Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]O)[CH:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][Cl:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1Cl
Solvent: ClCCl
Product: ClCc1cc(Br)ccc1Cl

Procedure:
A solution of 40.0 g 4-bromo-1-chloro-2-hydroxymethyl-benzene and 60 mL thionyl chloride in 150 mL dichloromethane are stirred at 45-50° C. for 5 h. Then the solvent and the excess reagent is removed in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH3:20])=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](=[N:1]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][O:5][C:6]3=[O:11])/[CH3:20])=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C/C(=N\c1cccc2c1COC2=O)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 36 h
Yield: 87.6 %

Procedure:
To a solution of 4-aminoisobenzofuran-1(3H)-one (1 g, 6.7 mmol) and 1-(4-fluorophenyl)ethanone (1.4 g, 10.1 mmol) in toluene (35 mL) was added anhydrous magnesium sulfate (8.8 g, 73.7 mmol) and acetic acid (0.2 mL) at room temperature under N2. The reaction mixture was then stirred at 120° C. for 36 hr. The reaction mixture was cooled to 90° C. and filtered. After filter cake was washed with acetonitrile, the filtrates were combined and evaporated to dryness to obtain yellow solid, which was washed by petroleum ether to obtain the title compound as a white solid (1.58 g, yield 88%). LC-MS (ESI) m/z: 270(M+1)+H-NMR (400 MHz, CDCl3) δ (ppm): 2.30 (s, 3H), 5.16 (s, 2H), 7.00-7.02 (d, J=7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.51-7.56 (t, J=7.6 Hz, 1H), 7.66-7.69 (d, J=7.6 Hz, 1H), 7.99-8.03 (m, 2H).
Reaction SMILES: Cl.[I:2][C:3]1([CH2:6][C@@H:7]([CH2:16][O:17][Si](C)(C)C(C)(C)C)[O:8][Si](C)(C)C(C)(C)C)[CH2:5][CH2:4]1>C1COCC1>[I:2][C:3]1([CH2:6][C@H:7]([OH:8])[CH2:16][OH:17])[CH2:5][CH2:4]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: OC[C@@H](O)CC1(I)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Aqueous HCl solution is added to a solution of (S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane in THF at 0° C. The mixture is slowly warmed to room temperature and stirred for 24 hours. The reaction is quenched by addition of aqueous NaHCO3 solution, extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrated under reduced pressure to provide (S)-3-(1-iodocyclopropyl)propane-1,2-diol (0.598 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCCCl)C1
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A mixture of 3-aminoazetidine-1-carboxylic acid tert-butyl ester (730 mg, 4.24 mmol) and triethylamine (1.74 mL, 1.29 g, 12.72 mmol) in DCM (10 mL) was cooled to 0° C. before the addition of 4-chlorobutyrylchloride (523 μL, 657 mg, 4.66 mmol). The resulting mixture was stirred for 16 h then quenched with H2O and extracted with DCM. The combined organic extracts were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 30-70%) affording 3-(4-Chlorobutyrylamino)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (1.04 g, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][CH:12](F)[C:13](Br)([F:15])[F:14])[O:8][C:4]=2[CH:3]=1.CO.II.CCCCCC>C(OC(=O)C)C.[Zn].[I-].[Zn+2].[I-]>[OH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:9][CH2:10][CH2:11][CH:12]=[C:13]([F:15])[F:14])[O:8][C:4]=2[CH:3]=1
Reactant: Oc1ccc2nc(SCCC(F)C(F)(F)Br)oc2c1
Agent: II
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: Oc1ccc2nc(SCCC=C(F)F)oc2c1
Yield: 56.3 %

