Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(CC)CC>COCCOC>[CH3:15][CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:5]3[N+:4]([O-:16])=[N:3][C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:7][C:6]=3[CH:8]=2)[CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: CC1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Yield: 95.5 %

Procedure:
A solution of chloride 95 (367 mg, 1.6 mmol), 3-(4-morpholinyl)propylamine (0.34 mL, 2.3 mmol) and Et3N (0.33 mL, 2.3 mmol) in DME (50 mL) was stirred at reflux temperature for 8 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 98 (525 mg, 98%) as a yellow solid: mp (MeOH/DCM) 138-140° C.; 1H NMR δ 8.04 (s, 1H, H-9), 7.35 (s, 1H, H-5), 6.10 (br t, J=5.0 Hz, 1H, NH), 3.75 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.56-3.61 (m, 2H, CH2N), 3.08-3.18 (m, 2H, CH2), 2.56-2.65 (m, 3H, CH, CH2), 2.44-2.52 (m, 6H, 3×CH2N), 1.83 (br p, J=6.5 Hz, 2H, CH2), 1.15 (d, J=6.1 Hz, 3H, CH3); 13C NMR δ 158.8, 154.2, 148.9, 142.8, 129.8, 120.7, 114.8, 67.0 (2), 57.3, 53.8 (2), 41.2, 40.8, 40.4, 34.9, 25.3, 20.4. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.2; H, 7.2; N, 20.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][C:27]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CN(C)c1ccc(Nc2nc(Cl)ncc2Cl)c(S(=O)(=O)N(C)C)c1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N(C)C)cc4S(=O)(=O)N(C)C)n3)cc21

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-dimethylamino-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as a tan solid (0.077 g, 64%). MP: 240-243° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.90 (s, 1H), 8.15 (d, J=9.1 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.30-7.19 (m, 2H), 7.14 (d, J=3.0 Hz, 1H), 6.93 (br s, 1H), 6.85 (dd, J=9.2 Hz and 2.9 Hz, 1H), 3.75-3.62 (m, 2H), 3.02 (s, 6H), 2.72 (s, 6H), 2.37-2.26 (m, 2H), 2.10-1.95 (m, 2H), 1.32 (s, 6H), 1.17 (t, J=7.1 Hz, 3H). MS: 586.24 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:31])[CH2:28][CH2:29][CH3:30].O>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 12 h

Procedure:
To a solution of 6 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine and 5.1 ml diisopropylethylamine in 500 ml dichloromethane was added 3.1 ml of butyryl chloride. This solution was stirred for 12 hours then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and the solid chromatographed on 500 g silica gel with dichloromethane-methanol (95:5). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystallized from dichloromethane-hexane to give 5.58 g of white crystals, mp 195°-198° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11](O)[CH3:12]>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CCO
Reactant: Cc1cnc(C(=O)O)cn1
Product: CCOC(=O)c1cnc(C)cn1
Yield: 67 %

