Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1=[O:28])[CH3:15].O>C(OCC)C>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[C:18]1([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:28])[CH3:13]
Reactant: COc1ccc2c(c1)CC(CN(C)C)C2=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)CC(CN(C)C)C2(O)c1cccnc1
Reaction time: 0.67 h

Procedure:
47 ml of n-butyllithium solution (1.6 mol./l in n-hexane) were added dropwise at a temperature of from −30 to −35° C. to a solution of 7.3 ml of 3-bromopyridine in about 125 ml of diethyl ether p.a. After a further 20 minutes at that temperature, 11 g of 2-dimethylaminomethyl-5-methoxy-indan-1-one, dissolved in diethyl ether p.a., were added dropwise, with continued cooling, stirring was continued for 40 minutes at that temperature, and heating was carried out overnight to room temperature. Then 46 ml of water were added at from −10 to 0° C., the phases were separated, the aqueous phase was extracted with diethyl ether (monitoring by thin-layer chromatography), and the combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The resulting crude product was chromatographed on silica gel with ethyl acetate/25% ammonia solution (v/v=98:2). 7.06 g of 2-dimethylaminomethyl-5-methoxy-1-pyridin-3-yl-indan-1-ol were obtained and were dissolved in about 125 ml of 2-butanone p.a. and converted into the corresponding hydrochloride with about 0.3 ml of water and about 4.2 ml of chlorotrimethylsilane, while cooling with ice; the hydrochloride was filtered off with suction with the exclusion of air and dried in vacuo (about 50 mbar) (yield 6.79 g, mixture of the two diastereoisomers).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][F:35]>CS(C)=O.O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:34][F:35])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nc(COCc2ccccc2)n(CF)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 1.5 °C
Reaction time: 3 h
Yield: 79.7 %

Procedure:
In dimethylsulfoxide (20 ml)was dissolved 814 mg (2.0 mmol)of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (16a), with cooling to 0 to 3° C., followed by addition of 1.44 g (10.4 mmol)of potassium carbonate with stirring, and the mixture was stirred at the same temperature for 15 minutes. Then, 270 mg (2.40 mmol)of bromofluoromethane was added, and the mixture was stirred for 30 minutes at the same temperature and then for 3 hours at room temperature, and left overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the crude product was fractionated by silica gel column chromatography (ethyl acetate:methylene chloride=1:19). From the first fraction, 137 mg (yield 16%)of positional isomer (17x')of the target compound was obtained as oil. From the subsequent fraction, 700 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-fluoromethyl-4-isopropyl-1H-imidazole (17x)of the target compound was obtained as oil (yield 80%).
Reaction SMILES: [Br:1][C:2](Br)=[N:3][OH:4].[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:10]=[C:9]([Cl:19])[CH:8]=1.C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Br:1][C:2]1[CH2:14][C:13]([C:11]2[CH:10]=[C:9]([Cl:19])[CH:8]=[C:7]([Cl:6])[CH:12]=2)([C:15]([F:16])([F:18])[F:17])[O:4][N:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(Br)=NO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.7 %

