Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:19]([O:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1-c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2′,6′-dichloro-5-fluorobiphenyl-2-ol (11.63 g, 45 mmol) in DMF (150 mL) was added allyl bromide (5.8 mL, 67.5 mmol) and potassium carbonate (18.6 g, 135 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight and poured into water. The mixture was extracted with methylene chloride and washed with water. The solvent was removed under vacuum. Chromatography with 0–30% ethyl acetate in hexanes afforded 12.7 g (94%) of 2-allyloxy-2′,6′-dichloro-5-fluorobiphenyl as a light yellow oil. MS (EI) m/z 296 (M+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4](F)([F:6])[F:5].C([Li])CCC.[CH:16](=[O:21])[CH2:17][CH:18](C)[CH3:19].Cl>O1CCCC1.CCCCCC>[F:1][C:2]([F:10])([F:9])[C:3](=[O:8])[C:4]([F:6])([F:5])[CH:16]([OH:21])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)CC=O
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(O)C(F)(F)C(=O)C(F)(F)F
Temperature: 5 °C
Reaction time: 5 h

Procedure:
With stirring in a nitrogen atmosphere, a mixture of 111 g of 1,1,1,3,3,3-hexafluoro-2-propanol and 700 ml of tetrahydrofuran was cooled below −40° C., to which 500 ml of a n-hexane solution of 2.64M n-butyllithium was added dropwise. At the temperature, the reaction mixture was stirred for 30 minutes. The cooling bath was changed to ice cooling, allowing the reaction mixture to warm to 5° C. A mixture of 50 g of isovaleraldehyde and 50 ml of tetrahydrofuran was added dropwise. With stirring, the reaction mixture was warmed up to room temperature, after which stirring was continued for a further 5 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining crude 1,1,1,3,3-pentafluoro-4-hydroxy-2-heptanone. The crude product was combined with 50 g of water at room temperature, to which 100 g of 25 wt % sodium hydroxide aqueous solution was added. The mixture was stirred overnight at room temperature. With stirring, the mixture was slowly heated to 90° C. After cooling, the reaction mixture was extracted with n-hexane, with the hexane layer being discarded. The water layer was made acidic by adding 20 wt % hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate solution was dried and concentrated, obtaining 107 g (qualitative yield) of the target compound, 2,2-difluoro-3-hydroxy-5-methylhexanoic acid (Intermediate 1). This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][CH2:7][CH:6]([OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCCN
Product: CCCNCC(O)c1ccc(C)cc1
Yield: 49.6 %

