Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=O)[CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1>>[F:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:56][CH2:57]2)=[CH:48][CH:47]=1
Reactant: O=C(CC1OCCc2cc(Br)ccc21)N1CCN(c2ccc(F)cc2)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: Fc1ccc(N2CCN(CCC3OCCc4cc(Br)ccc43)CC2)cc1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 4-fluorophenylpiperazine (XI) and the resulting amide, 1-(4-fluorophenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 1.64 mmol) is reduced following the general procedure of EXAMPLE 50 and making non-critical variations, to give the title compound, HRMS Calcd for C21H24N2O1Br1F1 =418.1056, found=418.1057.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CC(=CC)C.[OH:20]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+]>CC(O)(C)C>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]([OH:20])=[O:8]
Reactant: COc1c(Br)cc(C=O)c(Cl)c1OC
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1c(Br)cc(C(=O)O)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To the mixture of aldehyde 157 (11.1 g, 39.4 mmol), 2-methyl-2-butene (105 mL, 985 mmol) in t-BuOH (300 mL) was added KH2PO4 (38 g, 276 mmol). NaClO2 (32 g, 355 mmol, dissolved in H2O (160 mL)) was added to the reaction mixture. The mixture was stirred at r.t. for 15 hours. The mixture was evaporated in vacuo to remove the solvent. The residue was extracted with EtOAc/aq. 5% HCl solution (500 mL/300 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound 158 (11.6 g, 99%).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[O:19][CH3:20])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cu][C:28]#[N:29]>CN(C)C=O>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[C:5]2[C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:2]([C:28]#[N:29])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: N#C[Cu]
Reactant: COc1ccc(Cn2c(=O)[nH]c3cc(Br)cc(C(F)(F)F)c32)c(OC)c1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)[nH]c3cc(C#N)cc(C(F)(F)F)c32)c(OC)c1
Yield: 112.8 %

Procedure:
To a solution of 5-bromo-1-(2,4-dimethoxybenzyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (1090.7 mg) and copper(I) cyanide (793.8 mg) in N,N-dimethylformamide (100 ml) was heated at reflux for 34 hours. The reaction mixture was concentrated in vacuo. To the resultant residue were added saturated aqueous sodium bicarbonate solution and water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1076.5 mg, quantitative yield). HPLC retention time: 30.54 min (condition 2).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Br:26][C:27]1[CH:28]=[N:29][C:30](I)=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:30]3[N:31]=[CH:32][C:27]([Br:26])=[CH:28][N:29]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Brc1cnc(I)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ncc(Br)cn1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 187 mg (0.66 mmol) of 5-bromo-2-iodo-pyrimidine in 2 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 31 mg of a white powder. LC-MSD, m/z for C20H12Br2N4O2 [M+H]+=498.9, 500.9, 502.9; HPLC retention time: 2.2 min.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].[C:33](O)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:8][C:9]1[CH:17]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]3[O:25][C:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]4)=[N:23][C:22]=3[CH:32]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: CC(C)C(=O)O
Reactant: NC(=O)c1ccc(-c2ccc3oc(C4CCNCC4)nc3c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 69.8 %

Procedure:
Tert-butyl 4-[5-(4-carbamoyl-3-fluorophenyl)benzo[d]oxazol-2-yl]piperidine-1-carboxylate (190 mg, 0.32 mmol) dissolved in DCM (40 ml) and added trifluoroacetic acid (1.5 ml). This mixture stirred at rt for 3 h. After completion of the reaction, DCM removed on rotavapour and residue was co-distilled with ether to obtain 2-fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg). 2-Fluoro-4-(2-(piperidin-4-yl)-benzo[d]oxazol-5-yl)-benzamide 2,2,2-trifluoroacetate (190 mg, 0.42 mmol) was dissolved in DMF (7 ml) and added isobutyric acid (47 mg, 0.46 mmol), EDC.HCl (200 mg, 1.04 mmol), HOBt (70 mg, 0.5 mmol) and TEA (0.7 ml, 3.3 mmol). After completion of the reaction, water added to the reaction mixture to obtain solid. Solid was filtered and washed with ether to obtain the titled compound (120 mg) as a brown solid. M.P.: 193-196° C. MS (m/z): 410.2 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH:15]=[CH:14]2)C1C=CC=CC=1.S(Cl)(Cl)=O.[CH3:28]O>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:28])=[O:22])[CH:15]=[CH:14]2
Reactant: O=C(O)/C=C/c1ccc2cccc(OCc3ccccc3)c2n1
Reactant: CO
Agent: [Pd]
