Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:15](OCC)=[O:16])[O:12][CH2:11][CH2:10][O:9]1.C(OCC)(=O)C.[OH-].[Na+]>CCOCC.O>[CH3:7][C:8]1([CH2:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:15][OH:16])[O:9][CH2:10][CH2:11][O:12]1
Reactant: CCCCCCCCCCCCCCCCCCC(CC1(C)OCCO1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCC(CO)CC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91.9 %

Procedure:
To a suspension of about 3.75 g of lithium aluminum hydride in about 100 ml of ether at about 0° C., was added dropwise, under argon, over about 20 minutes, a solution of about 29 g of 2-methyl-α-octadecyl-1,3-dioxolan-2-propanoic acid, ethyl ester in about 200 ml of ether. This mixture was stirred about 40 minutes at room temperature, then about 15 ml of ethyl acetate were added dropwise, followed by about 1.5 ml of water, about 3 ml of about 15% sodium hydroxide and about 4 ml of water. The mixture was then filtered through celite and the solid washed with ether. The solvent was removed from the filtrate, giving an oil which crystallized on standing, giving about 24.1 g of the desired title compound, mp 34°-35° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11](C3C=CC=CC=3)[CH:12]=2)[N:7]=1.[Li]CCCC.C([O:39][B:40](OC(C)C)[O:41]C(C)C)(C)C.CO.ClCCl>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16](=[O:17])[NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:40]([OH:41])[OH:39])[CH:12]=2)[N:7]=1
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(-c3ccccc3)cc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(B(O)O)cc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
6-bromo-2-(furan-2-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.4 g, prepared as described above for compound 1) was dissolved in THF (15 ml) in a round-bottomed flask under argon atmosphere. The solution was cooled to −78° C., then n-BuLi (15% in hexanes, 1.0 ml, 1.5 eq) was added dropwise. The reaction was maintained at this temperature for 45 minutes, at which time triisopropylborate (0.376 g, 2.0 eq.) was added dropwise. The reaction was allowed to warm to RT and stirred for an additional 3 hours. The completion of the reaction was monitored on TLC using methanol:dichloromethane (1:9) as a mobile phase. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (10 ml), then was extracted with ethyl acetate (2*10 ml) which was discarded. The aqueous layer was added Conc.HCl to adjust pH up to 6-7. The solid was precipitated which further was filtered on Buckner funnel and washed with water (10 ml). The solid was dried to obtain (2-(furan-2-yl)-4-(pyridin-3-ylcarbamoyl)quinolin-6-yl)boronic acid (0.300 g) which was used as such in next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[N:6][C:7]=1[Br:8].C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[N:6][C:7]=1[Br:8]
Reactant: COC(=O)CCc1cnc(N)c(Br)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(CCC(=O)O)nc1Br
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(5-amino-6-bromopyrazin-2-yl)propanoate (55 mg, 0.211 mmol) in MeOH (961 μL) and H2O (96 μL) was added potassium carbonate (170 mg, 1.230 mmol). The reaction mixture was stirred for overnight. To the reaction mixture, anhydrous Na2SO4 was added. After diluted with EtOAc (3 mL) and filtered, the volatile materials were removed in vacuo. The crude 3-(5-amino-6-bromopyrazin-2-yl)propanoic acid was obtained and used for the next step without further purification. LCMS (m/z): 246.0/248.0 (MH+, major), 0.26 min.
Reaction SMILES: [Na].[CH2:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:15]([CH:3]([C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH2:2][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCI
Reactant: CCCC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCC(CC(=O)OCC)C(=O)CCC
Temperature: 25 °C