Procedure:
4-Methyl styrene oxide(1.0 g,8.0 mmol)and 3 ml of propylamine in methanolic solution were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 73.0–75.1 C, yield 49.6%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:9]=[C:8]([C:19]([OH:21])=[O:20])[CH:7]=1
Reactant: COc1ccc(-n2nc(C(=O)OC(C)(C)C)cc2-c2ccco2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccco2)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Part C. To tert-butyl 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 3.0 mmol) was added dichloromethane (7 mL) and trifluoroacetic acid (7 mL). The resulting black solution was maintained at rt under nitrogen for 2 h and was then concentrated to dryness. The resulting mixture was triturated with chloroform, and the remaining solid was washed with 50% hexanes in chloroform to afford 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (800 mg, 96%) as a light brown solid. 1H NMR (d6-DMSO) δ 7.75 (b m, 1H), 7.41 (d, 2H), 7.10 (d, 2H), 7.09 (s, 1H), 6.51 (br m, 1H), 6.09 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5][C:6]1[NH:7][CH:8]=[CH:9][N:10]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][S:5]([C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)=[O:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ccccc1CSc1ncc[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1CS(=O)c1ncc[nH]1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
To a solution of 2.5 g of 2-(2-aminobenzylthio)imidazole in a mixture of 25 ml of chloroform and 10 ml of methanol was dropwise added under stirring and under chilling with ice 2.6 g (12.1 mmol) of m-chloroperbenzoic acid. The mixture was further stirred for 15 min. Thus precipitated crystalline product was collected by filtration, washed twice with water and placed in 40 ml of saturated aqueous sodium hydrogencarbonate. The aqueous mixture was stirred, and then the crystalline product was collected by filtration. The obtained solid product was stirred in a mixture of 30 ml of chloroform and 10 ml of 1N aqueous NaOH. The aqueous portion was taken out and made ammonia-alkaline by addition of 20% aqueous ammonium chloride. The mixture was chilled after addition of sodium chloride, to give a crystalline precipitate. The precipitate was collected by filtration, washed successively with two portions of water and one portion of acetone, and dried under reduced pressure to give 340 mg of the desired compound as a pale brown crystalline powder, yield 12.7%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([NH:22][CH:23]([CH3:28])[C:24]([O:26]C)=[O:25])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:29][CH2:30][CH3:31])=[N:3]1.[OH-].[Na+]>CO.O.Cl>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([C:12]3[CH:13]=[C:14]([NH:22][C@H:23]([C:24]([OH:26])=[O:25])[CH3:28])[CH:15]=[N:16][C:17]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:6][C:5]=2[C:4]([CH2:29][CH2:30][CH3:31])=[N:3]1
Reactant: CCCOc1ncc(NC(C)C(=O)OC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCOc1ncc(N[C@@H](C)C(=O)O)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound of Example 83 in methanol (5 mL) was treated with a solution of sodium hydroxide (64 mg, 1.6 mmol) in water (2 mL) and the reaction mixture stirred at room temperature for 14 h. After concentration of the reaction mixture in vacuo, water (5 mL) was added and the solution acidified with conc. hydrochloric acid (5 drops) to afford a white precipitate, which was removed by filtration, and dried in vacuo to give the title compound as an off-white solid (180 mg, 0.43 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:14][CH:11]1[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: O=C(Cl)c1ccccc1Cl
Product: Clc1ccccc1CNC1CC1

Procedure:
Synthesized according to typical procedures B and D from 2-chlorobenzoyl chloride and cyclopropylamine.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](O)=[C:13]([N+]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C[N:24](C=O)C.CO>[Pd]>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:24])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCN(c2ccc(O)c([N+](=O)[O-])c2)CC1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1
Yield: 100 %

Procedure:
To a solution of 4-(1-N-trifluoroacetyl-4-piperazinyl)nitrophenol (2.0 g, 6.6 mmol) in DMF/MeOH (20 mL/30 mL) was added 10% Pd/C (0.8 g). Solution was hydrogenated (45 psi) for 2 hr. Solution was filtered through Celite and the filtrate was concentrated to give the title compound (1.9 g, 100%). MS (ES) m/e 274 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.[N+:31]([O-])([O-:33])=[O:32].[NH4+]>S(=O)(=O)(O)O>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[C:26]([N+:31]([O-:33])=[O:32])[C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 19.3 %