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (E)-3-[8-(benzyloxy)-2-quinolinyl]-2-propenoic acid (8d) (0.3 g, 0.98 mmol) in methanol (15 ml), 5% palladium on activated carbon (0.03 g) was added and the resulting suspension was hydrogenated by vigorous stirring for 2 hours at room temperature. The reaction mixture was filtered through a short column of silica gel (ca. 2 g) and the column was washed with methanol (10 ml). To the obtained filtrate, at room temperature, thionyl chloride (0.2 g, 1.7 mmol) was added with vigorous stirring. The reaction mixture was stirred overnight and then evaporated in vacuo. To the residue, a solution of 5% NaHCO3 (20 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The extract was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel with ether-petrol ether (1:2) as eluent to afford the title compound (0.158 g, 70%) as an oil. 1H NMR (CDCl3, HMDSO), δ: 2.89 (2H, t, J=7.0 Hz); 3.32 (2H, t, J=7.0 Hz); 3.65 (3H, s); 7.09 (1H, dd, J=2.0 and J=6.0 Hz); 7.16-7.49 (3H, m); 8.01 (1H, d, J=8.6 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[CH2:18]([C:11]1([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC1(OCCO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Solvent: CCO
Product: CCCCCCCC1(OCCO)CCNCC1
Yield: 36.3 %

Procedure:
A solution of 40 g of 2-(1-benzyl-4-heptyl-4-piperidyloxy)-ethanol in 300 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 0.4 g of 5% palladized charcoal until the theoretical amount of hydrogen was absorbed and the catalyst was then filtered off. The ethanol was distilled off and the residue was rectified to obtain 10.6 g of 2-(4-heptyl-4-piperidyloxy)-ethanol as a colorless oil boiling at 110°-130° C at 0.1 mm Hg.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[O:16]([C:18]#[N:19])[K]>O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:18]([NH2:19])=[O:16])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: N#CO[K]
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CCC(NC(N)=O)C1CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 50 mL round-bottom flask were placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (100 mg, 0.42 mmol, 1.00 equiv) in water (3 mL) and KOCN (38 mg, 0.47 mmol, 1.10 equiv). The resulting solution was stirred overnight at 70° C. The resulting solution was cooled and extracted with 3×10 mL of dichloromethane. The organic layers were combined, dried and concentrated under vacuum to give the title compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1.CC(C)([O-])C.[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:25]1([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)Cc1ccc(N2CCCC2)cc1
Temperature: 70 °C

Procedure:
Toluene (10 ml) was added to a mixture of palladium acetate (22.3 mg, 0.10 mmol), 2-(biphenyl)-di-tert-butylphosphine (59.8 mg, 0.20 mmol) and sodium tert-butoxide (2.40 g, 25.0 mmol), and then (4-bromophenyl)acetic acid (2.15 g, 10.0 mmol) and pyrrolidine (1.10 ml, 13.2 mmol) were added thereto. The obtained mixture was heated at 70° C. for 46 hours. Water (20 ml) was added to the reaction mixture. pH of the aqueous layer was controlled at 2 or below. The aqueous layer was washed with toluene and adjusted to pH 4 to 5. After stirring the reaction mixture in ice-bath for a while, it was filtered to obtain the title compound in the form of a light yellow solid (1.1 g, 54%).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:34]1([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>>[C:34]1([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](c2ccccc2Cl)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](c2ccccc2Cl)N2C[C@H](CN3CCC(CCCc4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 69 %

Procedure:
The title compound was prepared from 39 mg (0.085 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-(2-chlorophenyl)acetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 10, Step D) and 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 38 mg (69%) of the title compound: RF: 0.28 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.05-1.23 (m, 5H), 1.47-1.75 (m, 7H), 2.30-2.97 (m, 11H), 4.76 (s, 1H), 5.06 (s, 2H), 6.78-6.83 (m, 2H), 7.13-7.36 (m, 15H), 7.68 (m, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]OP(C=[N+]=[N-])(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[CH:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reactant: COP(=O)(C=[N+]=[N-])OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A solution of 1-BOC-3-formylpiperidine (1.46 g, 6.85 mmol) and (diazomethyl) phosphonic acid dimethyl ester (1.79 g, 11.94 mmol) in 50 mL methanol was stirred at ice-bath for 10 min, K2CO3 (1.96 g, 14.2 mmol) was added to the above mixture and stirred at ice-bath for 2 hrs, then stirred at rt overnight. The mixture was evaporated in vacuo, to the residue was added EtOAc and water, the organic layer was separated and water layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine successively, dried with Na2SO4, filtered, and the filtrate was evaporated in vacuo to give 1.44 g product as colorless oil (100.0%). 1H NMR (300 MHz, CDCl3) δ: 3.90 (1 H, brs), 3.70-3.75 (1 H, m), 2.95-3.02 (2 H, m), 2.40-2.47 (1 H, m), 2.05 (1 H, d, J=2.1 Hz), 1.94-1.99 (1 H, m), 1.69-1.73 (1 H, m), 1.50-1.63 (2 H, m), 1.46 (9 H, s).
