Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.BrC1C=CC=CC=1OC.[Mg].CO[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1C1=NC(C)(C)CO1
Reaction time: 20 h
Yield: 90 %

Procedure:
2-Methoxyphenylmagnesium bromide, prepared from 2-bromoanisole (22.4 g, 120 mmol) and magnesium (2.9 g, 120 mmol), in dry THF (75 ml) was added dropwise to a stirred solution of 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (20.4 g, 100 mmol) in dry THF (150 ml) under N2 at 20° C. Stirring of the solution was continued for 20 hours and then the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The resulting mixture was extracted with ether (2×500 ml), dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (ethyl acetate-hexane) to provide title compound as colorless crystals (25.3 g, 90%), mp 129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24]CC2C=CC(OC)=CC=2)=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-:23])=[O:22])[CH:7]=1.O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[N:11]=[CH:10][C:9]=2[N+:21]([O-:23])=[O:22])[CH:7]=1
Reactant: COc1ccc(COc2ccc(Cl)cc2-c2c([N+](=O)[O-])cnn2COCC[Si](C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc([N+](=O)[O-])c1-c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of 5-(5-chloro-2-(4-methoxybenzyloxy)phenyl)-4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (prepared according to the procedure described for Example 14) (1.193 g, 2.434 mmol) in 17 mL dichloromethane was added 3 mL water followed by dichlorodicyanoquinone (1.2208 g). The reaction was stirred at room temperature for 48 hours, and then additional Dichlorodicyanoquinone (0.4946 g) was added. After an additional 24 hours, the reaction was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic portion was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 35% ethyl acetate in heptanes) to yield 745.2 mg (83%) of 4-chloro-2-(4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)phenol. LCMS (ESI) m+H=270.2; 1H NMR (400 MHz, DMSO-d6) δ: 10.47 (s, 1H), 8.44 (s, 1H), 7.47 (d, J=2.6, 1H), 7.43 (dd, J=8.8, 2.7, 1H), 7.00 (d, J=8.8, 1H), 5.30 (dd, J=65.1, 10.8, 2H), 3.42 (t, J=8.1, 2H), 0.74 (t, 2H), −0.08 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O>O1CCCC1.ClCCl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][NH2:14])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(SCCN)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.04 g (43.4 mmol) of NaH was dissolved in 40 ml of tetrahydrofuran at 0° C. To the resulting solution, 4 ml of 4-methylthiophenol dissolved in dry tetrahydrofuran was added slowly. The resultant mixture was stirred at an ambient temperature for 20 minutes and 8.0 g (31 mnol) of N-(2-bromoethyl)phthalimide obtained in step 1 dissolved in dry tetrahydrofuran was added. The mixture was stirred overnight at an ambient temperature and then refluxed for 2 hours. The reaction mixture was distilled under a reduced pressure to produce a residue, which was dissolved in dichloromethane. Then, the resultant solution was washed with water and with an aqueous sodium chloride solution. The organic layer was dried and dichloromethane was removed under a reduced pressure. The residue was recrystallized from a mixture of ethyl acetate/hexane to obtain 6.86 g of the title compound as a yellow solid. The solution remaining after the recrystallization was purified by column chromatography (eluent; ethyl acetate: hexane=1:6) to obtain additional 1.40 g of the title compound. Therefore, a total of 8.26 g (yield 90%) of the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:4][CH:3]1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.Cl.O1CCOCC1>>[N:17]1([CH:3]2[CH2:4][C@@H:5]3[CH2:6][NH:7][CH2:8][C@@H:9]3[CH:2]2[OH:1])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(n3ccnc3)C(O)[C@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: OC1C(n2ccnc2)C[C@@H]2CNC[C@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a 4 mL vial were combined (3aR,6aS)-tert-butyl 4-hydroxy-5-(1H-imidazol-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (50 mg, 0.170 mmol) from Step 3 and 4 N HCl in 1,4-dioxane (0.554 mL, 2.216 mmol) to give a suspension. The reaction was stirred at room temperature for 6 hours, and then the solvent was removed in vacuo. The resulting HCl salt was triturated with 3 mL of 10% methanol (2 N ammonia)/dichloromethane and filtered to give crude (3aR,6aS)-5-(1H-imidazol-1-yl)octahydrocyclopenta[c]pyrrol-4-ol: MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2OC)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 352 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)[CH3:2].