Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 85.5 %

Procedure:
4-Nitrophenol (8 gm, 56 mmol) in 100 ml anhydrous tetrahydrofuran was placed under a nitrogen atmosphere and cooled in an icebath. To this was added triethylamine (6.2 g, 61 mmol) followed by the dropwise addition of bromoisobutyryl bromide (14.1 g, 61 mmol) in 20 ml anhydrous tetrahydrofuran over 5 min. After stirring for 16 h, the solids were filtered off and the solution concentrated, and then recrystallized from 100 ml methanol to give 13.8 g yellow solid, >99% pure by HPLC.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([NH:30][C:31]([C:33]3[CH:37]=[CH:36][S:35][CH:34]=3)=[O:32])[CH:28]=[CH:29][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.03 min, MH+ 521. NMR: δH [2H6]-DMSO 10.12, (1H, s), 9.33, (1H, t), 9.15, (1H, s), 8.78, (1H, b), 8.36-8.32, (2H, m), 7.86, (1H, s), 7.78, (1H, d), 7.69-7.65, (3H, m), 7.31, (2H, m), 7.21, (1H, s), 7.11, (2H, m), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)CCC.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:6]3[CH:7]=[CH:8][C:9]([S:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:13])=[O:14])=[CH:10][CH:11]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 72.7 %

Procedure:
(4-Tributylstannylphenyl)(3-benzyloxypropyl)sulfone (5.78 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (2.13 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.58 g) in xylene in nitrogen atmosphere for 7 hr. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate and adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-benzyloxypropyl)sulfonylphenyl]isoquinoline (2.56 g) as a pale brown amorphous.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[C:7]([CH2:9][C:10]([F:22])([F:21])[CH2:11][O:12][CH2:13][C:14]([F:20])([F:19])[C:15]([O:17]C)=O)[N:8]=1)([O-:3])=[O:2].[CH2:23]([CH2:25][NH2:26])[OH:24]>O1CCOCC1>[OH:24][CH2:23][CH2:25][NH:26][C:15](=[O:17])[C:14]([F:20])([F:19])[CH2:13][O:12][CH2:11][C:10]([F:22])([F:21])[CH2:9][C:7]1[N:8]=[C:4]([N+:1]([O-:3])=[O:2])[NH:5][CH:6]=1
Reactant: COC(=O)C(F)(F)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Reactant: NCCO
Solvent: C1COCCO1
Product: O=C(NCCO)C(F)(F)COCC(F)(F)Cc1c[nH]c([N+](=O)[O-])n1
Yield: 51.2 %

Procedure:
To a solution of methyl 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]-2,2-difluoropropionate (1.0 g, 3.0 mmol) in dioxane (10 ml), ethanolamine (370 mg, 6.0 mmol) was added and reacted for 5 hours at a room temperature with stirring. The reaction solution was concentrated and partitioned between ethyl acetate and water. The ethyl acetate phase was dried over magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography to obtain 3-[3'-(2"-nitroimidazolyl)-2',2'-difluoropropoxy]-2,2-difluoropropionic acid hydroxyethylamide (550 mg). m.p. 67°-68° C. 1H-NMR (DMSO-d6): δ=3.24-3.76 (5H, m), 4.14 (2H, t, --CF2CH2 --, J=13 Hz), 4.22 (2H, t, --OCH2, J=14 Hz), 4.88 (1H, brt, --OH), 5.24 (2H, t, CH2CF2, J= 15 Hz), 7.42 (1H, d, H5 "), 7.98 (1H, d, H4 "), 8.93 (1H, brt, NH)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of 10.0 g of 4-fluorophenol and 16.1 ml of bromoacetaldehyde diethylacetal in 100 ml dimethylformaldehyde was added 18.5 g of potassium carbonate at room temperature, and the mixture was stirred at 120° C. for two days. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=0:10 to 1:20), to give 17.3 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][N:3]1CC1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[C:7]([CH3:12])([CH2:8][CH2:9][CH2:10][OH:11])[CH:6]([CH3:13])[CH2:5][CH2:4][NH:3]1
Reactant: [H][H]
Reactant: CC1CCN(Cc2ccccc2)C(C)C1(C)CCCO
Agent: [Pd]
Solvent: CCO
Product: CC1CCNC(C)C1(C)CCCO
Yield: 82.4 %