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].CN(C)C=O>O>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][O:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:12]
Reactant: CCOC(CBr)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COCc1ccccc1)OCC
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a 2-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a reflux condenser and a glass stopper is added sodium benzoate (0.579 mol, 83.44 g, 1.1 equiv.), bromoacetaldehyde diethyl acetal (0.526 mol, 103.74 g, 1.0 equiv.) and N,N-dimethylformamide (1.0 L). The reaction was heated to reflux and stirred while monitoring progress by thin layer chromatography (TLC). When determined to be complete, the reaction was allowed to cool to ambient temperature and diluted with water (2.0 L). The product was extracted with methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 2-(benzyloxy)acetaldehyde diethyl acetal (111.85 g, 81.1% yield). The crude product was advanced to the next reaction step without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH:6]([OH:12])[CH:7]([OH:11])[CH2:8][CH2:9][NH2:10].[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>O>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[NH:3][CH2:4][CH2:5][CH:6]([OH:12])[CH:7]([OH:11])[CH2:8][CH2:9][NH:10][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])([O-:15])=[O:14]
Reactant: NCCC(O)C(O)CCN
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCC(O)C(O)CCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
A 25 mL round bottom flask fitted with a magnetic stirrer was charged with 221.1 mg (1.0 mmol) of 1,6 diamino-3,4-dihydrox-yhexane dihydrochloride, 409 mg (2.2 mmol) of 2,4-dinitrofluorobenzene, 130 mg (0.94 mmol) of K2CO3 and 10 mL of H2O. The mixture was stirred at 75° C. for 5 h. After cooling the yellow precipitate was isolated by filtration, washed with H2O and dried, affording 310 mg of crude product. This material (46 mg) was recrystallized from 2 mL of 1:1 H2O/DMF affording 20.4 mg of N,N'-bis(2,4-dinitrophenyl)-1,6 diamino-3,4-dihydroxy-hexane, mp 199° C. dec. Calcd for C18H20N6O10 : C, 45.00; H, 4.17; N, 1750. Found: C, 44.68; H, 4.19; N, 17.12. 200 MHz NMR (acetone-d6): 1.9 (m, 2H), 2.15 (m, 2H), 3.78 (m, 6H), 4.34 (d, J =4.8 Hz, 2H, active H), 7.30 (d, J=9.6, 2H), 8.30 (dd, J =2.2, 9.6, 2H), 8.99 (d, J=2.6 Hz, 2H), 9.1 (m, 1H).