[C:16](=[O:19])([O-])[O-].[Na+].[Na+].Cl.[OH2:23]>>[CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([N:10]2[C:8](=[O:23])[C:7]3[C:6](=[CH:5][CH:4]=[CH:15][CH:14]=3)[C:16]2=[O:19])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O
Reactant: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: CCOc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
O-Ethyl-L-tyrosine (IV. EXAMPLE 3, 20.9 g, 100 mmol) and N-carhethoxyphthalimide (23.0 g, 105 mmol) are suspended in water (210 mL). Sodium carbonate (11.1 g, 105 mmol) is added and the mixture is stirred at 20-25° for 24 hr. Hydrochloric acid (1N, 200 mL) is added to the resulting mixture and stirred for 2 hr. The mixture is filtered, washed with water (100 mL) and dried to give the title compound, NMR (MeOH-d4) δ7.78-7.72, 7.14, 6.68, 5.11, 3.90, 3.47 and 1.28; CMR (MeOH-d4) δ172.2, 169.0, 159.2, 135.6, 132.8, 130.9, 130.3, 124.2, 115.5, 64.3, 54.8, 34.7 and 15.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:11][NH2:12].Cl.C(N(CC)CC)C.[CH3:21][C:22]([O:25][C:26](ON=C(C1C=CC=CC=1)C#N)=[O:27])([CH3:24])[CH3:23]>O.O1CCCC1>[C:22]([O:25][C:26]([C:4]1[C:3]([CH2:11][NH2:12])=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])=[O:27])([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1cc(C(=O)O)ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(C(=O)O)ccc(Cl)c1CN
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of 4-chloro-3-aminomethylbenzoic acid.HCl (6.7 g, 30 mmol) and triethylamine (9.3 g, 92 mmol) in 50 ml of H2O, was added to a solution of Boc-ON (9.2 g, 38 mmol) in 50 ml of tetrahydrofuran cooled to 0° C. The reaction mixture was stirred at room temperature overnight, and the volatile compounds were removed by concentration under reduced pressure. The residue was diluted with H2O, washed with ether, acidified to pH 3 with 1N HCl, and extracted with ethyl acetate. The extracts were washed with H2O, brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This material was triturated with ether-hexane to provide the title compound (7.4 g, 87%) as a white powder. mp 159° C. (dec);
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:17][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH2:22])=[C:20]([F:26])[CH:19]=1>>[Cl:17][C:18]1[C:24]([OH:25])=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:20]([F:26])[CH:19]=1
Reactant: COc1cc2nncc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Product: COc1cc2nncc(Nc3cc(O)c(Cl)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6,7-dimethoxycinnoline hydrochloride (261 mg, 1 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoro-5-hydroxyaniline (193 mg, 1.2 mmol), (prepared as described in EP 061741), was treated in a manner similar to that described in Example 21 in order to produce 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6,7-dimethoxycinnoline as an hydrochloride salt (315 mg, 82%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([CH3:21])([NH2:20])[CH3:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C([N:29]([CH2:32]C)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[OH-].[NH4+]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][C:18]([NH:20][C:32]([NH2:29])=[O:36])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)N)ccc2n1CC1CC1
Reactant: CCN(CC)CC
