Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:60]1([CH2:66][NH2:67])[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH2:66][CH:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NCC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)NCC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.17 mL, 0.96 mmol), and the mixture was stirred at room temperature for 5 minutes. Then cyclohexylmethylamine (0.07 ml, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and the formed solid was filtered, washed by water, and dried to afford the title compound (187 mg) as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][C:35]1([CH3:52])[O:39][CH:38]([CH2:40][O:41][CH2:42][CH2:43][NH:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[F:51])[CH2:37][O:36]1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:44]([CH2:43][CH2:42][O:41][CH2:40][CH:38]2[CH2:37][O:36][C:35]([CH3:52])([CH3:34])[O:39]2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[F:51])[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC1(C)OCC(COCCNc2ccccc2F)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.115 ml), and DMF (0.005 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (5 ml). The reaction was stirred at room temperature for 1.5 h then [2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(2-fluoro-phenyl)-amine (0.121 g) as a solution in dichloromethane (0.5 ml), DMAP (0.005 g) and DIPEA (0.080 ml) were added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with further dichloromethane and extracted with saturated aqueous sodium bicarbonate. The aqueous layer was removed and the organic phase washed with water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (1:1, 2:1 and 4:1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (0.035 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][NH2:14])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1.[Br:24][CH2:25][C:26](=O)[CH3:27]>>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:13][N:14]=[C:26]([CH3:27])[CH2:25][Br:24])[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[CH:21]=1
Reactant: CC(=O)CBr
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Product: CC(CBr)=NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-(trifluoromethyl) -2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with bromopropanone to give 7-(trifluoromethyl)-2-[ (2-bromo-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][N:10]=[C:11]=[S:12]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:11]([NH:10][CH3:9])=[S:12])=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: Nc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(=S)Nc1ccc(Cl)nc1
Yield: 70.6 %

Procedure:
A mixture of 4.07 g of 2-chloro-5-aminopyridine, 2.55 g of methyl isothiocyanate and 30 ml of acetonitrile was refluxed for 13.5 hours, to which 0.70 g of additional methyl isothiocyanate was added and the mixture was refluxed for 3.5 hours. The reaction mixture was concentrated, and the residue was purified by a column chromatography [developing solvent: dichloromethaneethyl acetate (1:1)] to afford 4.51 g of 1-(6-chloro-3-pyridyl)-3-methylthiourea.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[C:40]([N:48]3[C:52]([CH3:53])=[N:51][N:50]=[N:49]3)[CH:39]=2)[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1cc(C(CC2CCCC2)C(=O)Nc2nccs2)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A solution of triphenylphosphine (100 mg, 0.38 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (68 mg, 0.38 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (85 mg, 0.22 mmol) in methylene chloride (3 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (55 mg, 0.55 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (42 mg, 41%) as a white solid: mp 148-154° C.; EI-HRMS m/e calcd for C20H24N6O3S2 (M+) 460.1351, found 460.1356.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1Cl)=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH3:2].[H-].[Na+].O>C(COC)OC>[CH2:1]([O:3][C:4]([C:5]1[C:15](=[O:25])[C:16]2[C:17](=[CH:18][C:19]([F:23])=[C:20]([F:22])[CH:21]=2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:6]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Yield: 90 %

Procedure:
2-(2-Chloro-4,5-difluorobenzoyl)-3-(4-fluoroanilino)-2-propenoic acid ethyl ester (11.0 g, 28.7 mmol) was dissolved in dimethoxyethane (200 ml) and cooled to 0°. Sodium hydride (1.65 g of a 50% suspension in mineral oil, 34.5 mmol) was added portionwise, and the mixture was heated to reflux for 3 hours. The reaction mixture was then poured into water (2 l) and the title product was collected by filtration (8.96 g, 25.8 mmol, 90% yield).
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][S:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:25]
Reactant: O=C(CCCCSc1ccccc1)N1CCc2ccoc2C1
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCCSc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.285 g (0.903 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-5-phenylthiopentan-1-one in 20 ml of acetic acid, 0.122 ml (1.35 mmol) of 50% aqueous dimethylamine and 0.110 ml (1.35 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 45 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:3].Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.O>[Br:26][C:24]1[N:25]=[C:20]([NH:3][C:2]([CH3:18])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:1])[C:21](=[O:39])[N:22]([C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([F:38])[C:36]=2[CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:23]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 83.2 %

