Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.4 %

Procedure:
A solution of 4-(2-methoxyethoxy)aniline (0.397 g, 2.37 mmol) and pyridine (1 mL, 12.4 mmol) in DCM (3 mL) in was treated with 4-nitrophenyl chloroformate (Aldrich) (0.505 g, 2.51 mmol) added in portions (exothermic!). The pale yellow solution was stirred at RT for 5 h. The reaction mixture was partitioned between 0.5 N HCl (20 mL) and DCM (30 mL). The organic phase was washed with 0.5 N HCl (30 mL), saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saturated aqueous sodium chloride (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (50 g, eluent: EtOAc in hexanes 10%-50%) to give 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.57 g, 72% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.25-8.32 (m, 2H); 7.32-7.43 (m, 4H); 6.87-6.97 (m, 3H); 4.09-4.15 (m, 2H); 3.72-3.79 (m, 2H); 3.46 (s, 3H). m/z (ESI, +ve ion) 333.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[CH3:23])=[O:4].C1C(=O)N([Br:31])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[C:6]=1[CH2:23][Br:31])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To 1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (0.27 g, 0.88 mmol) in 1,2-dichloroethane (5.0 mL) was added NBS (0.178 g, 1.00 mmol) and AIBN (0.032 g, 0.20 mmol and the reaction mixture was heated under reflux for 1 h. After cooling to ambient temperature the solvent was removed by evaporation and the resultant residue was purified by flash chromatography (silica, 5 g column, ISCO, 0-65% DCM in pentane) to afford the title compound as a white solid (0.26 g, 72%). LCMS (Method B): RT=3.95 min, M+H+=409/411.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=4[C:35]([F:36])([F:38])[F:37])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1C(F)(F)F
Yield: 3.1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-fluoro-2-(trifluoromethyl)benzeneboronic acid (available from Frontier Scientific, Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-2′-trifluoromethyl-biphenyl-2-carboxylic acid (4 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.26 (d, J=6.6 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[OH-].[K+].O>CS(C)=O>[N:17]1([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1N1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)cc1N1CCCCC1
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 1-(5-chloro-2-nitro-phenyl)-piperidine (184 mg, 0.760 mmol, as prepared in Example 3, step (a)) and imidazole (67.8 mg, 0.99 mmol) in 3 mL of DMSO was added KOH (64 mg, 1.1 mmol). The reaction was heated to 90° C. overnight. The dark solution was poured into 40 mL of water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL), dried (Na2SO4) and concentrated in vacuo to give 190 mg (92%) of the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C14H16N4O2, 273.1 (M+H), found 273.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:22](=[O:24])=[O:23]>O1CCCC1>[CH3:15][O:14][C:11]([C:10]1[O:16][C:5]2[C:6]([C:22]([OH:24])=[O:23])=[C:7]([F:8])[CH:2]=[CH:3][C:4]=2[N:9]=1)([CH3:13])[CH3:12]
Reactant: COC(C)(C)C(=O)Nc1ccc(F)c(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(C)c1nc2ccc(F)c(C(=O)O)c2o1

Procedure:
An additional 2.1 grams of [2-(1-methoxy-1-methylethyl)-6-fluorobenzoxazol-7-yl]carboxylic acid of was prepared in the manner of Step B, Example 1, with 4.2 grams (17 mmole) of N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methylpropionamide, 120 mL of tetrahydrofuran, 16 mL (40 mmole) of 2.5M n-butyllithium in hexanes, and 3.0 grams of solid carbon dioxide as reagents. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>CC#N>[CH3:8][C:6]1[NH:5][C:4](=[O:9])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:20][CH:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCC(N)CCC
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CC#N
Product: CCCC(CCC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Yield: 89.9 %