Procedure:
A mixture of 2,3,4-trimethyl-l-(phenylmethyl)-3-piperidinepropanol (45.0 g, 163 mmol), ethanol (200 mL) and 10% palladium on carbon (4.5 g) was placed on a Parr hydrogenator at 50 psi of hydrogen pressure until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was crystallized from ether to afford 24.9 g (82%) of 2.3.4-trimethyl-3-piperidinepropanol. The product was recrystallized from ethyl acetate and had a melting point of 89-91° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][N:14]=[C:13]2[O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1
Reactant: OCC1CCC(O)CC1
Reactant: COc1ccc2ncnc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncnc(OCC3CCC(O)CC3)c2c1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (79 mg (1.5 eq.) was added at 0° C. to a solution of 4-hydroxymethyl-cyclohexanol (3 g, 12 mmol, synthesised analogously to J. Org. Chem. 1994 59 p. 2748–2761) in DMF (30 ml). After 20 minutes, a solution of 4-chloro-6-methoxy-quinazoline (1.94 g, 10 mmol) in DMF (10 ml) was added and the reaction mixture was heated to 40° C. After a further 2 hours, the reaction mixture was concentrated to dryness. The residue was diluted with water (100 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc/hexane 1/2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34]>C(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([N:32]([O:33][CH3:34])[CH3:31])=[O:7])=[CH:3][C:2]=1[OH:1]
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(F)c(O)c1
Temperature: 78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a 5 L four necked round bottom flask was added 3-hydroxy-4-fluorobenzoic acid (100 g, 0.64 mol) and CH2Cl2 (2.3 L). Triethylamine (107 mL, 0.768 mol) was then added to the suspension. The solution was cooled to 78° C., and EDCI (184.2 g, 0.961 mol) was added portion wise followed by the addition of N,O-dimethylhydroxyamine hydrochloride (93.6 g, 0.96 mol). The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to 0° C. over a period of 2 h. The reaction mixture was transferred to a separatory funnel and washed water (2×1.2 L). The organic portion was dried over Na2SO4, filtered and concentrated in vacuo to give 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide as a white solid (94.4 g, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].C(#N)C.C(NC(C)C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].[Cu](I)I>[CH3:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH2:11][CH2:12][C:13]1[O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH:14]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: N#Cc1ccc(O)c(I)c1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCc1cc2cc(C#N)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.6 %

Procedure:
The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-1-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25° C. for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60° C. in an inert atmosphere for 16 h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 1HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s, 1H); MS (ESI) m/e 255 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]2[N:16]=[CH:17][CH:18]=[C:14]2[N:13]=[C:12]([CH3:19])[C:11]=1[CH2:20][CH2:21][Cl:22]>C(Cl)(Cl)Cl>[Cl:1][C:18]1[CH:17]=[N:16][N:15]2[C:10]([Cl:9])=[C:11]([CH2:20][CH2:21][Cl:22])[C:12]([CH3:19])=[N:13][C:14]=12
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Cl)cnn2c(Cl)c1CCCl
Reaction time: 1 h
Yield: 59 %

