Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](=[O:16])([S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH3:6].Cl[C:18](=[O:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[C:5]([S:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[C:18](=[O:30])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1)(=[O:16])[CH3:6]
Reactant: COC(=O)c1ccc(CC(=O)Cl)cc1
Reactant: COc1cccc(SC(C)=O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)c2ccc(OC)cc2SC(C)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.3 %

Procedure:
To a suspension of aluminum trichloride (9.9 g, 74.08 mmol) in DCM (100 ml) was added S-3-methoxyphenyl ethanethioate (step 1) (4.5 g, 30.57 mmol) at 0-5° C., followed by a solution of methyl 4-(2-chloro-2-oxoethyl)benzoate (step 2) (4.5 g, crude, 24.69 mmol) in DCM (20 ml). The mixture was stirred at room temperature for 3 days. The mixture was poured carefully into icy 1 N HCl (200 ml) and extracted with EtOAc (50 ml×2). The combined organic layers were washed with water (100 ml×2) and brine (100 ml), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (PE/EtOAc=15/1 to 10/1) to afford Intermediate F as a yellow solid (1.8 g, 14%). MS (ESI): m/z 359.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COCc1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (4-bromophenyl)methanol (1.0 g, 5.35 mmol) in DCM (25 mL) cooled in an ice bath was added rhodium(II) acetate dimmer (0.236 g, 0.535 mmol). To the resulting mixture was slowly added a solution of ethyl diazoacetate (0.721 mL, 6.95 mmol) in DCM (1 mL). The reaction mixture was stirred for 0.5 h. Additional ethyl diazoacetate (300 μL) was added and the resulting mixture was stirred for an additional 0.5 h. The mixture was concentrated and the residue was purified by chromatography (0, 5, 10, 15% EtOAc/Hexanes) to give the title compound. LCMS m/z=273.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.1 Hz, 3H), 4.12-4.15 (m, 2H), 4.16 (s, 2H), 4.52 (s, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7](B(O)O)=[CH:6][N:5]=[C:4]2[N:11]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[O:21][CH3:22])[C:3]=12.[CH3:31][N:32]([CH3:43])[C:33]([C:35]1[C:40]([NH2:41])=[N:39][CH:38]=[C:37](I)[N:36]=1)=[O:34].C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.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]>[CH3:31][N:32]([CH3:43])[C:33]([C:35]1[C:40]([NH2:41])=[N:39][CH:38]=[C:37]([C:7]2[C:2]([Cl:1])=[C:3]3[C:13]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[O:21][CH3:22])=[CH:12][N:11]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:4]3=[N:5][CH:6]=2)[N:36]=1)=[O:34]
Reactant: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncc(B(O)O)c(Cl)c12
Reactant: CN(C)C(=O)c1nc(I)cnc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(F)cc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(N)c(C(=O)N(C)C)n3)c(Cl)c12
Temperature: 110 °C
Yield: 47.3 %

Procedure:
42 mg (93 μmol) of 4-chloro-3-(5-fluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine-5-boronic acid, 5 mg (6 μmol) of (1,1′-bis(diphenylphosphino)ferrocene palladium(II)-dichloride dichloromethane adduct and 41 mg (0.14 mmol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid dimethylamide were dissolved in a mixture of 1 mL of acetonitrile and 1 mL of toluene. 2 mL of a saturated aqueous solution of sodium bicarbonate was added and the resulting mixture heated in closed vial to 110° C. for 20 h. The aqueous layer was removed and the organic phase evaporated. The residue was purified by flash chromatography on silica gel using a gradient of 10% v/v of methanol in ethyl acetate and hexanes to afford 25 mg (44 μmol, 47%) of 3-amino-6-[4-chloro-3-(5-fluoro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazine-2-carboxylic acid dimethylamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[N-:12]=[N+:13]=[N-:14].[Na+]>CC#N>[N:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]1=[O:11])=[N+:13]=[N-:14]
Reactant: O=C1CCc2c(F)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NC1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
A solution of 4-fluoro-2,3-dihydro-1H-inden-1-one (1.29 g, 9.34 mmol) and HNIB (5.02 g, 12.1 mmol) in CH3CN (190.0 mL) was refluxed for 1.5 h, until the solution was clear yellow. Upon cooling to r.t., NaN3 (1.21 g, 18.7 mmol) was added and the solution was stirred at r.t. for 12 h. Additional NaN3 (0.50 g, 7.7 mmol) was added and the solution stirred further at r.t. for 4 h. The reaction mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL). This solution was washed with H2O (75 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 5:1 hexanes/EtOAc) to give 1.61 g (96% yield) of 2-azido-4-fluoro-2,3-dihydro-1H-inden-1-one: 1H NMR (400 MHz, CDCl3): 7.59 (d, 1H), 7.41 (m, 1H), 7.32 (t, 1H), 4.15 (dd, 1H), 3.55 (dd, 1H), 2.89 (dd, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[C:33](OCC)(=[O:35])C.Cl>C[O-].[Na+].CO>[CH3:33][O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=4[C:25]([OH:27])=[O:26])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1cccc(CO[C@H]2CCC[C@@H](OCc3coc(-c4ccc(F)cc4)n3)C2)c1C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(CO[C@@H]3CCC[C@H](OCc4cccc(C)c4C(=O)O)C3)co2)cc1