Procedure:
A mixture of the product of step 1 (5.27 g, 14.7 mmol), Methanol (50 cm3), zinc powder (9.66 g, 147 mmol), zinc iodide (catalytic), and iodine (catalytic) was refluxed for 18 hours. The reaction mixture was filtered and the filtrate partitioned between diethyl ether and 1.4M hydrochloric acid. The organic phase was washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil. Chromatography on silica gel using 8:2 hexane:ethylacetate as eluent afforded the product as a white solid (2.13g). 1H NMR (CDCl3): δ7.45(1H,d); 6.95(1H,d); 6.8(1H,dd); 6.1(1H,s); 4.2-4.4(1H,m); 3.3(2H,t); 2.5(2H,m). M+ =257. m.p. 73.6°-75.4° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:1][CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)=[O:4])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CO)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.8 %

Procedure:
7-Hydroxyacetylimidazo[5,1-b]thiazole (1.42 g) was dissolved in 10 ml of DMF. Imidazole (847 mg) and 1.77 g of t-butyldimethylsilyl chloride were added to the solution in an argon atmosphere. The mixture was stirred at room temperature for 24 hr. Brine was added to the reaction solution, followed by extraction twice with ethyl acetate. The organic layers were combined together, washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give 2.19 g of 7-t-butyldimethylsilyloxyacetylimidazo[5,1-b]thiazole.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[C:26]([C:33](O)=[O:34])[CH:25]=1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[CH:25]=[N:24][N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cnn2ccccc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cnn3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with Pyrazolo[1,5-a]pyridine-3-carboxylic acid. LC-MS (basic): tR=0.84 min; [M+H]+=492.2.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([O:26]C)=[N:24][CH:23]=[CH:22][N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([OH:26])=[N:24][CH:23]=[CH:22][N:21]=3)[C@H:14]2[CH3:28])[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: COc1nccnc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-methoxypyrazin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (1000 mg, 2.297 mmol) in CH2Cl2 (3 mL) was added BBr3 (11.49 mL, 11.49 mmol) dropwise through an addition funnel. The resulting mixture was stirred cold (−78° C.) for 1 h then allowed to warmed to room temperature overnight. The reaction was not completed after overnight stirring. The reaction mixture was stirred at room temperature for 4 more days and LCMS of aliquot indicated completion of reaction. The crude mixture was poured into crushed ice. The resulting organic layer was separated. The aqueous phase was back extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and evaporated to give a glass. This glass was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/CH2Cl2 gradient mixture (0% to 100%). Related fractions were pooled and evaporated to afford a yellow solid as the titled compound. LCMS calc.=421.09; found=421.95 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Br)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C(N(CC)CC)C.C(Cl)Cl.[OH-].[Na+]>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:5]2[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CCBr)cc1OC
Reactant: OCC1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCC(CO)C2)cc1OC

Procedure:
3 g (0.03 mol) of 3-hydroxymethyl-pyrrolidine and 7.5 g of 2-(3,4-dimethoxy-phenyl)-ethylbromide are heated in 20 ml of triethylamine for 7 hours at 100° C. The excess triethylamine is then distilled off in vacuo and the residue obtained is dissolved in methylene chloride and 6 molar sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation in vacuo. The residue obtained is then purified over 400 g of alumium oxide (neutral, activity II) with methylene chloride and with increasing amounts of ethanol (up to 1%). Yield: 5.4 g (67.8% of theory), Rf value: 0.41 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([CH3:28])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([CH3:28])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[CH:2]([S:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4]2=[O:11])=[C:13]([F:19])[CH:14]=1
Reactant: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Cl)cc1F
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(Sc2ccccc2)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In 30 ml of dichloromethane were dissolved 3.0 g of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one and 1.1 g of thiophenol, and 1.0 g of triethylamine was added to the solution over a 10-minute period, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and freed of the dichloromethane under reduced pressure. The residue was purified by means of column chromatography with the use of silica gel (developing solvent of dichloromethaneacetone), thereby producing 3.2 g (yield of 86%) of the subject compound in white crystals, m.p. 86°-87° C.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][O:9][C:10]2[C:15]([CH:16]=[O:17])=[CH:14][C:13]([O:18][CH3:19])=[N:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:22]=[N:23][N:24]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[CH3:19][O:18][C:13]1[CH:14]=[C:15]([C:10]([O:9][CH2:8][C:7]2[C:2]([C:25]3[N:24]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][O:30]4)[N:23]=[CH:22][C:21]=3[CH3:20])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][N:12]=1)[CH:16]=[O:17]
Reactant: COc1cc(C=O)c(OCc2cccnc2Br)cn1
Reactant: Cc1cnn(C2CCCCO2)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccnc2-c2c(C)cnn2C2CCCCO2)cn1
Temperature: 125 °C
Yield: 86.9 %