Procedure:
1.60 g (12 mmoles) of N-chlorosuccinimide were added to a solution of 2.30 g (10 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1.5-a]pyrimidine (prepared as described in Example 3) in 10 ml of chloroform, and the resulting mixture was heated under reflux, with stirring, for one hour. At the end of this time, the reaction mixture was washed with a 2N aqueous solution of potassium hydroxide and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through alumina (eluted with chloroform) and recrystallized from diisopropyl ether to afford 1.56 g (yield 59%) of the title compound as light yellow needles, melting at 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:25]=[CH:24][C:18]2[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=2[CH:16]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]=[C:20]([S:22][CH3:23])[O:21][C:17]=4[CH:16]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cnc2c1
Reactant: CSc1nc2ccc(CCl)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a stirred solution of 6-bromo-3H-imidazo[4,5-b]pyridine (506 mg, 2.55 mmol) from Step 1 of this Example in anhydrous DMF (10 mL) at 0° C. was added in one portion sodium hydride (60% dispersion in mineral oil, 107 mg, 2.68 mmol), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]oxazole (600 mg, 2.81 mmol) from Step 3 of Example 56 in DMF (2 mL). The mixture was allowed to warm to rt, then stirred for a further 15 h. To the reaction mixture was added water and the mixture was extracted with EtOAc. The organic layer was separated and the aq layer extracted with additional EtOAc. The combined organic layers were washed with water then brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 100% DCM, followed by 1% MeOH in DCM to afford 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (460 mg, 48%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 5.59 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 375 and 377 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[N:11]1(S(O)(=O)=O)[CH2:15][CH2:14][N:13]=[CH:12]1>C(O)C(C)C.ClCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]3[NH:13][CH2:14][CH2:15][N:11]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=S(=O)(O)N1C=NCC1
Solvent: ClCCl
Solvent: CC(C)CO
Product: c1cc2c(cc1NC1=NCCN1)CCC2
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 5-aminoindan (200 mg, 1.50 mmol) and 2-imidazolinesulfonic acid (450 mg, 3.00 mmol) in isobutyl alcohol (5 mL) was heated at reflux for 3 h and then stirred overnight. The solvent was removed to give a dark oil. It was flash chromatographed over silica gel (EtOAc:MeOH:Et3N=6:2:1) to afford a yellow solid. The solid was redissolved in dichloromethane, and washed with saturated aqueous Na2CO3. The organic layer was dried and concentrated to give yellow crystals (220 mg, 73% yield) : mp 41-42° C.; EIMS m/z=201 (M+). Anal. Calcd. for C12H15N3 4/5H2O: C, 66.82; H, 7.74; N, 19.48. Found: C, 66.77; H, 7.31; N, 19.24.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[C:15]([O:23][CH3:24])=[C:16]([CH:17]=[N:1][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([CH3:12])=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: COc1c(F)cc(F)cc1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1c(F)cc(F)cc1C=Nc1cccc2nc(C)ccc12
Yield: 87.2 %

