Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccccn3)CC2)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
Sodium t-butylate (5.4 mmol, 3.0 eq.) was added to a stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.8 mmol, 1.0 eq.) and 2-bromopyridine (1.8 mmol, 1.0 eq.) in toluene (30 ml) and the reaction mixture was degassed with N2 for 15-20 min. BINAP (0.108 mmol, 0.06 eq.) and Pd(OAc)2 (0.036 mmol, 0.02 eq.) were added and the reaction mixture obtained is heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 30% ethyl acetate in hexane). Yield: 69%
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C([Mg]Cl)(C)C.C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>C1COCC1>[CH2:27]([O:26][C:24]([C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1)=[O:25])[CH3:28]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Reactant: CCOC(=O)C#N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a solution of 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at −40° C. was added drop wise a solution of 2M i-PrMgCl in THF (1 mL). The reaction was allowed to stir for 10 min at −40° C. and then cooled to −78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. The reaction allowed to attain RT and stirred for 1 h. The reaction was quenched with satd aq NH4Cl, diluted with EtOAc (20 mL) and washed with brine (2×20 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.4 g (74%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H). found 296.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.Cl>O1CCOCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[N:3]=[C:4]([OH:19])[C:5]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)cc1
Reactant: Oc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Agent: Cl
Solvent: C1COCCO1
Product: Oc1nc(NCc2ccc(F)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 93.3 %

Procedure:
A solution of 2-chloro-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ol (730 mg) and 4-fluorobenzyl amine (398 mg) in 1,4-dioxane (20 mL) was heated at 80° C. overnight. 1N HCl (5 ml) was added to the mixture and the resulting solid was filtered to provide 0.9 g of 2-(4-fluorobenzylamino)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4-ol which was characterized by its mass spectrum as follows: MS (m/z) 365 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=4[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]3=[O:18])[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccc(C)cc21
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Yield: 67 %

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 6 parts (67%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][C:33]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45].[Cl-].[NH4+]>O1CCCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[C@@H:25]([CH:26]([CH3:27])[CH3:28])[CH2:36][C:35]1[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[C:33]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:34]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCCCOc1cc(CBr)ccc1OC
Reactant: CC(C)CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C(C)C)ccc1OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
600 ml of tetrahydrofuran are added to a solution of 600 ml of 1M lithium hexamethyldisilazide and the mixture is stirred at -70° C. Then a solution of 156.6 g of 4(R)-benzyl-3-isovaleroyl-oxazolidin-2-one in 500 ml of tetrahydrofuran is added dropwise and the reaction mixture is stirred for a further 75 minutes at -70° C. Then a solution of 145 g of 4-methoxy-3-(3-methoxypropyloxy)-benzyl bromide in 500 ml of tetrahydrofuran is added dropwise. The temperature of the reaction mixture is allowed to rise from -70° to 0° C. over a period of 2 hours. The reaction mixture is left to stand for a further 18 hours at 4° C. and then, with stirring, 250 ml of saturated ammonium chloride solution are added. The tetrahydrofuran is evaporated off and the residue is extracted with ethyl acetate. The title compound is obtained from the residue of the extracts by purification by means of FC (2.4 kg of silica gel, ethyl acetate/hexane=1:1): Rf (ethyl acetate/hexane=1:2)=0.30; m.p. 55°-56° C.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[OH:11][CH2:12][CH:13]([CH2:19][N:20]1[CH2:24][CH:23]([CH2:25][CH2:26][CH3:27])[CH2:22][C:21]1=[O:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(Cl)Cl>[CH:12]([CH:13]([CH2:19][N:20]1[CH2:24][CH:23]([CH2:25][CH2:26][CH3:27])[CH2:22][C:21]1=[O:28])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11]
Reactant: CCCC1CC(=O)N(CC(CO)C(=O)OCC)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCC1CC(=O)N(CC(C=O)C(=O)OCC)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, DMSO (dried on CaH2, 0.83 g, 0.01 mol) in CH2Cl2 (5 ml) is added onto a solution of (COCl)2 (0.72 g, 0.0052 mol) in CH2Cl2 (5 ml) cooled at −78° C. After 0.5 h at −78° C., ethyl 3-hydroxy-2-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]propanoate x279 (0.92 g, 0.0035 mol) in CH2Cl2 (10 ml) is added, stirred for 2.5 h at −60° C., quenched with Et3N (2.75 ml), stirred overnight at 4° C., washed with saturated NH4Cl and extracted 3 times with CH2Cl2. The combined organic phases are dried over MgSO4, filtered, concentrated in vacuo to give the crude x280 (1.2 g) which is used in the next step without any further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(F)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 51.8 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.16 g of 4-fluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 4-(4-fluorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (35)), m.p.: 81.4° C.
Reaction SMILES: CO[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[C:24]([NH:25][NH2:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:27])[CH:21]=2)[N:16]=1>>[Cl:14][C:15]1[C:24]2[N:23]([C:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:26][N:25]=2)[C:22]2[C:17]([N:16]=1)=[CH:18][CH:19]=[C:20]([Cl:27])[CH:21]=2
Reactant: COC(OC)(OC)c1ccccc1
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Product: Clc1ccc2nc(Cl)c3nnc(-c4ccccc4)n3c2c1
Temperature: 120 °C