Procedure:
A solution of 5-methylpyrazine-2-carboxylic acid (15.0 g, 0.109 mol) in ethanol (70.0 mL) containing (1.5 g, 0.0079 mol) was heated to reflux for 4 h under argon atmosphere. The dark colored solution was cooled, added sod.bicarbonate (1.0 g) and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The organic layer was washed with water (2×25 mL), dried (Na2SO4), and concentrated under reduced pressure to afford ethyl 5-methylpyrazine-2-carboxylate (12.05 g, 67%) as an orange colored liquid: 1H NMR (CD3OD/400 MHz) δ9.1 (d. 1H, J=1.2 Hz), 8.62 (d, 1H, J=1.2 Hz), 4.45 (q, 2H, J=7.2 Hz), 2.63 (s, 3H), and 1.41 (t, 3H, J=7.2 Hz); ESMS m/z 167 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1F
Yield: 68.8 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11(v), ethyl 2-chloro-3-(2-fluorophenyl)-3-oxopropanoate (1.0 g, 4.09 mmol) produced in the above and 2-propanol (25 mL) as starting materials and in the same manner as in Example 11(vi), the title compound (341 mg, 68%) was obtained as a yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: OCCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCn1ccnc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Diethyl azodicarboxylate (295 μl, 1.8 mmol) was added dropwise to a solution of 1-(3-hydroxypropyl)imidazole (102 mg, 0.81 mmol), (EP 0060696 A1), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 24), and triphenylphosphine (492 mg, 1.8 mmol) in methylene chloride (4 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (60/35/5). The purified solid was dissolved in methylene chloride/methanol and 5M ethereal hydrogen chloride (2 ml) was added. The volatiles were removed by evaporation, the solid residue was suspended in ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-(imidazol-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (114 mg, 36%).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[C:35]([OH:38])(=[O:37])[CH3:36]>ClCCCl>[C:35]([O:38][CH2:23][C:14]1[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]2[C:12]([C:13]=1[C:24]1[C:33]3[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)(=[O:37])[CH3:36]
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reactant: CC(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CC(=O)OCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
1-Bromo-2,5-pyrrolidinedione (50 mg) was added to a solution of the product from Example 27 step b) (0.1 g) in 1,2-dichloroethane (5 ml) and acetic acid (2 ml), and the solution stirred for 1 hour. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid, which was filtered and dried to yield the title compound as a white solid (40 mg).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH2:7][C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:9].C(O)(C)C.C(O)(=O)C>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH2:7][CH:8]([OH:9])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.6 g (200 mmol) of sodium tetrahydridoborate were added at 0° C. to a solution of 36.8 g (100 mmol) of bis(3-bromobenzyl)ketone in a mixture of 500 ml of THF, 200 ml of isopropanol and 3 ml of acetic acid, and the mixture was stirred at 0° C. for a further 3 h. The ice bath was subsequently removed, and the mixture was stirred at room temperature for a further 12 h. After addition of 300 ml of saturated ammonium chloride solution, the organic phase was separated off, and the aqueous phase was extracted twice with 100 ml of dichloromethane. The combined organic phases were washed once with 500 ml of saturated sodium chloride solution and then freed from the solvent mixture in vacuo, giving 34.9 g (94 mmol), corresponding to 94.3% of theory, of the product in the form of an oil, 97% according to 1H-NMR, which were reacted further without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(Cl)Cl>O1CCOCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc([N+](=O)[O-])ccc2F)CC1
Temperature: 100 °C

Procedure:
Into a 1-neck round-bottom flask were added 2-bromo-1-fluoro-4-nitrobenzene (1760 mg, 8.000 mmol), potassium carbonate (2210 mg, 16.00 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2720 mg, 8.800 mmol), water (8 mL) and 1,4-dioxane (32 mL). The flask was degassed and filled with N2 for 3 times, and then [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with CH2Cl2 (1:1) (330.0 mg, 0.4000 mmol) was added. The mixture was degassed and filled with N2 for 3 times again and was then heated at 100° C. for 16 h. After that time, the mixture was concentrated in vacuo and was then purified by silica gel (240 g) eluting with 1800 mL of 5%, 1000 mL of 10%, 1000 mL of 15% and 1000 mL of 20% EtOAc/hexane to obtain the title compound as a colorless oil. 1H NMR (DMSO-d6, 400 MHz): δ=1.49 (s, 9H), 2.52-2.55 (m, 2H), 3.60 (t, 2H, J=5.6 Hz), 4.09 (brs, 2H), 6.21 (brs, 1H), 7.55-7.60 (m, 1H), 8.21-8.29 (m, 2H). MS (ES+): m/z 223.22 (100) [MH+-Boc]. HPLC: tR=3.83 min (ZQ2000, polar—5 min).
Reaction SMILES: C([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])(C)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C1(C#C)C=CC=CC=1>>[CH3:25][Si:26]([C:29]#[C:30][C:20]1[CH:19]=[C:18]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][N:11]=3)[C:16](=[O:17])[C:7]([C:5]([NH2:4])=[O:6])=[CH:8]2)[CH:23]=[CH:22][CH:21]=1)([CH3:28])[CH3:27]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#C[Si](C)(C)C
Solvent: C#Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-n2cc(C(N)=O)c(=O)c3cccnc32)c1