Procedure:
A solution of α,α-dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d, 5.25 g) dissolved in dioxane (40 mL) was treated with 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252g, 9.14 g) and N,N-diisopropylethylamine (5.59 mL) under nitrogen. The resulting solution was stirred at 100° C. for 10 h. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL×2). The organic was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography eluting with 20% ethyl acetate in iso-hexane) to afford the subtitle product (10.50 g).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:10]([C:11]2[S:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28]Cl)[CH:20]=3)=[N:14][N:15]=2)=[N:9][O:8][N:7]=1)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCO>O>[N:33]1([CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][C:17]([NH:16][C:13]3[S:12][C:11]([C:10]4[C:6]([NH2:5])=[N:7][O:8][N:9]=4)=[N:15][N:14]=3)=[O:30])[CH:24]=[CH:23][CH:22]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: C1CNCCN1
Reactant: O=C(Cc1cccc(OCCCCl)c1)Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Solvent: CCO
Solvent: O
Product: Nc1nonc1-c1nnc(NC(=O)Cc2cccc(OCCCN3CCNCC3)c2)s1

Procedure:
N-Trifluoroacetyl-4-(5-(3-(3-chloro-propoxy)-phenylacetyl)amino-[1,3,4]thiadiazol-2-yl)-furazan-3-ylamine (0.05 g, 0.1 mmol), piperazine (0.035 g, 0.4 mmol) and EtOH (0.3 mL) were heated by microwave irradiation at 120° C. for 2×10 minutes. The reaction was diluted with water and purified by preparative HPLC. Yield: 0.03 g (33%). 1H-NMR (MeOD) δ 7.25 (t, 1H), 6.90–6.95 (m, 2H), 6.85 (d, 1H), 4.12 (t, 2H), 3.82 (s, 2H), 3.3.10–3.15 (m, 6H), 3.00 (t, 3H), 2.10–2.15 (m, 3H). LCMS 445.2 (M+1), HPLC Method B Rt 1.6 minutes.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(N3CCN(c4ccccc4)CC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15](O)=[O:16])[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:65][C@@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:33])[C:5]2=[C:6]([CH2:8][C@H:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[N:26]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][C:15]([N:68]2[CH2:69][CH2:70][C@@H:66]([F:65])[CH2:67]2)=[O:16])[N:7]=1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)O)N2)n1
Reactant: F[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC(=O)N3CC[C@@H](F)C3)N2)n1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetic acid (0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28 mg), Et3N (0.125 mmol, 17 μL) and (R)-3-fluoropyrrolidin (0.06 mmol, 7.5 mg). The reaction mixture was stirred over night at r.t. and LCMS shows completion of the reaction. Purified by prep LCMS to afford the title compound (Compound 85, 13.0 mg, 50%) as light brown solid. 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.40 (m, 2H) 2.72 (s, 3H) 3.06 (dd, J=16.93, 10.36 Hz, 1H) 3.27-3.38 (m, 1H) 3.39-3.62 (m, 4H) 3.63-3.78 (m, 2H) 3.82 (s, 3H) 4.47-4.67 (m, 2H) 4.87 (dd, J=10.36, 3.03 Hz, 1H) 5.11-5.36 (m, 1H) 6.69 (d, J=8.34 Hz, 1H) 6.97 (d, J=7.33 Hz, 1H) 7.06 (dd, J=9.35, 2.53 Hz, 1H) 7.13 (t, J=8.34 Hz, 1H) 7.50-7.70 (m, 2H). MS (ES) [M+H] calculated for C26H28F2N7O3, 524.53. found 524.50.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[Na+].[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:18]([C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1cc[cH-]c1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CC(=C(Cc2ccccc2)c2ccccc2)C=C1
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, 2.45 g (25.7 mmol) of anhydrous magnesium chloride and 20 mL of dry THF were put into a 100-mL Schlenk flask and then stirred. To this mixed solution, 10.6 mL (21.2 mmol) of a solution of 2.0-M sodium cyclopentadienide in THF was added. Then, the product was heated for an hour under reflux, the obtained pink slurry was cooled in an ice bath, and a solution in which 3.5 g (17.8 mmol) of benzyl phenyl ketone had been dissolved in 15 mL of dry THF was subsequently added thereto. Then, the product was stirred at room temperature for 18 hours, and the obtained orange solution was quenched with dilute aqueous hydrochloric acid. Then, 30 mL of diethyl ether was added thereto, the soluble part in diethyl ether was extracted, and the organic layer was neutralized and washed with an aqueous solution of saturated sodium hydrogen carbonate, water, and a saturated salt solution and then dehydrated with anhydrous magnesium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography to obtain an objective that was a reddish orange solid (amount: 2.7 g and yield: 62%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24][C:25](=[N:27]O)[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][N:27]=[C:25]([CH3:26])[CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: CC(C)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)=NOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
After 15 g of 2-[p-(p-trifluoromethylphenoxy)phenoxy]-propionic acid are suspended in 20 ml of methylene chloride, 3.5 g of acetone oxime are added at room temperature. 9.8 g of dicyclohexylcarbodiimide, in 10 ml of methylene chloride, are then added dropwise over a period of 10 minutes as the temperature increases to about 40° C. The reaction mixture is then stirred at room temperature for 2 hours and filtered. The filtrate is evaporated to dryness on a rotary evaporator to yield acetone O-[2-[p-(p-trifluoromethylphenoxy)phenoxy]propionyl]-oxime, nD20 : 1.5212.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=2.N1C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35][C:36](Cl)=O>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:36]([CH2:35][CH2:34][O:33][CH3:32])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
1-(3-Amino-7-benzyloxyquinolin-4-ylamino)-2-methyl-propan-2-ol (25 g, 74.09 mmol) was added to 500 mL of pyridine. To this mixture was added in a dropwise manner a solution of methoxypropionyl chloride (10 g, 81.5 mmol) dissolved in 20 mL of toluene. After approximately half of the acid chloride had been added, the reaction mixture became completely homogenous. Two hours after the addition of the acid chloride, the reaction mixture was heated to reflux and maintained overnight. The solvent was concentrated through the use of a Dean-Stark trap. Cooling to ambient temperature provided a white precipitate, which was collected by filtration. The solid was slurried in 1 L of 1% hot aqueous sodium carbonate (75-80° C.) for 1 hour. The mixture was then cooled in an ice bath and the solid material was filtered, rinsed with water, and dried to yield 22.7 g of 1-[7-benzyloxy-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 170-171.5° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[NH2:7][C:8]1[C:13](O)=[C:12]([Br:15])[CH:11]=[C:10]([Cl:16])[CH:9]=1.[C:17]([C:21]1[CH:22]=[C:23]([CH2:32][C:33](Cl)=[O:34])[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:20])([CH3:19])[CH3:18].S(Cl)(Cl)=O>O>[C:17]([C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:7][C:8]2[C:13]([O:2][C:1](=[O:4])[CH2:32][C:23]3[CH:22]=[C:21]([C:17]([CH3:18])([CH3:20])[CH3:19])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=3)=[C:12]([Br:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:34])[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(CC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)cc(Br)c1O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2OC(=O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 1.5 h
Yield: 103.6 %