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC(C)(C)NC(N)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 1-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-2-amine (step G, 38 mg, 0.1 mmol) in dichloromethane (1.5 mL) were added triethylamine (28 μL, 0.2 mmol) and 4-nitrophenyl chloroformate (24 mg, 0.12 mmol) at 0° C. The mixture was stirred for 4 h at room temperature. To the resulting mixture was added ammonium hydroxide solution (25% in water; 20 μL, 0.12 mmol) and stirred continue to 20 h. The reaction was quenched by addition of saturated sodium 6 bicarbonate aqueous solution (10 mL) and water (10 mL). The organic phase was separated and the aqueous layer was extracted with dichloromethane (10 mL×2). The combined organic layer was washed with water (20 mL×4), brine (10 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel TLC eluting with dichloromethane/methanol (10/1) to afford 16 mg (38%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[NH3:13]>[Ni]>[NH2:13][CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: [Ni]
Product: CC(N)c1ccc(C(=O)O)cc1

Procedure:
4-Acetylbenzoic acid (4.1 g) is dissolved in 50 mL ammonia-saturated methanol. Raney nickel catalyst (1.5 g; activity grade III) is then added and the mixture reduced under hydrogen atmosphere (4750 psi) at 80° C. for 17 hrs. After removal of the catalyst by suction filtration, the filtrate is evaporated and the residue dissolved in H2O. The solution is passed through a 2.5×15 cm column of Dowex-50X8-400 resin (H+ form) and eluted with 1N NH4OH. Evaporation of the eluate leaves a residue (2.9 g) which is recrystallized from H2O/acetone and characterized as 4-(1-aminoethyl)benzoic acid, m.p.>300° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]3)[CH:37]=2)O1>>[NH:40]1[CH2:41][CH:38]([N:36]2[CH:37]=[C:33]([C:2]3[CH:24]=[CH:23][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)[CH:34]=[N:35]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1

Procedure:
Similarly to as described in General Procedure C, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate. Removal of the tertbutoxycarbonyl protecting group was accomplished with trifluoroacetic acid in dichloromethane. Purification of the crude reaction mixture by reverse phase HPLC gave 406. LCMS: 448.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:17][C:11]1([C:14]([O:16][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (5.0 g, 20.55 mmol) in methanol (60 mL) and toluene (100 mL) was added a 2M solution of trimethylsilyldiazomethane (20 mL) in hexanes (the addition was accompanied by effervescence and a small exotherm). The resulting pale yellow solution was allowed to stir at ambient temperature for 1 hr. The solvent was removed under reduce pressure to give the title compound as a pale yellow oil (5.28 g 20.55 mmol, 100%); 1H NMR (CDCl3) δ 1.20 (s, 3H), 1.34-1.39 (m, 2H), 1.44 (s, 9H), 2.03-2.07 (m, 2H), 2.96-3.03 (m, 2H), 3.70 (s, 3H), 3.72-3.77 (m, 2H); MS m/e MH+. 257
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)(C)C.[CH3:15][CH:16]([NH2:18])[CH3:17]>O>[CH:16]([NH:18][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:17])[CH3:15]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC(C)N
Solvent: O
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2[nH]ccc12
Temperature: 120 °C
Yield: 89.5 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 168 mg, 1.09 mmol), 2.00 mL of isopropyl alcohol is added, followed by 2-propanamine (11, 0.280 mL, 3.28 mmol). The reaction is heated by microwave at 120° C. for 20 minutes, then an additional 40 minutes. Another 0.250 mL of 2-propanamine is added and heated at 120° C. for 60 minutes. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 1-5% methanol in dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (12, 172 mg). MS (ESI) [M+H+]+=176.85.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: NCCCBr
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 3-bromopropylamine hydrobromide (5.0 g) and diisopropylethylamine (5.90 g) in dichloromethane (80 ml) was added portionwise 9-fluorenylmethoxycarbonyl chloride (5.91 g) and the mixture was stirred at ambient temperature for 3 hours and stand overnight. The resulting mixture was diluted with dichloromethane (50 ml) and the organic layer was washed successively with 1N hydrochloric acid and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-hexane (1:5) to give 3-(9-fluorenylmethoxycarbonylamino)propyl bromide (7.82 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][NH2:14].C(O[CH:19](Br)[CH2:20]Br)(=O)C>>[CH3:13][N:14]1[CH:20]=[CH:19][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]1[C:2]([F:12])([F:11])[F:1]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CC(=O)OC(Br)CBr
