. Pronounced release of gas for 1 hour then appearance of an insoluble brown substance. After 2 hours under reflux, stirring is maintained overnight at AT. The insoluble matter is filtered and rinsed with toluene. The filtrate is concentrated in order to obtain 21.8 g of expected product (Yd=96%). The product is stored in solution in THF (2 M) in a refrigerator.