Procedure:
Water (173 ml) and sodium carbonate (33.24 g, 310 mmol) were added to a stirred ethereal solution (123 ml) of 6-amino-2-bromo-4-chloro-phenol (17.45 g, 78.4 mmol). After 15 minutes 3,5-di-t-butyl-4-hydroxy-phenyl acetyl chloride (47.60 g, 93.1%, 156.8 mmol) (prepared with thionyl chloride from the corresponding acid), was added at −5E to 0EC and stirring continued for a further 1.5 hours without cooling. The aqueous phase was adjusted to pH 8 and the layers separated. The organics were washed with 1 N HCl (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated into give 58.1 g (103.6%) of the title compound which was suitable for the next step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl-].[N:13]1[C:22]2[C:17](=[CH:18][N:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[CH3:23]N(C=O)C>CCOC(C)=O.O>[CH3:23][C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][C:14]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N:13]2
Reactant: OCCN1CCCCC1
Reactant: CN(C)C=O
Reactant: c1cnc2ccncc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccc2nc(OCCN3CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
2-Piperidin-1-ylethanol (43 mg, 0.34 mmol) was treated with a 60% dispersion of NaH in mineral oil (17 mg, 0.42 mmol) in 2 mL of DMF. The mixture was stirred for 20 minutes and the 1,6-naphthyridine chloride was added, and the solution was stirred at 50° C. for 16 hours. The solution was cooled to room temperature and diluted with EtOAc and H2O. The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (NaHCO3) and brine, and dried over magnesium sulfate. The organics were filtered, concentrated, and purified by silica gel chromatography eluting with a gradient of dichloromethane/MeOH/NH4OH to yield 33 mg (41%) of compound 16. LCMS (EI) m/z 274 (M+1).