Procedure:
To a solution of dibromoformaldoxime (6.23 g, Tetrahedron Lett., 1984, 487) in ethyl acetate (150 ml) was added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.3 g, prepared according to WO 2005/085216) and sodium bicarbonate (9.5 g). The reaction was stirred at room temperature for 96 h. Water was added, then the two layers were then separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated to afford a white solid (6.23 g). 1H-NMR (CDCl3, 400 MHz): 7.47-7.43 (m, 3H), 3.95 (d, 1H), 3.58 (d, 1H)
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>O>[C:1]1([C:7]2[C:8]3[CH:18]([OH:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-phenylindeno[1,2-c]pyrazol-4(1H)-one (0.86 g), sodium borohydride (0.26 g) and absolute ethanol (200 ml) was stirred at ambient temperature for 72 hours. The mixture was filtered to remove a small amount of solid which was discarded and the filtrate was concentrated under reduced pressure to low volume whereupon crystals were formed. This suspension was diluted with water to approximately 250 ml and the solid was collected by filtration and recrystallized from methanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-4-ol, m.p. 269-272° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinic acid (D100) (70 mg, 0.22 mmol), methyl 4-(1-aminocyclopropyl)benzoate (D7) (50.31 mg, 0.22 mmol) and N,N-Diisopropylethylamine (0.115 ml, 0.66 mmol) in dimethylformamide (5 ml) was stirred at room temperature for 1 h. (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (137.9 mg, 0.265 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether (3×15 ml). The combined organic layers were washed with brine (2×10 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by Biotage column (10 g) eluting with a mixture dichloromethane/ethylacetate from 100/0 to 90/10. Collected fractions, after solvent evaporation, afforded the title compound (D144) (66 mg)
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 152–154° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.9 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1 H), 4.93–4.89 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1 H), 3.35 (s, 3 H), 3.12 (t, J=7.9 Hz, 2 H), 1.92–1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0050.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=O)[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.C([O-])(=O)C.[Na+].[CH3:24][O:25][NH3+:26].[Cl-]>CO>[CH3:24][O:25]/[N:26]=[C:6]1/[C:2]([CH3:18])([CH3:1])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]/1
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Reactant: CO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CO/N=C1\CN(C(=O)OCc2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
To a solution of benzyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate (2.91 g, 11.8 mmol) in MeOH (10 mL) was added sodium acetate (1.93 g, 23.5 mmol) and o-methylhydroxylamine hydrochloride (1.97 g, 23.5 mmol). The mixture was stirred at rt for 18 h. The reaction was concentrated and then diluted with dichloromethane (200 mL). The organic layer was washed with water (20 mL) and aq. sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. (Z)-benzyl 4-(methoxyimino)-3,3-dimethylpyrrolidine-1-carboxylate (3.17 g, 97% yield) was obtained as a colorless oil. m/z: 277.17 (M+H); LC retention time: 2.83 min (analytical HPLC Method I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)Cc1ccc(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]([O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide from step 4 in a mixture of MeOH/THF (20 mL, 1:1) was added 1 N NaOH. The reaction mixture was stirred at room temperature overnight. 1N HCl was added to acidify the solution to pH 4. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried and concentrated. The residue was then purified by reverse phase chromatography to afford the product (1.4 g).
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Br[CH2:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10](OC)=[O:11]>C1COCC1>[CH3:1][N:2]1[CH2:7][C:8]2[C:9](=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:11]
Reactant: CN
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1Cc2cccc([N+](=O)[O-])c2C1=O
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of methylamine in ethanol (10 mL, 80 mmol, 8M solution in ethanol) was added to a solution of methyl 2-(bromomethyl)-6-nitrobenzoate (Compound 17G, 8.1 g, 29.6 mmol) in THF (30 mL). After stirring for 2 h the reaction mixture was concentrated to dryness and water (30 mL) was added with rapid stirring. The solids produced were isolated by filtration and dried to give 4.35 g of 2-methyl-7-nitro-2,3-dihydro-1H-isoindol-1-one (yield: 78%). 1H NMR (CDCl3, 400 MHz): δ 3.21 (s, 3H), 4.44 (s, 2H), 7.64 (m, 2H), 7.73-7.74 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[N:5][CH:4]=1)=[O:2].O.O.P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:13]([O:12][C:11]([NH:10][CH:8]([C:6]1[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C=O)s1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
A mixture of tert-butyl 1-(5-formylthiazol-2-yl)ethylcarbamate (3.5 g, 0.014 mol), sodium dihydrogen phosphate dihydrate (2.9 g, 0.019 mol) and 2-methyl-2-butene (3.85 g, 0.055 mol) in tert-butyl alcohol (70 ml) and water (40 mL) was stirred at room temperature for 30 minutes. Sodium chlorite (3.22 g, 0.035 mol) was added and the reaction maintained at room temperature for an additional 2 hours. The reaction was concentrated, diluted with water (50 mL) and acidified (pH=4) with the addition of 3N H3PO4. The mixture was extracted with DCM, the organic layer dried over anhydrous Na2SO4 and evaporated to dryness to afford 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (2.35 g, 60%). LC-MS: (FA) ES+ 273.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO.CCCCCC>[Cl:12][C:4]1[N:3]=[C:2]([O:14][CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (20.0 g, 96.1 mmol) in MeOH (100 mL) was added 0.5 M NaOMe in MeOH (423 mL, 211 mmol) dropwise. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was then concentrated to ca. ⅓ of the volume and slowly poured into saturated NH4Cl solution (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried (Na2SO4), and concentrated in vacuo to yield a tan solid which was suspended in hexane (500 mL) and sonicated for 10 min. The resulting solid was collected by suction filtration and dried under suction to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a powder. 1H-NMR (400 MHz, CDCl3) δ: 6.39 (s, 1H), 6.28 (br s, 2H), 4.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCN(c2ccc(Br)cc2)C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1C(N2CCOCC2)=CCCCN1c1ccc(Br)cc1