Procedure:
4-Chloro-6-methyl-3-nitropyridone (2.9 g, 15.40 mmol) was treated with 1-propylbutylamine (4 mL, 26.8 mmol) in CH3CN (30 mL) at 25° C. for 64 h and at reflux for 2 h. The reaction mixture was partitioned between EtOAc (200 mL) and water (50 mL). The EtOAc was washed with water (2×50 mL), brine, dried (MgSO4) and stripped in vacuo. The residue was washed with 20% EtOAc/hexanes (2×20 mL) to give the product (3.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO.Cl[CH2:19][N:20]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=2[CH:32]([CH3:34])[CH3:33])[S:21]1(=[O:23])=[O:22]>O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:19][N:20]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[CH:32]([CH3:34])[CH3:33])[S:21]2(=[O:22])=[O:23])=[O:8])[O:4][N:3]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1cc(C)no1)C2=O
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A mixture of 3-methylisoxazole-5-carboxylic acid (0.63 g, 5.0 mmol), cesium carbonate (0.8 g, 2.45 mmol) and methanol was stirred for 30 minutes. The solvent was removed in vacuo and the residue was dried in high vacuum for 1 hour. The residue was suspended in DMF (30 ml) and 2-chloromethyl-4-isopropyl-6-methoxysaccharin (1.0 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 19 hours and was poured into water. The mixture was extracted with ethyl acetate/ether (4/1, 300 ml) and the organic layer was separated and wash with water, then brine. The solvent was removed in vacuo and the residue was purified by flash chromatography (30% ethyl acetate/hexanes) to afford 1.1 g (85%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3-methylisoxazole-5-carboxylate as a white powder, m.p. 157°-158° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36]Cl)=[N:34][CH:35]=1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)=[N:34][CH:35]=1
Reactant: ClCc1ccc(Cl)cn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(Cl)cn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 5-chloro-2-chloromethyl-pyridine (18.9 mg, 0.12 mmol) described in manufacturing Example 63-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (38.4 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl.[C:16]([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of (4-bromo-2-nitro-phenyl)-acetic acid (5.00 g, 19.2 mmol) in methanol (100 mL) is treated with conc. HCl (1.0 mL). The mixture is stirred at 85° C. for 16 hours and cooled to room temperature. The mixture is neutralized with aqueous Na2CO3 and concentrated under reduced pressure. The residue is extracted with ethyl acetate (50 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to provide the title compound (5.27 g, 100%) as a brown solid.
Reaction SMILES: [Mg].CO[CH:4]([O:12]C)[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:12])=[CH:10][CH:9]=1
Reactant: COC(OC)c1ccc(Br)cc1
Reactant: Brc1nccs1
Agent: [Mg]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under argon, 9.2 g (379 mmol) of magnesium are placed in 84 ml of THF and heated to 60° C. A solution of 82.6 g (357 mmol) of 4-bromobenzaldehyde dimethyl acetal (for preparation see J. Org. Chem. 56, 4280 (1991)) in 677 ml of THF is added dropwise thereto within a period of 30 min and the mixture is stirred at boiling temperature for a further 40 min. The Grignard solution is cooled, decanted into a dropping funnel and added dropwise within a period of 30 min to a reddish suspension of 31.7 ml (338 mmol) of 2-bromothiazole (Fluka, Buchs, Switzerland) and 5.39 g (9.95 mmol) of DPPP in 1.68 liters of THF. The mixture is stirred at room temperature for 12 hours; a further 5.39 g of DPPP are added and the mixture is stirred for a further 7 hours. 840 ml of water are added and the mixture is stirred for 10 min; the THF is evaporated off using a rotary evaporator and the residue is stirred for 1.5 hours in 1.0 liter of ether and 340 ml of 2N HCl. The aqueous phase is separated off and extracted 2× with ethyl acetate. The organic phases are washed 2× with 0.5N HCl, water, sat. NaHCO3 solution, water and brine, dried (Na2SO4) and concentrated by evaporation. Chromatography (SiO2; hexane/ethyl acetate 4:1) and digestion in hexane yield the title compound: TLC: Rf=0.21 (hexane/ethyl acetate 3:1); m.p: 91-92° C.; Anal. (C10H7NOS) calc. C, 63.47, H, 3.73, N, 7.40, S, 16.94: found C, 63.14, H, 3.79, N, 7.27, S, 17.08; 1H-NMR (CDCl3) δ 10.05 (s, HCO), 8.15 (d, J=8, 2H), 7.95 (m, 3H), 7.45 (d, J=3,1H).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[N:11]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[N:10]=1>CO.[OH-].[Na+].O>[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[N:10]2)=[CH:22][CH:21]=1)(=[O:26])[CH3:25]
Reactant: COC(=O)CCCCCc1nn(-c2ccc(NC(C)=O)cc2)c2c1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(-n2nc(CCCCCC(=O)O)c3c2CCC3)cc1
Yield: 64 %