Procedure:
To a mixture of 5-((2-bromopyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (100 mg, 0.31 mmol, 1 equiv), 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-ylboronic acid (98 mg, 0.47 mmol, 1.5 equiv), Pd(PPh3)4 (70 mg, 0.06 mmol, 0.2 equiv), K2CO3 (171 mg, 1.24 mmol, 4 equiv) in a 5 mL microwave tube was added DMF (2 mL). The mixture was heated 30 min at 125° C. in a microwave reactor. The solid was filtered off and the filtrate was concentrated to dryness. The crude was purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-methoxy-5-((2-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (110 mg, 87%) as a colorless oil. LRMS (M+H+) m/z 409.2.
Reaction SMILES: O1CCCC1.C(O)C.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27](=[N:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N+:38]([O-:40])=[O:39])[CH2:26][CH:25]=1.[BH4-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[N+:38]([O-:40])=[O:39])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(OC3=CCC(=NCc4ccccc4[N+](=O)[O-])C=C3)c2cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NCc4ccccc4[N+](=O)[O-])cc3)c2cc1OC
Temperature: 25 °C
Yield: 75.2 %

Procedure:
After adding tetrahydrofuran (2 ml), ethanol (2 ml) and chloroform (1 ml) to 6,7-dimethoxy-4-(4-(2-nitrophenylmethyl-imino)phenyloxy)quinoline (200 mg, 0.4657 mmol) and heating the mixture to complete dissolution, sodium borohydride (35 mg, 0.9314 mmol) was added and the mixture was heated to reflux for 1 hour and 30 minutes. After cooling to room temperature, water was added, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with an NH silica gel column (hexane-ethyl acetate system) to obtain the title compound (151 mg, 0.3500 mmol, 75.15%) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cccc(OCCN3CCCCC3)c2o1
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: Nc1ccccc1NC(=O)c1cc2cccc(OCCN3CCCCC3)c2o1