Procedure:
N-[4-bromophenyl]-3-oxocaprolactam (1.31 g, 4.63 mmol), morpholine (1.60 mL, 18.52 mmol), and p-toluenesulfonic acid (catalytic amount) were refluxed with 50 mL benzene using a Dean Stark apparatus under N2 for 12 h. The solvent was then removed in vacuo and the residue was dried under vacuum to give 1,5,6,7-tetrahydro-1-[4-bromophenyl]-3-(morpholin-4-yl)-2H-azepin-2-one as a yellow solid. LRMS (AP+): 351.0, 353.0, (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:32][C:31]=1[CH:43]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:43][C:31]3[CH:32]=[C:33]([C:36]4[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=4)[CH:34]=[CH:35][C:30]=3[F:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2ccc(O)cc2)ccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(-c2ccc(F)c(CNc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-fluoro-4′-hydroxy-biphenyl-3-carbaldehyde according to the procedure of Example 66. MS (ESI) m/z 579.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[N:27][C:28]=1[Cl:29]>C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([Cl:22])=[CH:24][C:25]([O:30][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[CH:26][N:27]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (2.74 ml, 18.3 mmol) and cesium carbonate (9.93 g, 30.5 mmol) were added to an N,N-dimethylacetamide solution (10 ml) of 5,6-dichloropyridin-3-ol (1.0 g, 6.10 mmol), and stirred under a nitrogen atmosphere at 100° C. for 16 hours. Saline solution and ethyl acetate were added to the reaction solution, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=11:1 to 9:1) to obtain 2,3-dichloro-5-(2,2-diethoxyethoxy)pyridine (1.51 g, yield: 88%) as an orange oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22]>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[O:22][CH:8]([CH3:10])[CH3:9]
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Powdered potassium carbonate (1.72 g, 12.5 mmol) and 2-iodopropane (1.16 mL, 1.98 g, 11.6 mmol) were added to a solution of 2-bromo-4-(trifluoromethyl)phenol (2.00 g, 8.30 mmol) in DMF. The mixture was stirred overnight at RT and then partitioned between hexane (100 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium chloride (50 mL) and the aqueous layers were extracted in succession with hexane (50 mL). The organic layers were dried over sodium sulfate, decanted, and evaporated. The crude product was purified by flash column chromatography, eluting with hexane, to give the title compound. Mass spectrum (EI): m/z=282 (M+).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12](O)=[O:13])=[CH:6][N:5]([CH3:15])[C:4]=2[CH:3]=1.C([N:18](CC)CC)C.ClC(OCC)=O.N>O1CCCC1>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([NH2:18])=[O:13])=[CH:6][N:5]([CH3:15])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)c(=O)c(C(=O)O)cn2C
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1cc2c(s1)c(=O)c(C(N)=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid (1.27 g), triethylamine (0.6 ml) and dry tetrahydrofuran (120 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled to 0° and a solution of ethyl chloroformate (0.6 ml) in dry tetrahydrofuran (10 ml) was added during 3 minutes, before being allowed to warm to ambient temperature. Stirring was continued for 18 hours and a further quantity of ethyl chloroformate (0.3 ml) was added at ambient temperature. After stirring for a further 2 hours, the mixture was cooled to 5° and aqueous ammonia (specific gravity 0.880, 10 ml) was added. The mixture was stirred for 20 minutes and the solid was collected, washed with water (50 ml) and dried to give a second sample of crude 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide. The two samples of the carboxamide from (e) and (f) were combined and crystallised from industrial methylated spirit to give pure novel compound 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, m.p. 328°-330°.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:4].OC(C(F)(F)F)=O.[NH2:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35].C[O-].[Na+]>CCO.C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[CH:7][N:6]=[C:5]([C:3]([NH:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O)C(=O)O
Temperature: 150 °C
Yield: 27.8 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (19 mg, 0.061 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (71 mg, 0.31 mmol) and NaOMe (33 mg, 0.61 mmol) in 2 mL of EtOH was heated at 150° C. in a microwave reactor for 6 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M was added with vigorous stirring until pH about 1. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 6.7 mg of the title compound. MS: (+) m/z 396.30 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:20][C@H:21]1[O:23][CH2:22]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[O:23]1[CH2:22][C@H:21]1[CH2:20][O:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1c2ccccc2-c2cccc(OC[C@@H]3CO3)c21
Yield: 20.3 %

Procedure:
Prepared from 1-hydroxy-9-fluorenone (3.0 g, 15.2 mmol), (S)-glycidyl nosylate (3.06 g, 15.2 mmol) and potassium carbonate (2.1 g, 15.2 mmol) according to the procedure used for Intermediate 1 to give 0.78 g product as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]#[N:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)#[N:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrophenol (10 g), bromoacetonitrile (6 mL) and K2CO3 (15 g) were suspended in acetone (100 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and acetone was removed under reduced pressure. The light-yellow precipitate was collected by filtration, washed with water and dried to give O-cyanomethyl-4-nitrophenol.