Procedure:
A solution of the product of Example 320C (47 mg, 0.11 mmol) in concentrated sulfuric acid (2 mL) at 0° C. was treated with ammonium nitrate (10 mg, 0.13 mmol). After stirring at ambient temperature for 25 minutes, the solution was poured into ice water and the precipitate was filtered, dried, and purified by flash chromatography, eluting with 2% methanol in dichloromethane to yield the title compound (10 mg, 19%). MS (ESI−) m/z 470 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.14 (d, J=4.04 Hz, 2 H) 0.41 (m, 2 H) 1.01 (m, 1 H) 2.84 (d, J=6.99 Hz, 2 H) 7.44 (m, 2 H) 7.77 (d, J=9.56 Hz, 1 H) 7.88 (t, J=7.91 Hz, 1 H) 8.08 (d, J=8.46 Hz, 1 H) 8.16 (dd, J=8.09, 1.10 Hz, 1 H) 11.83 (s, 1 H).
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20])[CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C=O)C>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:25][C@H:26]1[CH2:27][O:28]1)[CH:10]=[CH2:11]
Reactant: C=CCOc1ccc(Cl)cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 4.0 g (79 mmole) of 60% sodium hydride/mineral oil dispersion in a one liter flask was added 300 ml of hexane. The mixture was swirled briefly, the solid allowed to settle and the supernatant liquid decanted. DMF (500 ml) was added, followed by a solution of 14.6 g (79 mmole) of 2-allyloxy-5-chlorophenol in 100 ml of DMF. The mixture was stirred at room temperature under nitrogen for 30 minutes, then 18.0 g (79 mmole) of (R)-glycidyl tosylate added. The mixture was heated under a nitrogen atmosphere at 80° C. for 24 hours. The solvent was evaporated in vacuum and replaced with 750 ml of methylene chloride. The solution was washed with 500 ml portions of 2N HCl (aq), saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 20 g of a crude gum. This was column chromatographed on silica gel using methylene chloride as eluant to give 9.2 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.93 δ(1 H); doublet, 6.90 δ(1 H); doublet, 6.80 δ(1 H);.multiplet, 6.05 δ(1 H); doublet, 5.40 δ(1 H); doublet, 5.25 δ(1 H); doublet, 4.55 δ(2 H); doublet of doublets, 4.25 δ(1 H); doublet of doublets, 3.97 δ(1 H); multiplet, 3.35 δ(1 H); triplet, 2.95 δ(2H); triplet, 2.75 δ(1 H).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][N:4]=[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:6]#[N:7].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5](=[N:4][O:3][CH:2]([F:15])[F:1])[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1C(C#N)=NOC(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=NOC(F)F)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A solution of 8.0 g of α-difluoromethoxyimino-o-tolylacetonitrile and 0.07 g of dibenzoyl peroxide in 50 ml of carbon tetrachloride is heated to reflux. With radiation from a lamp, 6.77 g of N-bromosuccinimide are added thereto in several small portions and the mixture is left to react for 0.5 hour. The reaction mixture is cooled to room temperature, the succinimide is filtered off and the residue is concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (15:1) yields pure 2-(2-bromomethylphenyl)-2-difluoromethoxyimino-acetonitrile in the form of a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH:16]C(OC(C)(C)C)=O)[C:4]([NH2:6])=[O:5])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([CH:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][NH2:16])[C:4]([NH2:6])=[O:5])[CH3:2]
Reactant: CCC(Oc1ccc(Cl)cc1CNC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(Oc1ccc(Cl)cc1CN)C(N)=O

