Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1,4-cyclohexanedione mono-ethylene ketal (8.1 g, 50 mmol) in THF (20 mL) at 10° C. was added a 1 M solution of 4-fluorophenyl magnesium bromide in THF (65 mL, 65 mmol). The resulting mixture was stirred at room temperature for 2 hours before quenching with saturated NH4Cl solution. The solution was extracted with EtOAc 3 times. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was taken up in toluene (80 mL). To it was added p-toluenesulfonic acid monohydrate (80 mg). The mixture was stirred at reflux with removal of water using a Dean-Stark trap for 2 hours. The resulting solution was washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5%, 10% and then 15% EtOAc in hexanes provided the title compound (8.8 g, 75%) as a solid. MS calculated (M+H)+ 235. found 235.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:33])[CH:5]=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1.Cl>CCO.[OH-].[Na+].O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:18]=2)[C:9]([O:28][CH3:29])=[C:8]2[C:3]=1[C:4](=[O:33])[CH:5]=[CH:6][N:7]2[CH:30]1[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1ccc(NCCNc2c(F)c(N)c3c(=O)ccn(C4CC4)c3c2OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(NCCNc2ccc(C(=O)O)cn2)c(F)c(N)c2c(=O)ccn(C3CC3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.3 %

Procedure:
To a solution of ethyl 2-[2-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]ethylamino]pyridine-5-carboxylate (320 mg, 0.703 mmol) in EtOH (8 mL), 1M aq. NaOH was added. The mixture was stirred at room temperature for 5 h and then stirred at 50° C. for 3 h. After cooling, the reaction mixture was diluted with water (30 mL) and neutralized with 1M HCl. The product was extracted with CH2Cl2-MeOH (5:1, 2×50 mL). The extaction mixture was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (50 mL) and water (50 mL), and the solution was concentrated in vacuo until ca. 30 mL. The resulting precipitate was collected by filtration, washed with water and dried to give 2-[2-[(5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl)amino]ethylamino]pyridine-5-carboxylic acid (115 mg, 38%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH:25]=O)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2].[CH2:28]([NH2:30])[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:16]=2[CH2:25][NH:30][CH2:28][CH3:29])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: 2-(2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-propionic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1ccc(Cl)nc1

Procedure:
A solution of (6-chloropyridin-3-yl)acetic acid (5.0 g), N,O-dimethylhydroxyamine hydrochloride (2.98 g), EDC.HCl (5.87 g), and N-methylmorpholine (9.6 mL) in DMF (70 mL) was stirred at room temperature for 4 days. Under ice cooling, water (150 mL) was added thereto, followed by extraction with EtOAc. The organic layer was sequentially washed with water and brine and was dried over Na2SO4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil: 50 g, mobile phase: n-hexane/EtOAc=75/25 to 0/100 (v/v)) to yield the title compound (3.56 g, light yellow oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:25])[CH3:2]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (6.65 g) in toluene (50 mL) was added to a solution of o-tolylmagnesium chloride in THF (1M, 30.9) at 0° C. After the addition was complete, the solution was heated to 85° C. for 1.5 hours, and stirring was continued at rt overnight. The mixture was heated for additional 2 hours to 85° C., cooled and poured onto ice. 1M HCl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Et2O/n-heptane 1:3) to yield the title compound (6.45 g, 73%) as a light yellow oil, MS (ESI−): m/z=370.0444 ([M−H]−, 1Br).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:35][CH:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)=[CH:22][CH:21]=1
Reactant: O=C1CC(c2ccc(F)cc2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1)O2

Procedure:
2-(4-Fluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1,5 g of 2-(4-fluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.84 (s, 1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.89 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.7 Hz), 5.42 (bs, 1H), 5.12 (d, 1H, J 10.7 Hz), 4.87 (m, 1H), 2.25 (m, 1H), 1.89 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20]([O:24][C:25](SC1N=C(C)C=C(C)N=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:25]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11])([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26]
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 33.4 g (0.2 mol) of p-hydroxyphenylglycine were added 110 ml of water, 42 ml (1.5 eq.) of triethylamine, 52.8 g (1.1 eq.) of S-t-butoxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine and 110 ml of dioxane, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added 300 ml of water, and the mixture was extracted with 400 ml of ethyl acetate. The organic layer was extracted with 100 ml of a 5% aqueous solution of sodium hydrogencarbonate. The aqueous layers were combined, adjusted to pH 3 with 5N hydrochloric acid under ice-cooling and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was distilled off. The thus-obtained crystals were collected by filtration with ethyl acetate/hexane. Yield: 46.0 g (86.1%).
Reaction SMILES: [CH:1]1([CH:6]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCOCC1.O>[CH:1]1([CH:6]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[N:31]3)=[CH:25][CH:24]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C=Cc1cccc(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
827 mg (1.461 mmol) of ethyl (2E)-3-{3-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]phenyl}prop-2-enoate (Example 174A) were dissolved in 28 ml of dioxane/water (3:1 v/v), and 2.2 ml of 1 N aqueous sodium hydroxide solution were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then acidified to pH 1 with 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. This gave 780 mg (95% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@:9]([CH3:22])(O)[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>COCCO>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[CH2:22])[C:8]=3[CH:7]=[CH:6][N:5]2[C:23]=1[CH3:24]
Reactant: Cc1nc2c3c(ccn2c1C)[C@@](C)(O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCO
Product: C=C1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.3 %