Procedure:
Following the procedure of Step 5 of EXAMPLE 1, but substituting the 1-(3-Bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from present Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for phenylacetylene, the 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was obtained as a solid.
Reaction SMILES: [Co].[Co:2](Cl)Cl.[CH3:5][CH:6]([C:8]1[CH2:17][CH2:16][CH:15]2[C:10](=[CH:11][CH2:12][CH:13]3[C:21]([C:23]([OH:25])=[O:24])([CH3:22])[CH2:20][CH2:19][CH2:18][C:14]32[CH3:26])[CH:9]=1)[CH3:7].[Na]>>[CH3:7][CH:6]([C:8]1[CH2:17][CH2:16][CH:15]2[C:10](=[CH:11][CH2:12][CH:13]3[C:21]([C:23]([O-:25])=[O:24])([CH3:22])[CH2:20][CH2:19][CH2:18][C:14]32[CH3:26])[CH:9]=1)[CH3:5].[CH3:7][CH:6]([C:8]1[CH2:17][CH2:16][CH:15]2[C:10](=[CH:11][CH2:12][CH:13]3[C:21]([C:23]([O-:25])=[O:24])([CH3:22])[CH2:20][CH2:19][CH2:18][C:14]32[CH3:26])[CH:9]=1)[CH3:5].[Co+2:2]
Reactant: CC(C)C1=CC2=CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Reactant: Cl[Co]Cl
Agent: [Co]
Agent: [Na]
Product: CC(C)C1=CC2=CCC3C(C)(C(=O)[O-])CCCC3(C)C2CC1
Product: [Co+2]

Procedure:
A cobalt salt of a monovalent acid, for instance, an aqueous solution of cobalt chloride, is added to a metal salt of a resin acid, for instance, aqueous solution of sodium gum rosinate at a temperature of not more than 50° C. to proceed the metathetical reaction, thereby producing the cobalt resinate. The resulting metal salt is precipitated without performing extraction with a solvent and separated through mechanical way such as a centrifugal separation or filter press. The resulting cobalt resinate was washed with water, and dried at a temperature of not more than 60° C.
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH:18]([NH2:20])[NH2:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)=O.C(OCC)(=O)C>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[NH:19][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[N:20]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)N)CC1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20 %