Procedure:
170 mg (0.39 mmol) of 6b were heated in 4 ml of 5.6 M NaOMe/MeOH solution at an oil bath temperature of 120° C. for 20 hours. Ethyl acetate and 2 N HCl were added, and the mixture was then worked up analogously to the synthesis of 6b. This gave 7b as a colorless amorphous solid. TLC: (methylene chloride/methanol/conc. ammonia, 30/5/1). Rf˜0.3. C26H29NO6 (451.52) MS(ESI): 452 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O:15][C:16]([NH:18][C@@H:19]([CH3:23])[C:20](O)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[C:11]([O:15][C:16]([NH:18][CH:19]([CH3:23])[C:20]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1cccn1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn1NC(=O)C(C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
Methyl 1-amino-1H-pyrrole-2-carboxylate (6 g, 48.1 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (8.10 g, 48.1 mmol) were dissolved in ethyl acetate (40 ml) and cooled in an ice-bath. Under an argon atmosphere, diisopropylethylamine (24.6 ml, 141.2 mmol) was added and, after stirring for 15 min, T3P solution (35.7 ml, 60 mmol, 50% in ethyl acetate) was dropwise added. After stirring for 20 min at 0° C., the reaction was left overnight at room temperature. The reaction mixture was poured onto water and extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate and the solvent evaporated under reduced pressure. 8.6 g (83% yield) of the final product was obtained and use in the next synthetic step without further purification.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
A solution of the product of Example 2 (0.95 g) in ethanol (20 ml) was treated at 0° with sodium borohydride (0.76 g). The mixture was stirred for 30 min. and extracted with ethyl acetate. After evaporation of the solvent the residue was purified by column chromatography on silica gel eluting with cyclohexane/ethyl acetate 1:1 to give the title compound (0.2 g) as a white solid. M.p. 163°-164°. T.l.c. (cyclohexane/ethyl acetate 1:1) Rf 0.23.
Reaction SMILES: [C:1]([N:3]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[O:31][CH:32]=2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)#[N:2].Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CN(C=O)C>[NH2:2]/[C:1](/[N:3]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([CH:33]3[CH2:34][CH2:35]3)[O:31][CH:32]=2)=[CH:24][CH:23]=1)[CH2:4][CH2:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=[N:37]\[OH:38]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(C#N)Cc2ccc(-c3coc(C4CC4)n3)cc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(-c3coc(C4CC4)n3)cc2)/C(N)=N/O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.5 %

Procedure:
To a solution of ethyl 2-[4-(2-{cyano[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.38 g, 0.80 mmol) in DMF (2 ml) was added hydroxylamine hydrochloride (0.20 g, 2.94 mmol) followed by sodium acetate (2.88 g, 3.59 mmol). The mixture was stirred at rt for 12 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (2×20 ml). The combined organic phases were washed with brine, dried with MgSO4, and concentrated in vacuo to yield ethyl 2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.46 g) which was used directly without purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:23](NN)[CH3:24]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: CCNN
Product: CCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reaction time: 16 h

Procedure:
Compound 18 was synthesised following similar procedures outlined in Example 22 (Compound 9), using ethyl hydrazine instead of hydrazine hydrate in Step 3. As a slightly modified procedure, Step 3 was performed at 90° C. for 16 h in a sealed tube. Subsequently, the reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated using a phase separating cartridge and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 5% ethyl acetate/isohexane) yielding Compound 18 as a solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19](C)(C)C)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16]([C@@H:15]1[CH2:23][CH2:24][C@H:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Temperature: 4 °C