Procedure:
In a 250 ml. three-necked reaction flask equipped with mechanical stirrer and reflux condenser, there were placed 50.0 g. (0.274 mole) of trimethyl orthobenzoate that had been preheated to ca. 70° C. Stirring was commenced and 10.0 g (0.0437 mole) of 2,6-dichloro-3-hydrazinoquinoxaline, the product of Preparation L(a), were added thereto. The resulting reaction mixture was then heated at ca. 120° C., with continued stirring, for a period of 24 hours, followed by cooling to room temperature (~20° C.) and stirring overnight for approximately 16 hours to give a yellow slurry. The latter slurry was then filtered, and the recovered solid product was subsequently washed with two-50 ml. portions of ethanol and air-dried to constant weight to ultimately afford 9.8 g. (72%) of crude 4,8-dichloro-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 305°-307° C. Mass Spectrum: m/e, 316/314 (P+).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=O.[CH3:27][CH2:28][O:29][C:30]([CH:32](P(OCC)(OCC)=O)[CH3:33])=[O:31].Cl.C(O)C>O1CCCC1>[CH2:28]([O:29][C:30](/[C:32](/[CH3:33])=[CH:3]/[C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=[O:31])[CH3:27]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
0.52 g (0.013 mol) of sodium hydride was added to a solution of 4.00 g (0.0117 mol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 250 ml of tetrahydrofuran. 2.8 ml (0.013 mol) of triethyl 2-phosphonopropionate was dropped into the mixture prepared above under stirring and cooling with ice. The mixture thus prepared was stirred under cooling with ice for a while, heated to room temperature and stirred for additional one hour, followed by the addition of 1.5 ml of 8M hydrochloric acid/ethanol. The obtained mixture was passed through a small amount of silica gel and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 2.00 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[I-].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([Zn+])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C(=O)C.[Cu]I.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]>[O:11]=[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[N:14][CH:13]=1)[CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC([Zn+])CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1C(CC(=O)c1ccnnc1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 85 °C
Yield: 28.8 %

Procedure:
To a yellow solution of 3-(4-bromophenyl)-1-(pyridazin-4-yl)-3-o-tolylpropan-1-one (example 2, step 3; 180 mg, 472 μmol) in N,N-dimethylacetamide (4 mL) were added copper(I) iodide (9 mg, 47 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (17.3 mg, 23.6 μmol) and (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide solution (0.5 M in N,N-dimethylacetamide, 1.9 mL, 0.95 mmol; J. Org. Chem. 2004, 69, 5120). The reaction mixture was heated at 85° C., then after 5 h another portion of copper(I) iodide (9 mg, 47 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.3 mg, 23.6 μmol) was added, then after 1 h the reaction mixture was partitioned between sat, aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate/heptane 1:1 and insoluble material was removed by filtration. The filtrate was purified by chromatography (SiO2; ethyl acetate/heptane 1:1) to produce the title compound (66 mg, 29%). Orange foam, MS: 486.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1/[CH:4]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[S@](=O)/N=C/c1cc(F)ccc1Br
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-5-fluorobenzaldehyde (2.44 g, 12.0 mmol) and (S)-(−)-2-methyl-2-propane-sulfinamide (1.45 g, 12.0 mmol) in THF (30 mL, anhyd.) was added titanium tetraethoxide (2.8 mL, 13.2 mmol, tech) at room temperature. After stirring 16 hours the reaction mixture was charged with brine (25 mL) and EtOAc (40 mL). After stirring 10 minutes the mixture was filtered through a pad of Celite™. Combined filtrates were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica chromatography with EtOAc/Hex (0-25%) as eluent to give (S,E)-N-(2-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (I-44) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.94 (d, J=2.2 Hz, 1 H), 7.77 (dd, J=3.1, 9.1 Hz, 1 H), 7.64 (dd, J=5.0, 8.8 Hz, 1 H), 7.12 (ddd, J=3.1, 7.5, 8.8 Hz, 1 H), 1.30 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[OH:12])=[CH:9][N:10]=2)[N:7]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Solvent: CC(C)=O
Product: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Yield: 95 %

