Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)cc(Cl)n1
Yield: 56 %

Procedure:
Following the method described in Example 1, 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine and 4-chloro-phenylboronic acid gave 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-(4-chloro-phenyl)-amine in 56% yield. 1H NMR (acetone-d6) δ 3.92(s, 3H, CH3), 6.86 (d, 1H, J=8.9 Hz, Ar), 6.90 (t, 1H, J=1.9 Hz, Ar), 7.18 (d, 1H, J=8.9 Hz, Ar), 7.20 (d, 1H, J=8.9 Hz, Ar), 7.36 (d, 2H, J=8.9 Hz, Ar), 7.41 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.46 (d, 2H, J=8.9 Hz, Ar), 7.72 (t, 1H, J=1.9 Hz, Ar), 7.95 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][CH2:23]O)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1)[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:22][CH2:23][N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)[C:12]2=[O:25])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCO)CN2c1ccccc1
Reactant: CN1CCNCC1
Product: CN1CCN(CCN2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)CC1

Procedure:
The title compound, MS: m/e=598.1 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-methylpiperazine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1)(=O)=O.[CH3:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)Cl.CO>[I:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][N:26]2[CH2:27][CH2:28][C:23]([CH3:22])([OH:29])[CH2:24][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCOc1ccc(I)cc1
Reactant: CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC1(O)CCN(CCOc2ccc(I)cc2)CC1

Procedure:
The product was obtained analogously to Example 1.1g (3 hours at 70° C., potassium carbonate as base) from 4.79 g (14.0 mmol) of 2-(4-iodophenoxy)ethyl methanesulfonate and 1.94 g (16.8 mmol) of 4-methylpiperidin-4-ol. Yield: 3.40 g (67% of theoretical); C14H20INO2 (M=361.219); calc.: molpeak (M+H)+: 362; found: molpeak (M+H)+: 362; Rf value: 0.20 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])OC(C)(C)C)[CH3:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:3][CH2:2]1.Cl.[C:37](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:33])[CH3:37])[CH3:25])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3F)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-2,3-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.18 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (902 mg). 1H NMR (300 MHz, CDCl3) δ 0.35-0.46 (2H, m), 0.66-0.77 (2H, m), 1.24-1.41 (4H, m), 2.02 (3H, s), 4.00 (2H, d, J=6.8 Hz), 4.05-4.18 (2H, m), 4.34-4.49 (1H, m), 5.86 (1H, d, J=7.9 Hz), 6.86 (1H, ddd, J=9.1, 7.2, 1.9 Hz), 7.05 (1H, dd, J=8.7, 7.2 Hz), 7.48 (1H, dd, J=8.7, 1.1 Hz), 7.89 (1H, td, J=8.1, 2.3 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:23])[CH:10]([NH:22][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:36])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(=O)c2ccc(F)cc2)c2ccccc12
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (600 mg, 1.73 mmol) and 4-methyl-1-naphthalenecarboxylic acid (354 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg, 2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixture was stirred overnight. To the reaction solution were added 1N aqueous hydrochloric acid solution (10 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (50 ml×2): The extract was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 and recrystallized from ethyl acetate-hexane to give N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide (665 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]1[O:12][CH2:11]1.[NH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1>C(O)(C)C>[C:21]([C:20]1[CH:24]=[CH:25][C:17]([O:16][CH2:15][CH2:14][NH:13][CH2:11][CH:10]([OH:12])[CH2:9][O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:18][CH:19]=1)(=[O:22])[NH2:23]
Reactant: Clc1ccccc1OCC1CO1
Reactant: NCCOc1ccc(C(N)=O)cn1
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCNCC(O)COc2ccccc2Cl)nc1

Procedure:
9.2 g of 3-(2-chloro-phenyloxy)-1,2-epoxy-propane are added to a solution of 9.0 g of 6-(2-aminoethoxy)-nicotinic acid amide in 200 ml of isopropanol and the mixture is heated under reflux for 4 hours. After evaporating off the solvent under reduced pressure, 1-[2-(5-carbamoyl-2-pyridyloxy)ethyl-amino]-3-(2-chloro-phenoxy)-2-propanol is obtained; its hydrochloride melts at 202°-204° C. after recrystallisation from methanol.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[C:24]([CH2:29][CH3:30])[C:23]([C:31]([O:33]C)=[O:32])=[CH:22][C:21]=4[C:20]3=[O:35])[CH2:15][CH2:14]2)[CH:7]=[C:6]([CH:36]2[CH2:38][CH2:37]2)[C:5]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=1[F:46]>C(O)C>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[C:24]([CH2:29][CH3:30])[C:23]([C:31]([OH:33])=[O:32])=[CH:22][C:21]=4[C:20]3=[O:35])[CH2:17][CH2:18]2)[CH:7]=[C:6]([CH:36]2[CH2:37][CH2:38]2)[C:5]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=1[F:46]
Reactant: CCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(Cl)c3OC)CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)c(Cl)c3OC)CC1)CC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.5 mL) was added at room temperature to an ethanol (8 mL) solution of methyl 6-(1-((2-chloro-6-cyclopropyl-2′,4′-difluoro-3-methoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (301 mg), and the mixture was stirred at 80° C. for 1 hour in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was neutralized with 2 M hydrochloric acid. Then, the deposited crystals were collected by filtration and dissolved in ethanol, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethanol) to obtain the title compound (241 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17][CH2:18]O>>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:18]
Reactant: CCO
Reactant: O=C(O)c1cc(O)ccc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(O)ccc1Cl