Procedure:
0.6 g of tert-butyl cis-4-(4-methoxycarbonylcyclohexyloxy)benzoate (1.79 mmol, 1 eq.) is placed in 2.5 mL of dichloromethane. The reaction medium is cooled to a temperature of 4° C. with stirring in an ice bath. 1 mL of trifluoroacetic acid (13.46 mmol, 7.5 eq.) is added and the ice bath is removed. After stirring for 5 hours at room temperature, the medium is concentrated, taken up in diethyl ether, drained and filtered to give 0.30 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid. M+H+=279.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[N:8]=2)=[CH:5][NH:4][N:3]=1.[CH:28]1([CH:33]=[CH:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH:28]1([CH:33]([N:4]2[CH:5]=[C:6]([C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[C:9]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:8]=3)[C:2]([CH3:1])=[N:3]2)[CH2:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: N#CC=CC1CCCC1
Reactant: Cc1n[nH]cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1nn(C(CC#N)C2CCCC2)cc1-c1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
Reaction time: 8 h
Yield: 41.3 %

Procedure:
4-(4-(5-(3-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0690 g, 0.191 mmol), 3-cyclopentylacrylonitrile (Table 1, compound g; 0.0696 g, 0.574 mmol) and DBU 0.0661 mL, 0.479 mmol) were suspended in DMF (3 mL) and stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5-2% (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(3-methyl-4-(7-(4-morpholinophenyl) imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.0380 g, 0.078905 mmol, 41.2% yield). MS (apci) m/z=482.2 (M+H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[O-]CC.[Mg+2].[O-]CC.[Cl:17][C:18]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1C(O)=O.C(OCC)(=O)C>O1CCCC1.CCCCCC>[Cl:27][C:25]1[N:26]=[C:18]([Cl:17])[CH:19]=[CH:23][C:24]=1[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: CC[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
Monoethyl malonate (6.61 g, 50.0 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), and after adding magnesium ethoxide (3.15 g, 28.0 mmol) thereto while cooling with ice, it was stirred at room temperature for 3 hours. The reaction solution was then concentrated under a reduced pressure, thereby preparing a magnesium salt of monoethyl malonate. 2,6-dichloronicotinic acid (3.84 g, 20.0 mmol) was then dissolved in anhydrous tetrahydrofuran (80 ml), and after adding 1,1-carbonyldiimidazole (4.87 g. 30.0 mmol) while cooling with ice, it was stirred at room temperature for 1.5 hours. To this solution, a solution, wherein the previously prepared magnesium salt of monoethyl malonate was dissolved in anhydrous tetrahydrofuran (160 ml), was added dropwise over a period of 10 minutes while cooling with ice. After completion of dripping, the temperature was gradually brought back to room temperature and thereafter, stirring was performed for 4 hours. After adding ethyl acetate (200 ml) to the reaction solution, the organic layer was washed with a 10% aqueous citric acid solution (150 ml×2), saturated sodium bicarbonate water (150 ml), and saturated saline solution (150 ml), in that order, and then dried over anhydrous sodium sulfate. After filtering, the residue obtained by concentration under a reduced pressure of the filtrate was applied to a silica gel chromatography, and 4.24 g (81%) of the title compound was obtained in the form of a pale-pink, oily substance from an n-hexane:ethyl acetate=3:1 eluate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[CH2:33](I)[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:33]([N:30]1[CH2:31][CH2:32][CH:27]([N:25]2[CH:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([CH2:12][C:3]5[CH:4]=[C:5]6[C:10](=[CH:11][C:2]=5[F:1])[N:9]=[CH:8][CH:7]=[CH:6]6)=[CH:14][N:15]=4)[N:18]=3)[CH:23]=[N:24]2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol) and ethyliodide (19 μL, 0.234 mmol) in dioxane (1 mL) was stirred at rt for 2 h. Cs2CO3 (19 mg, 0.059 mmol) was then added and the RM was stirred at rt for 5 h more. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 9:1+NH3)=100:0→0:100) to afford the title compound as a foam (tR 3.10 min (conditions 3), MH+=456.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.50 (s, 1H); 8.34 (m, 1H); 8.08 (m, 2H); 8.04 (d, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.18 (m, 1H); 2.96 (m, 2H); 2.35 (q, 2H); 1.97 (m, 6H); 1.01 (t, 3H)).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:15])=O)=[CH:8]2)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([Cl:19])=[O:15])=[CH:8]2)#[N:2]
Reactant: N#Cc1cccc2cc(C(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cccc2cc(C(=O)Cl)ccc12

Procedure:
To a suspension of 5-cyano-naphthalene-2-carboxylic acid, 2, (0.084 g, 0.426 mmol) in CH2Cl2 (2 mL) at room temperature containing 1 drop of DMF is added oxalyl chloride (0.074 mL). Once the solution is homogeneous, the solution is concentrated in vacuo and the crude product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[OH:14].C(O)(=O)C>CO.[Fe]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[OH:14]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1O
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(N)c1O
Temperature: 25 °C