Procedure:
A mixture of 1.0 g of (7R,8R,9R)-2,3,7-trimethyl-7,8-dihydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine and 0.45 g of conc. sulfuric acid in 15 ml of 2-methoxyethanol is vigorously stirred at room temperature for 48 h, the reaction mixture is poured into 50 ml of saturated aqueous sodium hydrogencarbonate solution, extracted three times with 50 ml of dichloromethane each time, and the organic phases are combined and washed with a little water. After stripping off the solvent in vacuo, the oily residue obtained is purified on silica gel (eluent: dichloromethane/methanol 100/1). 0.22 g of the title compound is obtained as pale yellow crystals of melting point 199-202° C. (diethyl ether).
Reaction SMILES: [CH3:1][O-:2].[Na+].C([C@H]1COC(=O)N1[C:17](=[O:39])[C@@H:18]([O:36][CH2:37][CH3:38])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][C:22]=1[CH3:35])[OH:20])C1C=CC=CC=1>CO>[CH3:1][O:2][C:17](=[O:39])[C@@H:18]([O:36][CH2:37][CH3:38])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][C:22]=1[CH3:35])[OH:20]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Temperature: 0 °C
Yield: 69.4 %

Procedure:
A 5.4 M solution of sodium methoxide (7.3 ml, 39.5 mmol) was added to an ice-cooled and stirred suspension of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one (17.6 g, 36 mmol) in dry methanol (87 ml). The mixture was stirred at 0° C. for 15 min, quenched and neutralized by the addition of dilute aqueous hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure and the residue dissolved in ice water/ethyl acetate 1/1. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 8.6 g (25 mmol, 69%) of the title compound as light yellow oil. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(OC(C)C)c(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(C(=O)O)cc1CO
Temperature: 80 °C
Yield: 89 %

Procedure:
To methyl 3-(hydroxymethyl)-4-isopropoxy-benzoate (180 mg, 0.80 mmol) and 1,4-dioxane (1.895 mL) was added sodium hydroxide (2.1 mL of 1.0 M, 2.1 mmol) and the mixture was heated at 80° C. for 50 minutes. The solvent was evaporated under reduced pressure. The crude mixture was dissolved in water (10 mL) and was washed with ethyl acetate (3×10 mL) which was discarded. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 3-(hydroxymethyl)-4-isopropoxy-benzoic acid (89%) as a white solid. ESI-MS m/z calc. 210.2, found 211.3 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br>>[Br:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1cccc(Br)c1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(Br)c2)cc1

Procedure:
Analogously to Method D, 4.14 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 2.31 g of 3-bromobenzyl bromide are reacted. The title compound is obtained as a yellowish oil. Rf=0.40 (1:2 EtOAc-heptane); Rt=6.45.
Reaction SMILES: O.[Na].[CH:3]1[C:16]2[C:7](=[CH:8][C:9]3[C:14]([C:15]=2[CH2:17][OH:18])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23])[CH3:20].CCCCCC>O1CCCC1>[CH2:19]([N:21]([CH2:25][CH3:26])[C:22](=[O:23])[O:18][CH2:17][C:15]1[C:14]2[C:9]([CH:8]=[C:7]3[C:16]=1[CH:3]=[CH:4][CH:5]=[CH:6]3)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:20]
Reactant: CCN(CC)C(=O)Cl
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCN(CC)C(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To the solution containing 1.6 g of 50% sodium hydrate (33 mmol) and 4 mL of dehydrated tetrahydrofuran (dehydrated THF), the solution dissolved 6.3 g of 9-anthracenemethanol (30 mmol; produced by Wako Pure Chemical Industries, Ltd.) into 26 mL of dehydrated tetrahydrofuran (dehydrated THF) was dropped. Then, after this solution of 4.5 g of N,N-diethylcarbamoyl chloride (33 mmol; produced by Sigma-Aldrich Japan Co.) in 4 mL of dehydrated tetrahydrofuran (dehydrated THF) was added, the solution was reacted by stirring for 2 hours at 60° C. After completing reaction, reaction solution was cooled, and n-hexane was poured into the cooled solution, then, the solution was washed with water, and organic layer after washing was condensed. The resultant condensed residue was purified with column chromatography (Filler: Silica-Gel (Wako-Gel C-200; produced by Wako Pure Chemical Industries, Ltd.), Developing solvent: n-heptane) to obtain 5.7 g of 9-anthrylmethyl N,N-diethylcarbamate (yield: 61%) represented by the above-described formula [7] as yellow crystal. Measurement results of 1H-NMR and melting point are shown as the follows:
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[OH:18].CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Br:1][C:2]1[C:3]([O:18][CH3:21])=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1Br
Temperature: 40 °C
Yield: 100.3 %