Procedure:
Under an atmosphere of argon, 1.59 g (69.3 mmol) of sodium were added a little at a time to 50 ml of ethanol. The mixture was then stirred under reflux until a homogeneous solution was obtained. 11.0 g (69.3 mmol) of ethyl hexan-3-onecarboxylate were added to the hot alkoxide solution, and the mixture was stirred for 45 min. 6.51 ml (7.93 g, 52.5 mmol) of 1-iodohexane were then slowly added dropwise to the boiling mixture. The mixture was stirred under reflux for 16 h, cooled to room temperature and filtered, and the solvent was then removed under reduced pressure. The residue was taken up in dichloromethane, filtered again and concentrated. The crude product was purified chromatographically (silica gel, petroleum ether: ethyl acetate 30:1). MS (DCI, NH3): 309 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: c1cn[nH]c1
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)c1cccc(-n2cccn2)c1
Temperature: 195 °C
Yield: 58 %

Procedure:
To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (1.5 g, 7.5 mmol) and pyrazole (1.02 g, 15 mmol) in N-methylpyrrolidinone (10 mL) in a quartz tube were added potassium carbonate (2.1 g, 15 mmol), and copper (1) iodide (143 mg, 0.75 mmole), and the resulting mixture was heated at 195° C. for 5 h in a Mars 5 microwave oven (600 W). The reaction mixture was cooled down to room temperature and filtered. The crude product was purified by flash chromatography (10% MeOH/89% EtOAc/1% triethylamine) to provide the title compound (814 mg, 58% yield) as a brown oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:15]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:5]1[C:9]2[C:10]([Br:15])=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: BrBr
Reactant: CC(C)Cn1cnc2ccc(N)cc21
Agent: N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Cn1cnc2ccc(N)c(Br)c21
Yield: 29 %

Procedure:
To a solution of 3-isobutyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 1.0 g (3.7 mmol, 29%) of the product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=3[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]2=[O:33])[CH2:3][CH2:2]1.Cl.C(OCC)C>ClCCl>[CH2:1]([N:4]1[C:13]2[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:33])[CH:2]=[CH2:3]
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C3CC3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCn1c(=O)c2cnccc2c2ccc(OC[C@@H](N)CC(C)C)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 10298.6 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-cyclopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.221 mmol) in anhydrous dichloromethane (2 mL) was added a 2 M solution of HCl in diethyl ether (0.176 mL, 0.353 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (0.1% TFA in water) to afford (S)-6-allyl-8-((2-amino-4-methylpentyl)oxy)benzo[c][2,7]naphthyridin-5(6H)-one (8 mg, 22.76 mmol, 10% yield) as a yellow solid. LC/MS (ESI) m/e 352.2 [(M+H)+, calcd for C21H26N3O2 352.2]; LC/MS retention time (method C): tR=1.80 min; HPLC retention time (method A): tR=8.06 min; HPLC retention time (method B): tR=9.21 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (s, 1H), 8.85 (d, J=6.27 Hz, 1H), 8.55 (d, J=9.04 Hz, 1H), 8.48 (d, J=6.27 Hz, 1H), 7.20 (dd, J=8.91, 2.38 Hz, 1H), 7.14 (d, J=2.26 Hz, 1H), 6.08 (dd, J=17.32, 10.54 Hz, 1H), 5.28 (dd, J=10.54, 1.00 Hz, 1H), 5.18 (dd, J=17.32, 1.25 Hz, 1H), 5.09-5.13 (m, 2H), 4.44 (dd, J=10.54, 3.26 Hz, 1H), 4.27 (dd, J=10.42, 6.40 Hz, 1H), 3.77 (dd, J=6.78, 3.51 Hz, 1H), 1.64-1.88 (m, 3H), 1.07 (dd, J=6.40, 4.89 Hz, 6H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[N:7]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:13][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:12])=[N:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nccc(-c2ccco2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Br)c(-c2ccco2)n1
Reaction time: 6 h
Yield: 83.6 %