Procedure:
5-Chloro-2-hydroxy-3-nitro-benzoic acid methyl ester 1 g (4.31 mmol) is dissolved in methanol (30 mL) and acetic acid (30 mL) and then iron powder is added (4.8 g, 86 mmol) at room temperature. The resulting suspension is stirred and heated to reflux for 1 hour. The reaction is allowed to cool to room temperature and then gravity filtered though a pad of celite. The celite cake is washed 3× with ethyl acetate (50 mL) and then the combined washings evaporated in vacuo. The oil is then taken up in ethyl acetate (250 mL) and washed with water (100 mL) and saturated sodium bicarbonate (100 mL). The organic layer is dried (MgSO4), decolorized with charcoal, filtered and evaporated to give the title compound that is used without further purification (730 mg, 3.6 mmol, 84%). LCMS (ESMS): m/z 202.5 (M+H+).
Reaction SMILES: N[C:2]1[N:7]([C:8]2[C:9]([F:21])=[CH:10][C:11]([Cl:20])=[C:12]([CH:19]=2)[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6](=[O:22])[N:5]=[CH:4][C:3]=1[C:23]#[N:24].Cl.C([OH:29])(C)C>>[Cl:20][C:11]1[CH:10]=[C:9]([F:21])[C:8]([N:7]2[C:2](=[O:29])[C:3]([C:23]#[N:24])=[CH:4][NH:5][C:6]2=[O:22])=[CH:19][C:12]=1[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)OC(=O)c1cc(-n2c(N)c(C#N)cnc2=O)c(F)cc1Cl
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]cc(C#N)c2=O)c(F)cc1Cl

Procedure:
3.40 g of isopropyl 5-[6-amino-5-cyano-2-oxo-1(2H)-pyrimidinyl]-2-chloro-4-fluorobenzoate in a solution of 100 ml isopropanol and 10 ml of 2N hydrochloric acid are stirred for 1 hour at room temperature. The reaction mixture is substantially concentrated under reduced pressure and extracted with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution, thereafter with water, and dried over anhydrous sodium sulphate. Then the organic phase is evaporated to dryness under reduced pressure and the residue dissolved in diethyl ether and the solution treated with charcoal and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. Isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 143°-145° C., is obtained.
Reaction SMILES: C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25])=[C:20]([C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH:19]=1.[CH3:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[C:51](=[O:52])[N:50]3[C:45]([C:46](=[O:53])[O:47][CH2:48][CH2:49]3)=[CH:44][CH:43]=2)[CH:41]=1>O1CCCC1>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH:26][C:46]([C:45]2[N:50]([CH2:49][CH2:48][OH:47])[C:51](=[O:52])[C:42]([N:40]3[CH:41]=[C:37]([CH3:36])[N:38]=[CH:39]3)=[CH:43][CH:44]=2)=[O:53])[CH3:25])=[C:20]([C:29]([CH3:34])([CH3:35])[C:30]([F:31])([F:32])[F:33])[CH:19]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Reactant: C[C@H](N)COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)COc3ccc(Cl)cc3C(C)(C)C(F)(F)F)n(CCO)c2=O)cn1
Temperature: 40 °C

Procedure:
Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (97%, 398 mg, 1.51 mmol) was added portion-wise over 5 minutes to a solution of (2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine (C50) (400 mg, 1.51 mmol) in tetrahydrofuran (8 mL), and the reaction mixture was heated to 40° C. for 45 minutes. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (555 mg, 2.26 mmol) was then added portion-wise over a period of approximately 5 minutes, and the reaction mixture was heated to 70° C. for 6 hours, whereupon it was cooled to 0° C. and slowly quenched with aqueous hydrochloric acid (1 M, 1 mL). After addition of water, the mixture was extracted three times with dichloromethane; the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale yellow solid, which was used in the next step without additional purification. Yield: 690 mg, 1.28 mmol, 85%. LCMS m/z 541.3, 543.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.41 (d, J=6.8 Hz, 3H), 1.69 (br s, 6H), 2.23 (d, J=1.0 Hz, 3H), 3.85 (t, J=5.8 Hz, 2H), 4.05 (dd, half of ABX pattern, J=9.6, 5.4 Hz, 1H), 4.14 (dd, half of ABX pattern, J=9.6, 6.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 2H), 4.48-4.57 (m, 1H), 6.54 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.24-7.26 (m, 1H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.37-7.40 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H).