Procedure:
To a suspension of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-fluoro-quinolin-6-yl)-methanol (1.8 g, 5.48 mmol) in acetone (200 mL) was added IBX (8.52 g, 45%, 13.69 mmol). The reaction mixture was stirred at reflux for 1 day. Then the solvent was removed under reduced pressure and the residue was dissolved in 200 mL of water. The solution was basified by 3N NaOH solution and the precipitate was collected, washed with water and dried over vacuum oven to afford 1.7 g (95%) of the title compound as a gray solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.04 (dd, 1H), 8.56 (d, 1H), 8.47 (m, 2H), 8.41 (s, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.64 (q, 1H). LCMS (method B): [MH]+=327, tR=2.03 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(CC)CC.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][C:30]=1[O:39][CH3:40]>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([NH:11][C:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([NH:2][S:35]([C:32]3[CH:33]=[CH:34][C:29]([OH:28])=[C:30]([O:39][CH3:40])[CH:31]=3)(=[O:37])=[O:36])[CH2:4][CH2:5]2)=[O:10])[CH3:13])=[CH:15][CH:16]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](N)CC1)c1ccc(F)cc1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trans-4-Amino-N—((R)-1-(4-fluorophenyl)ethyl)cyclohexanecarboxamide hydrochloride (Intermediate 45, 200 mg, 0.66 mmol) and Et3N (371 ul, 2.66 mmol) were dissolved in DCM (10 ml). 4-Hydroxy-3-methoxy-benzenesulphonyl chloride (178 mg, 0.798 mmol) was added, and the reaction mixture was stirred for 3 hr at room temperature, after which LCMS indicated that the reaction was complete. The mixture was concentrated in vacuo, and the crude material was purified via reverse phase chromatography on prep-HPLC (150 mm, C8 luna, 15-20 min run, 10%-100% MeCN in water containing 0.1% TFA). Fractions containing the product were lyophilized to yield the title compound as a white solid (14 mg, 0.031 mmol). MS MH+ 451.1
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:30])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:21]([C:20]([OH:30])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (116.8 g, 0.49 mol) in CH2Cl2 (260 ml) was added dropwise over 90 min to a stirred solution of (4-chloro-phenyl)-propynoic acid ethyl ester (72.0 g, 0.34 mol) and trifluoroacetic acid (2.5 ml, 0.03 mol) in CH2Cl2 (350 ml). The reaction mixture was stirred at 25° C. overnight and afterwards evaporated to dryness. The residue was dissolved in dioxane (0.8 l); an aqueous solution of NaOH (91.0 ml, 1.02 mol, 3 eq.) was added, and the resulting emulsion was stirred at r.t. for 48 h. The low boiling organic solvent was removed under vacuum, water (0.9 l) was added, and the aqueous layer was separated and washed with TBME (1 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight; the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 62.0 g (60%) of IIa as a white solid.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(OCC)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Reaction time: 0.33 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 20 parts by volume of glacial acetic acid and 12.3 parts of acetic anhydride. Anhydrous magnesium acetate, 0.40 parts, was added to the slurry which thinned briefly and then thickened rapidly. After 20 minutes, the slurry was thinned by addition of 10 parts by volume of dry ethyl acetate. The resulting slurry was again thinned after an additional 15 minutes upon addition of 10 parts by volume of dry ethyl acetate. The product was collected on a filter under nitrogen after a total reaction time of 60 minutes. After the solid was rinsed with dry ethyl acetate, it was dried in a vacuum dessicator at 0.1 mm to afford 17.2 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:16]C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[Br:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCc1cccc(Br)c1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1ccccc1Br
Yield: 80 %

Procedure:
The title compound was prepared as described for B4 using 3-bromobenzyl bromide (1.250 g, 5.00 mmol), magnesium (0.134 g, 5.50 mmol) and diethyl oxalate (1.462 g, 10.00 mmol). The product was isolated in the form of colorless oil in 80% yield and use instantly in next step.