Procedure:
To 2.0 g (12.6 mmol) 5-amino-2-methylquinolin and 2.2 g (12.6 mmol) 3,5-difluoro-2-methoxybenzaldehyde in 38 ml toluene are added 0.1 ml acetic acid and 5 g molecular sieve. The mixture is heated over 5 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene. 3.43 g of [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine are obtained as a yellow solid. 1.93 ml (22.3 mmol) 1,1,1-trifluoroepoxypropane in 40 ml THF and 10 ml hexane are cooled to −100° C. and 14 ml of a 1.6 M n-butyl lithium solution in hexane are added over 2 hours while the temperature does not exceed −96° C. 10 Minutes after complete addition 3.44 g (11.2 mmol) [(3,5-difluoro-2-methoxyphenyl)methylene]-2-methylquinolin-5-amine in 50 ml THF are added over 1.5 hours while the temperature temperature does not exceed −95° C. After one hour at −100° C. the reaction mixture is warmed to 0° C. over two hours. The reaction was quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer was extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (isopropanol in hexane 5% to 20%) yields 1.68 g of the desired epoxide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=2[CH:30]=1)=[NH:19].C(N=C=NCCCN(C)C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CS(C)=O.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([CH2:28][OH:29])=[CH:25][C:24]=4[CH:30]=3)[N:17]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: N=C(NO)c1ccc2oc(CO)cc2c1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: [F-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(-c3ccc4oc(CO)cc4c3)no2)cc1OCC
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.21 g; 1 mmol), the product of Step C (0.2 g; 0.97 mmol) and hydrochloride salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.22 g; 1.15 mmol) in anhydrous dimethylsulfoxide (DMSO) (2 ml) was stirred for 20 min at ˜40° C. under N2. To it 1 M tetra-n-butylammonium fluoride (TBAF) in terahydrofuran (THF) (0.4 ml) was added and the resulting mixture was stirred for 1 h at ˜120° C., then overnight at room temperature. The solvents were removed in vacuo and the residue was partitioned between EtOAc (15 ml) and H2O (5 ml). The organic phase was washed with brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.13 g; 34%), as greyish solid. 1H-NMR (CDCl3) 8.36 (d, 1H, J=3 Hz); 8.09 (dd, 1H, J=3, 9 Hz); 7.79 (dd, 1H, J=3, 9 Hz); 7.68 (d, 1H, J=3 Hz); 7.55 (d, 1H, J=9 Hz); 6.98 (d, 1H, J=9 Hz); 6.73 (s, 1H); 4.8 (s, 2H); 4.2 (m, 4H); 2.02 (s, 1H); 1.51 (m, 6H);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.CC([N:20]([C@@H:24]([C:27](NC1C=NC(OC2C=CC(C#N)=C(C(C)C)C=2)=CC=1)=[O:28])[CH2:25]C)[C:21](=O)[O-:22])(C)C.Cl>ClCCl>[CH3:25][C@H:24]1[NH:20][C:21](=[O:22])[N:13]([C:12]2[CH:14]=[CH:15][C:9]([O:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:10][CH:11]=2)[C:27]1=[O:28]
Reactant: Cc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(Oc2ccc(N3C(=O)N[C@H](C)C3=O)cc2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4-[(3-methylphenyl)oxy]aniline (90 mg, 0.45 mmol) in dichloromethane (1 mL) was added with shaking at 35° C. an aliquot of approximately 1/3 of solution 1 slowly via syringe (over ca. 1 min). After 30 min, HCl (ca. 0.8 mL) was added and the heterogeneous mixture was heated at 100° C. for 2 hours with shaking, allowing the dichloromethane to distill off through a glass capillary. After cooling to room temperature the aqueous HCl was pipetted off and the residue dried under vacuum. The residue was purified by silica gel chromatography (Biotage instrument, 10 g column) eluting with 0-100% EtOAc/cHex to give after drying the title compound as a solid (30 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24]([CH2:23][O:11][C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1)=[O:25]
Reactant: COC(=O)CCl
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To a mixture of (4-nitrophenoxy)acetic acid 22 (150 g, 761.4 mmol) and triethyl-amine (85 g, 840 mmol) in acetone (750 ml) was added methyl chloroacetate (91.6 g, 844 mmol) drop wise and stirred under reflux for 8 hours. Solids were filtered off and poured onto cold 5% sodium bicarbonate solution (4 L). Crude 44 was filtered, dried and recrystallised from chloroform:hexane (1:6) to get pure 44 (186 g, 90.8%) as a white powder with an m.p. between 88-90° C.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[CH2:9]1[C:13]2([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1.CC(O)=O>C1COCC1>[O:19]=[C:18]1[CH:17]([C:5]([O:6][CH3:7])=[O:8])[CH2:16][CH2:15][CH2:14][C:13]21[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: O=C1CCCCC12CCCC2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: 80 °C

Procedure:
In a flask containing NaH (4.73 g, 118.20 mmol) in THF (30 mL) was added dimethylcarbonate (8.30 mL, 98.52 mmol). The mixture was heated at 80° C. To the mixture was added a solution of spiro[4.5]decan-10-one, 59, (6.00 g, 39.41 mmol) in THF dropwise (25 mL). The reaction was heated for 6 hrs at 80° C. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated and the crude residue was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1OCCCCO1
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl- 1,3-dioxepane (15 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxepan-2-ylmethyl)-2,6 -diethylaniline.