Reactant: CN
Product: CCOC(=O)c1ccn(C)c1C(F)(F)F
Temperature: 10 °C

Procedure:
Ethyl 4,4,4-trifluoro-3-oxo-butanoate (29 ml, 0.219 mmol) is added to methylamine (40% solution in water) (50 ml, 0.580 mmol) cooled to 10° C.; a white precipitate forms. 1,2-Dibromoethyl acetate (prepared according to Molecules, 16, 9368-9385; 2011) is added dropwise. The reactor is then sealed and heated at 70° C. for 45 minutes. The reaction mixture is cooled, then extracted with ethyl acetate, dried over sodium sulphate (Na2SO4) and evaporated to dryness. The crude reaction product obtained is purified by chromatography over silica gel using heptane and ethyl acetate as eluants. The expected compound is obtained in the form of crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:27]([Si:24]([CH3:26])([CH3:25])[O:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[CH:12]=1)([CH3:30])[CH3:29]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)C(C)(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(=O)C(C)(C)C)c1
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a stirred solution of 66.13F (1.00 g, 3 mmol) in DCM (10.00 mL) at 23° C. was added tert-butyldimethylsilyl chloride (0.6 mL, 4 mmol), followed by TEA (0.5 mL, 4 mmol) and DMAP (0.04 g, 0.3 mmol). The reaction was stirred for 16 hours and then the reaction was concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30A as a colorless oil (1.30 g, 96% yield).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C)C(=O)C>[C:34]([O:33][C:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:6]2[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:21]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCc1nc(C(=O)CCC)c(C#N)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(=O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 51 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 0.877 g of 2-butyl-4-butyrylimidazole-5-carbonitrile (prepared as described in Preparation 26), 1.53 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 0.175 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 18 ml of N,N-dimethylacetamide, 0.99 g of the title compound was obtained as a viscous oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[I:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH2:13])[CH:9]=[CH:10][CH:11]=1.P([O-])([O-])([O-])=O>C(#N)C>[I:5][C:6]1[CH:7]=[C:8]([N:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[NH:13][C:3]([NH:2][CH3:1])=[O:4])[CH:9]=[CH:10][CH:11]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(I)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CNC(=O)NN(CC(=O)OC)c1cccc(I)c1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
Methyl isocyanate (1.24 g) was added to a solution of methyl [1-(3-iodophenyl)hydrazino]acetate (3.0 g) in acetonitrile (50 ml) and the mixture was stirred under nitrogen for 2 h. The mixture was added to pH 6.5 phosphate solution (150 ml) and extracted with ethyl acetate (200 ml). The organic phase was washed with brine (100 ml) and water (100 ml), dried and evaporated to give a solid (3.0 g) which was crystallised from ethyl acetate to give the title compound (2.0 g), m.p. 150°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCBr)cc1
Temperature: 70 °C
Yield: 19.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (10 mL), KOH (1.02 g, 18.2 mmol) was added. Then, 1,5-dibromopentane (3.09 mL, 22.7 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate intermediate 14a (0.94 g, 3.62 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.76-6.84 (m, 4H), 4.50 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H), 1.92-1.96 (m, 2H), 1.77-1.84 (m, 2H), 1.60-1.67 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([Cl:20])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (4.2 g, 14.89 mmol) was dissolved in CH2Cl2 (42 mL) under N2 atmosphere. Oxalyl chloride (2.6 mL, 29.78 mmol) and DMF (5 drops) were added and the reaction stirred for 2.5 hours at room temperature. Then, additional oxalyl chloride (5 mL, 57.3 mmol) was added. After 30 minutes, the reaction mixture was concentrated and placed under high vacuum. The crude material was used directly in the next step.