Procedure:
To a solution of 4-(2-furyl)-2-pyrimidinylamine (4.10 g, 25.4 mmol) in N,N-dimethylformamide (40 ml) was added N-bromosuccinimide (4.53 g, 25.5 mmol) at 2° C., followed by stirring as it was. After 6 hours, the reaction mixture was diluted with an aqueous saturated sodium bicarbonate solution (240 ml). The mixture was ice-cooled, and then the crystals were collected by filtration and washed with water, to give the title compound (5.10 g, 84%) as a pale brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.80 g), methyl 4-hydroxyphenylacetate (0.42 g), anhydrous potassium carbonate (0.35 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.70 g, 63%) of methyl 2-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 93-94° C.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[Si]([O:46][CH2:47][CH2:48][N:49]([CH:83]1[CH2:85][CH2:84]1)[C:50]([C:52]1[C:57]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]2([C:73]3[C:82]4[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:76]=[CH:75][CH:74]=3)[CH2:72][CH2:71][CH2:70][CH2:69]2)[N:53]=1)=[O:51])(C(C)(C)C)(C)C>>[CH:83]1([N:49]([CH2:48][CH2:47][OH:46])[C:50]([C:52]2[C:57]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[C:56]([OH:66])[N:55]=[C:54]([CH2:67][C:68]3([C:73]4[C:82]5[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=5)[CH:76]=[CH:75][CH:74]=4)[CH2:72][CH2:71][CH2:70][CH2:69]3)[N:53]=2)=[O:51])[CH2:84][CH2:85]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (354) (270 mg, 0.41 mmol). The yield was 150 mg, 67% (white solid)
Reaction SMILES: O[Li].O.[CH2:4]([O:11][CH2:12][C:13](=[O:24])[CH:14]([CH3:23])[C:15](=[O:22])[CH:16]([CH3:21])[C:17]([O:19]C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C1C[O:29][CH2:28][CH2:27]1>>[C:28]([O:22][C:15]1[C:14]([CH3:23])=[C:13]([CH2:12][O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:24][C:17](=[O:19])[C:16]=1[CH3:21])(=[O:29])[CH3:27]
Reactant: COC(=O)C(C)C(=O)C(C)C(=O)COCc1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]O
Solvent: O
Product: CC(=O)Oc1c(C)c(COCc2ccccc2)oc(=O)c1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An aqueous solution (6 ml) of LiOH-hydrate (64 mg) was added to a solution of methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate (430 mg) in THF (10 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was neutralized with diluted hydrochloric acid, and after distilling off the volatile components under reduced pressure, extraction was performed with AcOEt at pH 3. The organic layer was dried with MgSO4 and then filtered and concentrated. Ac2O (6 ml) was added to the residue, and after stirring at room temperature for 30 minutes, pyridine (4 ml) was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=3/1→12/5) to obtain 4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one.
Reaction SMILES: C([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)C.[CH2:10]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[OH:37])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH2:10]([O:17][C:18]([N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[O:37][CH2:7][CH2:6][CH2:5][C:4]([OH:9])=[O:3])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(F)ccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1ccc(F)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl-4-bromobutyrate (45 μL, 0.30 mmol, 1.50 eq.) was added to a solution of (±)-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (75 mg, 0.20 mmol, 1.00 eq.) and K2CO3 (83 mg, 0.60 mmol) in DMF (0.7 mL). The mixture was stirred at r.t. for 2 hours. Ethyl-4-bromobutyrate (22 μL, 0.15 mmol, 0.75 eq.) was added again and the mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with AcOEt and water. The layers were separated and the aq. phase was extracted with AcOEt (2×). The combined org. phases were washed with water and sat. aq. NaCl soln., dried over MgSO4, filtered and concentrated in vacuo. To a solution of the crude ester in THF (0.9 mL), 1M aq. NaOH soln. (0.50 mL) was added. The resulting solution was stirred at r.t. during 62 hours. The org. solvent was removed in vacuo. The residue was diluted with water and 1M aq. HCl soln. (0.8 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO4, filtered and concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) and evaporated (genevac) to give the desired acid.
Reaction SMILES: [Na].[CH3:2][OH:3].Cl[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>O>[CH3:2][O:3][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1cccnc1Cl