Procedure:
was prepared from (2-{[7-(2-Piperidin-1-yl-ethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (22) in an analogous manner to that described for the preparation of (1) example 1, step 5; white solid; exact MW [M+H] calc'd: 380.20; MW found [M+H]: 380.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-])=O.NN>CO.[Ni]>[OH:11][C:6]1[CH:5]=[C:4]([CH:10]=[CH:9][C:7]=1[OH:8])[NH2:1]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: Nc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitrocatechol (310 mg, 2.0 mmol) in methanol (20 mL) is added hydrazine (200 μL) and a catalytic amount of Raney-Nickel (50 mg). The reaction mixture is left to stir at ambient temperature for 16 hours. The solution is then filtered over celite to remove Raney-Nickel and the filtrate evaporated to dryness. The 3,4-dihydroxyaniline thus produced is used as such for the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[NH2:21][C:22]1[N:23]=[CH:24][N:25]([CH:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)[CH:26]=1>>[OH:31][CH:29]1[CH2:28][CH:27]([N:25]2[CH:26]=[C:22]([NH:21][C:15](=[O:17])[CH:14]([NH:13][CH:7]3[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=4)[CH2:8]3)[CH2:18][CH2:19][CH3:20])[N:23]=[CH:24]2)[CH2:30]1
Reactant: Nc1cn(C2CC(O)C2)cn1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C2CC(O)C2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 3-(4-Amino-imidazol-1-yl)-cyclobutanol to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 28.2, 28.9, 29.7, 36.5, 40.2, 41.9, 43.4, 48.7, 52.9, 60.5, 60.9, 64.5, 100.8, 101.1, 101.3, 105.1, 105.3, 110.7, 110.9, 131.6, 131.9, 137.7, 139.8, 159.8, 162.3, 172.6; MS m/z 419.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18]C)=[CH:8][O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1coc2cc(O)ccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccccc2O)coc2cc(O)ccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a stirred solution of 7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (5 gm, 18.7 mmol) in dry CH2Cl2 (50 ml) at −80° C. was added BBr3 (3.6 ml in DCM, 37.4 mmol). The reaction mixture was then stirred for 1 hour at −80° C. and 12 hours at room temperature. The reaction was then quenched with ice-cooled water. The reaction mixture was then extracted with CH2Cl2 and the organic layer was separated, washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography using hexane-chloroform as the eluent to give 7-hydroxy-3-(2-hydroxy-phenyl)-chromen-4-one (3.8 gm, 80%) as white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl>[OH-].[Na+]>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](=[O:12])[NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of glycine (15 g, 0.2 mol) in 175 mL of 5% aqueous sodium hydroxide is cooled to 10° C. to 15° C. p-Fluorobenzoyl chloride (31.6 g, 0.2 mol) is then added dropwise to the mixture and stirred vigorously for 0.5 hour while maintaining the temperature of the mixture of about 10° C. to 15° C. The pH of the reaction mixture is maintained at pH>9 by the dropwise addition of 50% aqueous sodium hydroxide. The mixture is stirred at 10° C. to 15° C. for two hours and the resulting clear solution then acidified to pH-1 with concentrated HCl. The resulting product is filtered off, washed with water (2×100 mL) and air dried to give a white solid (30.8 g, 78.1%); mp=161°-163° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][CH:8]([OH:14])[CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].[I:32]I>C(OCC)C.O>[CH3:4][C:2]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][CH2:7][C@H:8]1[O:14][C@H:11]([CH2:12][I:32])[CH2:10][C@H:9]1[OH:13])([CH3:1])[CH3:3]
Reactant: II
Reactant: C=CCC(O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CI)C[C@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 0° C. solution of 14.67 g of product from Example 274 in 200 ml of3:1 diethyl ether/water is treated with 4.99 g of sodium bicarbonate and 15.07 of iodine. The reaction mixture is stirred vigorously for 24 hours at room temperature, quenched with 15 ml of saturated sodium sulfite, and diluted with 100 ml of water. the reaction mixture is extracted with diethyl ether, dried, concentrated in vacuo, and purified by chromatography (silica gel: 0-10% ethyl acetate/hexane) to give 15.0 g of the desired product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[N:17][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1.[BH4-].[Na+]>CO>[CH3:18][NH:17][CH2:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1
Reactant: CN=Cc1ccc2c(c1)ncn2C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 66 (1.0 g, 4.11 mmol) in MeOH (10 mL) cooled to 0° C. was added NaBH4 (300 mg, 8.23 mmol). After stirring at RT overnight, the mixture was quenched with water (3 mL) and extracted with DCM (3×50 mL). The organic layers were separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford 880 mg (66%) of N-methyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (68) as yellow oil: MS (ESI) m/z=246.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][C:5]([O:7][CH3:8])=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[O:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1Br
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Then, 110 g (0.44 mol) of methyl 2-bromo-4-fluorophenoxyformate was dissolved in 250 ml of sulfuric acid, to which a mixed acid of 30 g of fuming nitric acid and 30 ml of sulfuric acid was added dropwise at 5° C. or lower, and the mixture was stirred for 2 hours. The reaction mixture was poured onto ice, and the precipitated crystals were collected by filtration, washed with water, and dried, which afforded 126 g (0.43 mol) of methyl 2-bromo-4-fluoro-5-nitrophenoxyformate.