Procedure:
To a mixture of commercially available 2-chloro-5-hydroxybenzoic acid (4 g, 23.18 mmol) in dry EtOH (90 mL), concentrated sulphuric acid (1 mL, 17.62 mmol) was added. The mixture was stirred under reflux overnight, then solvent evaporated under reduced pressure and the residue dissolved with DCM. A saturated solution of NaHCO3 was added, phases were separated, organics dried over sodium sulphate, filtered and evaporated to obtain 5 g of the corresponding 2-chloro-5-hydroxy-benzoic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:21][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])cc1

Procedure:
To the solution of 10 g ethyl 4-nitrophenylacetate in 400 ml dimethyl formamide-toluene (1:1), 2.5 g 50% sodium hydride are added portionwise during 15 minutes while stirring and cooling with ice, after which the solution of 9.6 g cyclopropylmethyl bromide in 50 ml toluene is added dropwise and the mixture stirred overnight at room temperature. It is diluted with 200 ml water, extracted with diethyl ether, the extract dried, evaporated, the residue distilled and the fraction boiling at 132°-138°/0.25 mm Hg collected, to yield the ethyl α-(4-nitrophenyl)-β-cyclopropylpropionate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:32]2[CH:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:29]=[CH:28][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:32]2[CH:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:29]=[CH:28][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2cnc(C(F)(F)F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (99 mg, 0.66 mmol.) in THF (2 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (1.3 mL of a 1 M solution in THF, 1.3 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 1-ethyl-6-trifluoromethyl-1H-furo[3,4-c]pyridin-3-one, (100 mg, 0.44 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, 40% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (30 mg, 19%).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[CH2:30]([N:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([N:37]1[CH2:42][CH2:41][C:40]([C:29]2[C:20]([Cl:19])=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)([OH:43])[CH2:39][CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 38.2 mL, 61.1 mmol) was added to a solution of diisopropylamine (8.6 mL, 61.1 mmol) in tetrahydrofuran (140 mL) at −78° C. under argon. After 1 h, a solution of 2-chloroquinoline (10.00 g, 61.1 mol) in tetrahydrofuran (30 mL) was added via syringe. After 1 h, a solution of 1-benzyl-4-piperdinone (11.3 mL, 61.1 mmol) was added, and the reaction stirred for an additional 40 min at −78° C., then allowed to warn to room temperature. The reaction was cooled to −20° C. and quenched with water. The reaction solution was extracted with ethyl acetate, and the organic phase washed with saturated brine and dried over magnesium sulfate. Chromatographic purification (silica gel,0 to 10% {5% ammonium hydroxide/methanol} in methylene chloride gradient elution) gave the title compound, 11.3 g. MS 353 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.72 (dt, J=1,10 Hz, 1H), 7.57 (dt, J=1,8 Hz, 1H), 7.39–7.26 (m, 5H), 3.61 (s, 2H), 2.85 (d, J=11 Hz, 2H), 2.59 (t, J=12 Hz, 2H), 2.48 (dt, J=4,13 Hz, 2H), 2.13 (d, J=12 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[OH:15].CS([C:20]1[N:21]=[C:22]([O:46][CH2:47][CH2:48][CH3:49])[C:23]2[N:28]=[C:27]([C:29]3[CH:43]=[C:42]([CH3:44])[C:32]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:31]([CH3:45])[CH:30]=3)[O:26][C:24]=2[N:25]=1)(=O)=O.S(=O)(=O)(O)[O-].[Na+]>CN(C)C=O.O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[O:15][C:20]1[N:21]=[C:22]([O:46][CH2:47][CH2:48][CH3:49])[C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[C:31]([CH3:45])[C:32]([O:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[C:42]([CH3:44])[CH:43]=3)[O:26][C:24]=2[N:25]=1
Reactant: Oc1cc(F)ccc1F
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
62 mg of potassium carbonate and 32 mg of 2,5-difluorophenol were added to a solution of 100 mg of tert-butyl [4-(5-methanesulfonyl-7-propoxyoxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate in 1.5 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 12 h. The mixture was then poured into water, neutralized by addition of 10% strength aqueous sodium bisulfate solution and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by preparative HPLC, giving 69 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33].N>C(Cl)Cl.CO>[CH3:29][O:30][CH2:31][C:32]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:33]
Reactant: COc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c(OC)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a suspension of 4-(3-methoxy-4-nitrophenoxy)pyridin-2-amine (420 mg, 1.61 mmol) in DCM (4.0 mL) containing DIPEA (562 μL, 3.22 mmol) at 0° C. was added 2-methoxyacetyl chloride (220 μL, 2.41 mmol) in a single portion. The reaction mixture was warmed to RT for 1 hr and then a solution of NH3 in MeOH (7M, 2.0 mL) was added. The resulting mixture was kept at RT for 30 min, was evaporated in vacuo and the residue was partitioned between DCM (5.0 mL) and water (5.0 mL). The organic phase was separated and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford 2-methoxy-N-(4-(3-methoxy-4-nitrophenoxy)pyridin-2-yl)acetamide as pale yellow oil (401 mg, 75%); Rt 1.87 min (Method 2); m/z 334 (M+H)+ (ES+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](OS(C(F)(F)F)(=O)=O)=[CH:2]1.C(N(CC)CC)C.[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][BH:28][O:27]1.C(Cl)Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][C:26]1([CH3:33])[C:30]([CH3:32])([CH3:31])[O:29][B:28]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][CH:2]=2)[O:27]1
Reactant: CC1(C)OBOC1(C)C
Reactant: O=S(=O)(Oc1coc2ccccc12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2coc3ccccc23)OC1(C)C
Temperature: 150 °C