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1ncccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-chloronicotinonitrile is added at 0° C. The reaction medium is stirred at 25° C. for 16 hours. The reaction is hydrolyzed by slowly adding water at 0° C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH2:13]([NH:15][CH2:16][CH2:17][OH:18])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][OH:18])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Reactant: CCNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
3-Chloro-2,4-difluorobenzoylchloride (211 mg, 1 mmol) in DCM (1 mL) was added to a stirred solution of 2-(ethylamino)ethanol (98 mg, 1.1 mmol) in a mixture of DCM (1 mL) and 10% sodium hydroxide solution (1 mL) at 0° C. After the addition of the acid chloride was complete, the mixture was warmed to RT and stirred for approximately 4 hours. The two layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to give a colourless oil (220 mg). The material was used without further purification or analysis.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8](=O)[C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=O)[CH:10]=2)=[CH:4][CH:3]=1.B.CC(O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([CH2:12][NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:10]=2)=[CH:27][CH:28]=1
Reactant: O=C(NCc1ccc(F)cc1)c1cccc(C(=O)NCc2ccc(F)cc2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Fc1ccc(CNCc2cccc(CNCc3ccc(F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a partially heterogeneous mixture of N1,N3-bis(4-fluorobenzyl)isophthalamide (5.1 g, 13.41 mmol) in THF (70 mL) at ice bath temp was added a cold solution of borane (100 mL of 1 M solution in THF) slowly. It was stirred at ice bath tem for 1 h. It was warmed to rt and stirred for 30 h at rt. The mixture was warmed to ˜60° C. and stirred for 2 h. To the mixture was added 5 mL of HOAc, stirred for 1 h and it was mostly concentrated. To the residue was slowly added 150 mL of MeOH and 150 mL of 1N HCl with stirring, stirred for 2 h at rt, heated at 65° C. for 30 min and it was mostly concentrated. The mixture was mixed with EtOAc and aq NaHCO3, the EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain the desired product (4.5 g, 95%) as a viscous material of crude product. This crude product was used directly for the next step without any further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH2:26]>CC(O)CCC>[ClH:2].[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH:26][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccncc1
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1ccncc1
Yield: 29.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (268 mg, 0.71 mmol), (prepared as described for the starting material in Example 10), and 2-fluoro-5-hydroxy-4-methylaniline, (109 mg, 0.77 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (6 ml) was heated at reflux for 4 hours. After dilution with isopropanol, the solid was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (92 mg, 29%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:28][O:29]C(=O)C)([CH2:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[O:7][C@@:6]1([SiH:41]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[N:33]1[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]1=[O:35])(=O)C.C(N)(C)(C)C>CO>[C:24]([O:23][CH2:22][C@@:8]1([CH2:28][OH:29])[O:7][C@@:6]([SiH:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([N:33]2[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@H:5]([OH:4])[C@@H:9]1[O:10][CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC[C@]1(COC(C)(C)C)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](OC(C)=O)[C@@H]1OCc1cccc2ccccc12
Solvent: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)OC[C@@]1(CO)O[C@](n2ccc(=O)[nH]c2=O)([SiH](c2ccccc2)c2ccccc2)[C@H](O)[C@@H]1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.6 %

Procedure:
To a solution of Compound 45 (34.9 g, 47.08 mmol) in anhydrous methanol (250 mL) was added tertbutylamine (26.3 mL, 250 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated in vacuo, redissolved in EtOAc (0.8 L), washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, evaporated and dried under high vacuum to yield Compound 46 (30.6 g, 99%) as a pale yellow foam.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:21])[O:7][CH:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]>C(O)C.[Pd]>[CH2:1]([NH:5][C:6](=[O:21])[O:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCNC(=O)OC1CCNCC1

Procedure:
1-(Phenylmethyl)piperidin-4-yl butylcarbamate (Preparation 109, 13.0 g) in ethanol (100 ml) containing palladium (5% on carbon) was hydrogenated at 60 psi to give the title compound as a green oil that solidified upon standing.