Reaction SMILES: C([O:4][C:5]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[C:7]2[S:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:6]=12)(=O)C.CC([OH:23])C.C(Cl)(Cl)Cl>CC(O)=O>[C:11]([C:9]1[S:8][C:7]2[C:14](=[O:23])[C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:5](=[O:4])[C:6]=2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1c2cc(C(C)=O)sc2cc2ccsc12
Reactant: CC(C)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of crude 8 (7.5 g) in HOAc (30 mL) was added CrO3 (5.7 g, 57 mmol). After stirring for 1 h, i-PrOH (20 mL) and CHCl3 (300 mL) were added and stirred for 30 min. The resulting solution was poured into ice water, and the aqueous layer was extracted with CHCl3 three times. The combined extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CHCl3) to give 9 (mp 223-225 ° C.) in a 45% yield. IR (KBr) 1650, 1670 (C═O) cm−1; 1H NMR (CDCl3) δ 2.67 (s, 3H, CH3), 7.68 (d, J=5.1 Hz, 1H, H-7), 7.74 (d, J=5.1 Hz, 1H, H-6), 8.12 (s, 1H, H-3); 13C NMR (CDCl3): δ 26.9 (C-2-CH3), 126.9 (C-7), 129.4 (C-3), 134.3 (C-6), 170.0 (C-4), 174.4 (C-8), 190.7 (C-2-C═O); MS m/z 262 (M+); Anal. (C12H6O3S2) C, H.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH3:16][C:15]1[N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:11]([CH3:13])=[CH:10][CH:14]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 4,6-dimethyl-2-aminopyridine (7, 12.2 g, 100 mmol) in toluene (100 mL) was added acetonylacetone (12.3 mL, 105 mmol) and p-TsOH (190 mg, 1.0 mmol). The reaction mixture was heated in a Dean-Stark apparatus under reflux for 6 h. After cooling to room temperature, the mixture was concentrated with a rotary evaporator, and the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:19-1:9) to give 8 (18.2 g, 91 mmol, 91%) as a pale yellow solid: 1H NMR (500 MHz, CDCl3) δ 2.13 (s, 6H), 2.40 (s, 3H), 2.56 (s, 3H), 5.88 (s, 2H), 6.85 (s, 1H), 7.00 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.4, 21.2, 24.4, 106.8, 119.9, 123.1, 128.6, 149.6, 151.7, 158.4; LCQ-MS (M+H+) calcd for C13H17N2 201. found 201; LC-TOF-MS (M+H+) calcd for C13H17N2 201.13917. found 201.13881.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[N:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: CCOC(=O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2CO)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidine-5-carboxylate (2 g; 5,89 mmol) in dry dichloromethane (20 mL) at (−78° C.) under nitrogen atmosphere was slowly added a solution of diisobutylaluminium hydride (1M in dichloromethane) (13 mL; 13 mmol) and the reaction was stirred for 1 h at (−78° C.), then allowed to warm up to 0° C. and the stirring was carried on 2 h more. The reaction was quenched by adding a solution of hydrochloric acid 1N and the mixture was vigorously stirred for 1 h. The phases were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium potassium tartrate and brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The desired compound was obtained as a white solid (1.48 g; 84%) and used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[N:7]=1.[CH3:29][NH:30][CH3:31]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:18][CH2:17][OH:16])[C:15]([N:30]([CH3:31])[CH3:29])=[O:19])[N:7]=1
Reactant: Cc1nc(N)nc2c1/C(=N/OC1CCOC1=O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1nc(N)nc2c1/C(=N/OC(CCO)C(=O)N(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (310 mg, 0.668 mg) in THF (2 mL) was added N,N-dimethylamine (2.0M solution in MeOH, 0.86 mL, 1.72 mmol) and the reaction mixture was stirred overnight at r.t. The solvent was removed and purified by LCMS to afford the title compound 2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (89, 80 mg, 24%) as white solid. 1H NMR (400 MHz, METHANOL-d4) 62.63 (d, J=2.78 Hz, 3H) 2.84-2.99 (m, 1H) 3.01 (d, J=3.28 Hz, 3H) 3.08-3.25 (m, 4H) 3.61-3.93 (m, 2H) 4.99 (dddd, J=15.03, 4.86, 2.59, 2.27 Hz, 1H) 5.09-5.23 (m, 3H) 5.91 (d, J=9.09 Hz, 1H) 6.98-7.14 (m, 1H) 7.33 (ddd, J=7.89, 4.99, 2.53 Hz, 1H) 7.38-7.48 (m, 1H). MS (ES) [M+H] calculated for C20H25BrFN6O3, 495.34; found 495.30.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[CH:63][C:64]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[N:65][CH:66]=2)[C:50]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:73])[C:51]([C:61]1[CH:66]=[N:65][C:64]([N:67]3[CH2:72][CH2:71][O:70][CH2:69][CH2:68]3)=[CH:63][CH:62]=1)=[N:52]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccc(N3CCOCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCOCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 5-morpholinopyridin-3-amine (0.057 g, 0.32 mmol), 4-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)morpholine (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (2.7 mL) at 100° C. for 2.5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1H, dd, J=2.5, 0.6 Hz), 8.45 (1H, d, J=1.6 Hz), 7.92 (1H, dd, J=8.9, 2.4 Hz), 7.79 (1H, d, J=2.5 Hz), 7.57-7.62 (2H, m), 7.35-7.42 (1H, m), 6.96 (1H, d, J=8.6 Hz), 6.56 (1H, t, J=2.3 Hz), 3.71 (8H, dt, J=12.1, 4.8 Hz), 3.53-3.59 (4H, m), 3.05-3.11 (4H, m), 2.18 (3H, s). Mass Spectrum (ESI) m/e=519.2 (M+1).