Procedure:
Suspend 4-Diaminomethyl-piperidine-1-carboxylic acid tert-butyl ester acetic acid salt (685 mg; 1.00 equiv; 2.38 mmoles) in dimethylformamide (10 mL; 129.33 mmoles) and add powdered potassium carbonate (1400 mg; 10.13 mmoles). Stir 10 minutes at room temperature then add 2-Bromo-1-(3-chloro-phenyl)-ethanone (1400 mg; 6.00 mmoles) dissolved in 4 mL DMF dropwise to the amidine at room temperature. After 3 h, dilute the reaction with ethyl acetate and wash with 50% aq. sodium bicarbonate. Dry the organic layer over sodium sulfate, filter and concentrate to a crude oil. Purify using ISCO chromatography over a biotage 40M column, eluting with a gradient of DCM to 6% MeOH/DCM. Concentrate the appropriate fractions to give a 20% yield of 4-[4-(3-Chloro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester. MS (ES): m/z=262.0 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][CH2:49][OH:50])[CH:46]=2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O.N.CO>>[OH:50][CH2:49][CH2:48][CH2:47][N:45]1[CH:46]=[C:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH:43]=[N:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 289A, 633.5 mg, 2.212 mmol). in TFE (12 mL) was charged with TFA (654.2 mg, 5.737 mmol) and irradiated by microwave heating [Biotage, 105° C.] for 1 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue was dissolved in MeOH (unmeasured amount), cooled to 0° C., and charged with 7.0 M of NH3 in MeOH (5 mL, 40 mmol). After stirring from 0° C. to rt over 1 h 45 min, the suspension was concentrated in vacuo and the crude product purified using a Teledyne/ISCO Combiflash system eluting with a solvent system of 0-10% MeOH:CH2Cl2 to afford the title material as a white solid, 1.1017 g (78%). 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.84 Hz, 1H), 7.41 (d, J=7.07 Hz, 1H), 7.10 (br. t, J=2.00 Hz, 1H), 6.96 (br td, J=2.30, 8.00 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.06, 8.12 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.06 Hz, 2H), 3.36 (d, J=19.96 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.63 Hz, 2H), 1.17 (t, J=6.95 Hz, 6H). MS (ES+): m/z 704.23 (100) [MH+]. HPLC: tR=3.73 min (ZQ3, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 61.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.47 g, 61%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=O)C.[H-].CO.O>C1(C)C=CC=CC=1>[F:23][C:20]([F:21])([F:22])[S:17]([O:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([CH:4]=[O:3])[CH:15]=1)(=[O:18])=[O:19]
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2n1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 4-trifluoromethanesulfonyloxy-quinoline-2-carboxylic acid ethyl ester (4.5 g, 12.88 g) in toluene (80 mL) was added slowly under argon at −78° C. diisobuthylaluminum hydride (1.5M in toluene, 12.88 mL, 19.33 mmol). The reaction mixture was stirred at −78° C. for 1 hour. Methanol (13 mL) was added slowly followed by water (26 mL). The reaction mixture was slowly warmed up to room temperature extracted with ethylacetate and washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (5–10% ethylacetate in hexane) to give 2.9 g of 4-trifluoromethanesulfonyloxy-quinoline-2-carbaldehyde (74%). 1H NMR (300 MHz; DMSO-d6): 8–8.2 (m, 4 H), 8.43 (m, 1 H), 10.05 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].C(N(CC)CC)C.[CH3:13][Si:14](OS(C(F)(F)F)(=O)=O)([CH3:16])[CH3:15]>C(Cl)Cl>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:5][C:2]([CH:3]=[CH2:4])=[CH2:1]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=C)O[Si](C)(C)C

Procedure:
70 μl (0.86 mmoles) of 3-buten-2-one [compound of formula 5 wherein R1 ═R2═R6═H] and 2 ml of anhydrous CH2Cl2 are charged, at 0° C. under argon in a two-necked round bottom flask equipped with magnetic stirrer and dropping funnel. 170 μl (1.22 mmoles) of triethylamine (distilled on KOH) and 209 μl (1.08 mmoles) of trimethylsilyltrifluorometansulphonate (TMDOTf) (drop by drop) are added to the mixture. In this conditions 2 -(trimethylsilyloxy)-1,3-butadiene [compound 6 wherein R1 =R2═R6═H] is formed “in situ”. The mixture is stirred for 45 minutes and thereafter a solution of 100 mg (0.36 mmoles) of the product from Example 2 in 2 ml of anhydrous CH2Cl2 is added therein, drop by drop, together with 69 μl (0.36 mmoles) of TMSOTf. The mixture is brought to room temperature and after 30 minutes 4 ml of a saturated solution of NAHCO3 are added and the mixture is stirred vigorously for 36 h.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][CH2:27][CH:26]=[CH2:25])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: C=CCBr
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNC[C@H]1CN(c2ccc(N3CCC(=CC#N)CC3)c(F)c2)C(=O)O1
Yield: 35 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.12 mmol), allyl bromide (0.18 mmol), and potassium carbonate (0.25 mmol) in tetrahydrofuran was heated at reflux temperature for 12 hours. Solvent evaporation and purification to provided the title compound in 35% yield.