Procedure:
To a solution of 2-bromo-4-nitro-3-phenylaminophenol (450 mg, 1.45 mmol) in acetone was added methyl iodide (0.34 mL, 5.44 mmol) and potassium carbonate (751 mg, 5.44 mmol) and the reaction mixture heated at 40° C. for 16 h. The mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo to give the title compound as a yellow oil (470 mg, 100%). 1H NMR 400 MHz δ (CDCl3): 8.36 (1H, br s), 8.19 (1H, d, J=9.6 Hz), 7.28-7.22 (2H, m), 7.05-7.00 (1H, m), 6.89-6.84 (2H, m), 6.69 (1H, d, J=9.7 Hz), 4.01 (3H, s).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2>C(Cl)Cl>[Br:1][CH2:15][C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Solvent: ClCCl
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of bromine (0.682 mL, 13.3 mmol) in DCM (20 mL) was added to a solution of 1-(6-bromonaphthalen-2-yl)ethanone (3.30 g, 13.3 mmol) (>90% purity) in DCM (60 mL) and the reaction was stirred at rt overnight. The reaction mixture was concentrated to yield 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g) as an off white solid which was used without further purification. LC-MS retention time 2.177 min; m/z 342.92 (MNa+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 1H), 8.03-8.10 (m, 2H), 7.86 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.0 Hz, 1H), 4.56 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][CH2:7][CH2:8][N:9](C(=O)C)[C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[Na+].[Na+].[OH-].[K+]>O.CO>[O:18]1[CH2:19][CH2:20][N:1]([C:2]2[CH:14]=[CH:13][C:5]3[O:6][CH2:7][CH2:8][NH:9][C:4]=3[CH:3]=2)[CH2:16][CH2:17]1
Reactant: CC(=O)N1CCOc2ccc(N)cc21
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: c1cc2c(cc1N1CCOCC1)NCCO2
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(6-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (0.5832 g, 3.03 mmol), 1-bromo-2-(2-bromoethoxy)ethane (0.774 g, 3.34 mmol), MeOH (3 mL), and Na2CO3 (0.6432 g, 6.07 mmol) in a pressure vessel was stirred at 150° C. After 1.5 h, the mixture was cooled to rt. To the cooled mixture was added a solution of KOH (1.1066 g, 19.72 mmol) in water (2 mL) and the mixture was stirred at 55° C. After 1 h, the mixture was cooled to rt, poured into ice water (50 mL), and extracted with EtOAc (50 mL×2). The combined organics were washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a violet solid. The violet solid was purified by column chromatography on a silica gel column using 0 to 100% gradient of EtOAc in hexane as eluent to give 6-morpholino-3,4-dihydro-2H-benzo[b][1,4]-oxazine as a white solid: Mass Spectrum (ESI) m/e=221.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[Li]CCCC.[CH3:22][O:23][C:24](=O)[CH2:25][O:26]C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:16][C:6]1[C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[C:2]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH:3]=[N:4][CH:5]=1
Reactant: COCC(=O)OC
Reactant: Clc1cncc(Br)c1COC1CCCCO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)c1cncc(Cl)c1COC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.30 g, 0.98 mmol) was dissolved in anhydrous THF (15 mL) under Ar and the solution was cooled to −78° C. n-BuLi (0.62 mL, 1.6 M in hexanes, 0.98 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 0.5 h. Then methoxy-acetic acid methyl ester (0.97 mL, 9.8 mmol) dissolved in anhydrous THF (10 mL) was added dropwise and stirring was continued at −78° C. for 2 h. At completion of the reaction, monitored by TLC, saturated NaHCO3 was added with vigorous stirring. The quenched mixture was extracted with EA (2×20 mL) and the combined organic extracts were washed with saturated NaHCO3 (20 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel with EA/hexane to provide the title compound as a colorless oil. MS (m/z): 300.5 [M+H+].
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)[CH2:6][N:7](C)[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:11][CH:10]=1.Cl[CH2:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH3:51]>>[CH3:6][N:7]([CH2:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][C:42]=1[CH3:51])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[N:11][CH:10]=1
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(=O)N(C)Cc1c(C)ccc2ccccc12

Procedure:
The parent compound was obtained as a white solid in comparable yield according to the procedure described above for the preparation of N-(3,5-bis-trifluoro-methylbenzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 16, step d) using 1-chloromethyl-2-methylnaphthalene instead of 3,5-bis-trifluoromethyl-benzyl bromide.