Procedure:
A solution of the compound of Example 19 (0.13 g) in methanol (7 ml) and 1N sodium hydroxide (3.5 ml) was reacted at 25° C. for 2 hours. The solution was diluted with water, acidified, and the precipitate was extracted into ethyl acetate. The residue from drying and evaporation of solvent was recrystallized from acetonitrile to provide pure title compound (80 mg), m.p. 149°-150° C.
Reaction SMILES: FC(F)(F)C(O)=O.CC([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)[C:23](=[O:41])[CH:22]=2)=[CH:15][CH:14]=1)(C)C>>[OH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:29][CH:28]=3)[C:23](=[O:41])[CH:22]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)Oc1ccc(/C=C/c2ccn(-c3ccc(OCCN4CCCC4)cc3)c(=O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(/C=C/c2ccc(O)cc2)ccn1-c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Trifluoroacetic acid (2 mL) was added to 4-((E)-2-{4-[(2-methyl-2-propyl)oxy]phenyl}vinyl)-1-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}-1H-pyridin-2-one (120 mg, 0.26 mmol) and stirred at room temperature for 30 minutes. After concentrating the reaction liquid under reduced pressure, chloroform was added to the reaction liquid which then was washed with aqueous sodium hydrogencarbonate solution and dried over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the title compound (97 mg, 92%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH2:14][CH2:12][OH:13])[C:5]2=[N:4][CH:3]=1
Reactant: NCCO
Reactant: Clc1nccn2c(Br)cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1nccn2c(Br)cnc12
Temperature: 100 °C

Procedure:
3-Bromo-8-chloro-imidazo[1,2-a]pyrazine (0.70 g, 3.0 mmol) (from Example 1 supra) was stirred in nBuOH (10 mL) and ethanolamine (0.22 mL, 3.65 mmol) followed by Hunig's base (1.04 mL, 6.0 mmol) Reaction mixture was then heated at 100° C. overnight. The mixture was concentrated to dryness and water was added (150 mL) followed by a saturated aqueous solution of NaHCO3 (50 mL). The reaction was then extracted with EtOAc (3×20 mL) and the organic phases were combined, washed with water (2×20 mL), dried over MgSO4 and concentrated to dryness to give 2-(3-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-ethanol. (Yield 0.59 g, 77%). 1H (400 MHz; DMSO-d6) δ 3.52-3.56 (2 H, m), 3.58-3.62 (2 H, m), 4.79 (1 H, t, J=5.4 Hz), 7.42 (2 H, d, J=5 Hz), 7.56 (1 H, d, J=5 Hz), 7.66 (1 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[OH-].[K+].Cl[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][N:14]=1>CO.C1(C)C=CC=CC=1>[NH2:19][C:18]1[C:13]([O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ncccc2N)cc1
Reaction time: 2 h
Yield: 108.5 %