Procedure:
To a solution of trifluoromethanesulfonic acid benzofuran-3-yl ester (half of the amount from step A) in THF is added triethylamine (732 mg, 7.23 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.2 mL of a 1.0M in THF, 3.2 mmol) and Pd(dppf)Cl2.CH2Cl2 (76 mg, 0.096 mmol). The mixture is heated at 150° C. under microwave conditions for 3 min. The mixture is filtered and the filtrate evaporated under reduced pressure. The residual oil is purified by flash chromatography using hexane/EtOAc (9:1) as eluent to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][NH:12][C:13]1[NH:18][C:17](=[O:19])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:36](Br)[CH:37]=[CH2:38].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][NH:12][C:13]1[N:18]=[C:17]([O:19][CH2:38][CH:37]=[CH2:36])[C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)[nH]c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCOc1nc(NCc2cc(Br)ccc2OCc2ccccc2)ccc1C(=O)OCC
Reaction time: 120 h

Procedure:
A mixture of ethyl 6-[2-benzyloxy-5-bromobenzylamino]-2-oxo-1,2-dihydropyridine-3-carboxylate (2.78 g), sodium carbonate (0.97 g) and allyl bromide (0.77 ml) in DMF (10 ml) was stirred for 5 days, poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic solution was washed with HCl solution, saturated aqueous sodium hydrogen carbonate and brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography, eluting with 2.5% ethyl acetate/dichloromethane, to give ethyl 6-[2-benzyloxy-5-bromobenzylamino]-2-allyloxypyridine-3-carboxylate (1.99 g) as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N:8]([CH3:11])=[C:9]=[S:10]>O1CCCC1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]([NH:8][CH3:11])=[S:10]
Reactant: COC(CN)OC
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)NCC(OC)OC
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 4.2 g of 2,2-dimethoxyethanamine, 3.6 g of isothiocyanatomethane and 100 ml of tetrahydrofuran was stirred overnight. The reaction mixture was evaporated, yielding 7.1 g (99%) of N-(2,2-dimethoxyethyl)-N'-methylthiourea as an oily residue (interm. 34);
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:18]2([C:21]([F:24])([F:23])[F:22])[NH:20][NH:19]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOCC>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:18]2([C:21]([F:22])([F:23])[F:24])[N:19]=[N:20]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2(C(F)(F)F)NN2)cc1CO[Si](C)(C)C(C)(C)C
Solvent: CCOCC
Product: COc1ccc(C2(C(F)(F)F)N=N2)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
A mixture of 3-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyldiaziridine (200 mg, 0.55 mmol) and freshly prepared Ag2O(255 mg, 1.1 mmol) in ether (3 ml) was stirred for 24 h. The solid was filtered, washed with ether, and the filtrate evaporated in vacuo. The resulting residue was purified by chromatography (SiO2, 10% ether/petrol) to give the title compound (187 mg, 94%) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.C([O-])=O.[NH4+]>CO>[NH2:1][C:4]1[C:17]2[C:8](=[N:9][C:10]3[C:15]([C:16]=2[NH2:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1c2ccccc2nc2cccc([N+](=O)[O-])c12
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc2nc3ccccc3c(N)c12
Yield: 40.1 %

Procedure:
To a 50 mL rbf equipped with a nitrogen bubbler were charged 1-nitro-9-aminoacridine (162 mg, 0.68 mmol) and ethyl acetate (3.4 mL). Methanol (1.7 mL) and Pd/Alumina 10% (22 mg) were added and the reaction mixture was stirred to a fine suspension. Ammonium formate (85 mg, 1.35 mmol) was added and the mixture was stirred for 20 min at room temperature. A further portion of ammonium formate (128 mg, 2.03 mmol) was then added. Stirring was maintained overnight. The reaction mixture was filtered to remove catalyst and concentrated to dryness. The residue was purified by flashmaster column eluting with a gradient elution (DCM→DCM:MeOH 98:2) to afford pure 1,9-diaminoacridine as a brown-yellow solid (57 mg, 40%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccco1
Product: C[C@]1(c2cc(NC(=O)c3ccco3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and furan-2-carboxylic acid following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=354.4 [M+H]+.