Procedure:
5.87 g of 4-methoxyphenol were dissolved in 8 ml of methanol; 2.61 g of KOH were added, the whole was stirred for 2 hours, and the solvent was evaporated. The solid obtained was dissolved in 150 ml of anhydrous toluene. With stirring, 5 g of 2-chloro-3-nitropyridine were added at 70°-80° C. in the course of 4 hours under a nitrogen atmosphere. The whole was then stirred at ambient temperature for 2 hours. It was washed with 10% aqueous NaOH and then with plenty of water. The organic phase was treated with active carbon at room temperature for 60 minutes. It was filtered and the filtrate was dried with anhydrous magnesium sulphate. After evaporation of the solvent at low pressure, 7.4 g of 3-amino-2-(4-methoxyphenoxy)pyridine (95% yield) were obtained as a pale yellow solid which melted at 105°-107° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16]C)=[C:11]2[C:3]=1[CH:4]1[CH:9]([C:10]2=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5]1.[I-].[Na+].[Cl-].[Al+3].[Cl-].[Cl-].O>C(#N)C>[CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]2[C:3]=1[CH:4]1[CH:9]([C:10]2=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)c2c(c1O)C(=O)C1CCCCC21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10 Grams of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone was dissolved in 45 ml of acetonitrile and to the solution were gradually added 12.14 g of sodium iodide and 10.79 g of freshly ground aluminum chloride. After stirring at room temperature for 1.5 hour, the reaction mixture was poured into water and extracted with dichloromethane. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:20) and thereafter recrystallized from ethanol to obtain 9.34 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].O>CN(C=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][NH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:13]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a mixture of 7-(4-Amino-3-benzyloxybenzyl)-azepan-2-one (600 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) in DMF (10 mL) is added methyl bromoacetate (383 mg, 2.5 mmol). The mixture is stirred at 60° C. for 4 h then is allowed to cool to RT. It is poured into water and extracted with EtOAc and the organic phase is washed with water (3×), brine (1×), and dried over Na2SO4. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:14]>C(O)C>[NH2:14][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Solvent: CCO
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a mixture of 2,4-difluoro-5-nitrobenzonitrile (2 g, 10.86 mmol, prepared as described in: [Ohmori, J.; Sakamoto, S. et. al. J. Med. Chem., 1994, 37(4), 467-475.]) in ethanol (1.25 ml) was added ammonia (6.25 mL, 10.86 mmol) at r.t. The mixture was stirred overnight. Filtered to collect the precipitate, washed w/H2O (3×). The solid was dried in vacuo for 24 hrs to afford 1.9 g of 4-amino-2-fluoro-5-nitrobenzonitrile (1.8 g, 9.44 mmol, 87% yield), which was used in the next reaction without further purification. 1H-NMR (CD3OD, 500 MHz): δ 8.55 (1H, s), 6.82 (1H, s). m/e (M+H): 182.1.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[CH:2][CH3:3].Br[CH2:12][CH2:13][CH2:14]Br>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][CH2:14][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]=[CH:2][CH3:3])=[CH:2][CH3:3]
Reactant: BrCCCBr
Reactant: CC=Cc1ccccc1O
Product: CC=Cc1ccccc1OCCCOc1ccccc1C=CC

Procedure:
1,3-bis(ortho-propenylphenoxy)propane is prepared in a procedure similar to Example I, except that 537 grams (4.0 moles) of propenyl phenol is employed along with 403 grams (1.98 moles) of 1,3-dibromo-propane to produce a reaction mixture extracted with methylene chloride and dried over magnesium sulfate, then vacuum distilled to give 311 grams (50% yield) of a solid with melting point 45°-48° C.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1)=[O:4].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[N:23][CH:24]=1>C(#N)C.O.[Ag-]=O>[C:11]([C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:26])([F:17])[F:27])=[CH:24][N:23]=2)[CH3:15])[O:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Agent: O=[Ag-]
Solvent: O
Solvent: CC#N
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 60 °C
Yield: 5 %

Procedure:
To a solution of 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (0.53 g, 1.78 mmol) and 5-trifluoromethyl-2-pyridinol (0.30 g, 1.84 mmol) in acetonitrile/water (95/5, 15 mL) is added silver (I) oxide (0.85 g, 3.68 mmol). The reaction is heated to 60° C. for 18 h. After cooling, the reaction mixture is filtered through a plug of Na2SO4/cotton wool. The filtrate is concentrated under reduced pressure to give a brown oil, which is triturated with heptanes/ethyl acetate to afford a grey powder. Further purification by column chromatography (silica, eluent heptanes, 2.5-20% ethyl acetate) afforded N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-2-(5-trifluoromethyl-pyridin-2-yloxy)-propionamide as a white solid (33 mg, 5%). m/z 372 [M+H+]