Procedure:
Ethyl-(2-t-butoxycarbonylaminomethyl-4-chlorophenoxy)-acetamide from Step F was dissolved in 2:1 methylene chloride/TFA (3 ml) and after 15 min the solvent was evaporated in vacuo. The residue was dissolved in water and the solution was washed with methylene chloride (twice). The aqueous layer was then basified with saturated sodium carbonate solution and NaCl was added to saturation. The mixture was extracted with ethyl acetate, and the organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound as a crystalline solid:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.CC1([N:34]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:34])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: Cn1cnc(-c2ccc(I)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Iodophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 63) in place of 6-(1-Methylphenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Solid (116 mg, 74%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:26]2[CH2:28][CH2:27]2)[N:9]2[CH2:14][CH2:13][C:12]([CH2:21][C:22]([CH3:24])=[CH2:23])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:11][C:10]2=[O:25])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:26]2[CH2:28][CH2:27]2)[N:9]2[CH2:14][CH2:13][C:12]([CH2:21][C:22]3([CH3:24])[CH2:23][O:34]3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:11][C:10]2=[O:25])=[CH:6][CH:7]=1
Reactant: C=C(C)CC1(c2ccccc2)CCN(C(c2ccc(Br)cc2)C2CC2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CC2(c3ccccc3)CCN(C(c3ccc(Br)cc3)C3CC3)C(=O)O2)CO1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
3-[(4-Bromo-phenyl)-cyclopropyl-methyl]-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one (diastereomer 2 from Step 3; 1.60 g) dissolved in dichloromethane (15 mL) was added to a solution of 3-chloroperoxybenzoic acid (77%, 0.94 g) in dichloromethane (15 mL) cooled to 5° C. The solution was stirred at room temperature for 3 h, before another portion of 3-chloroperoxybenzoic acid (77%, 0.13 g) was added. After stirring the solution at room temperature for another 1.5 h, aqueous 10% Na2S2O3 solution (10 mL) and aqueous saturated NaHCO3 solution (10 mL) were added and the resulting mixture was stirred for further 30 min. Dichloromethane (20 mL) was added and the organic phase was separated and washed with a 1:1 mixture of aqueous 10% Na2S2O3 solution and aqueous saturated NaHCO3 solution. Then the organic phase was washed with water, dried (MgSO4), and concentrated to furnish the title compound. Yield: 1.86 g (ca. 85-90% pure, quantitative); LC-MS (Method 1): tR=4.00 min; Mass spectrum (ESI+): m/z=456/458 (Br) [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1>C1C=CC=CC=1>[Cl:3][CH2:6][C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (15 mL, 200 mmol) was added dropwise to a suspension of 1-hydroxymethylpyrene (9.3 g, 40 mmol) in dry benzene (150 mL) at 0° C. and the mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure gave a creamy-white solid, m.p. 146°-148° C., yield: 9.6 g, 96%.
Reaction SMILES: O[CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(=O)([O-])O.[Na+]>C(#N)C>[C:26]([CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:3]1[CH2:4][CH:5]23)(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)C1C2CC3C1OC(=O)C3C2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
In 2,500 ml of acetonitrile were dissolved 500 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate and 318 g of triethylamine. To the solution below 15° C., 288 g of methacrylic chloride was added dropwise. The solution was stirred at room temperature for 2 hours, another 32 g of methacrylic chloride added, and the solution stirred overnight. A saturated aqueous solution of sodium hydrogen carbonate, 500 ml, was added to the reaction solution, followed by ordinary work-up. Recrystallization from hexane yielded 437 g of the title compound (yield 69%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH:37]1[O:41][C:40](=[O:42])[NH:39][CH2:38]1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][CH:37]3[O:41][C:40](=[O:42])[NH:39][CH2:38]3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C1NCC(CCl)O1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: O=C1NCC(CN2CN(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)O1

Procedure:
The title compound, MS: m/e=604.9 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 5-chloromethyl-2-oxazolidinone.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:23](=[O:24])[CH2:22][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Cc1ccccc1)Nc1nc2cccc(-c3ccoc3)n2n1
Yield: 33 %

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 41 mg; 0.20 mmol; 1.0 eq.) and phenylacetyl chloride (38 μl; 0.41 mmol; 2.0 eq). Purification of the compound by flash chromatography on silica (EtOAc/c-Hex, 50:50) gave the title compound as a white powder (21 mg, 29%). 1H NMR (DMSO-d6) δ 8.98 (brs, 1H), 8.61 (brs, 1H), 7.55 (m, 3H), 7.37 (m, 5H), 7.22 (m, 1H), 6.91 (s, 1H), 3.96 (brs, 2H), 1.99 (brs, 3H, water). HPLC, Rt: 3.27 min. (purity 94.5%). LC/MS, M+(ESI): 319.3, M−(ESI): 317.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([C:23]#N)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1C[O:40]CC1>O.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=[O:40])=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C1CCOC1
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(C#N)ccc3[nH]2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(Cc2nc3cc(C=O)ccc3[nH]2)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile INT-46 (1.22 g, 3.51 mmol) in THF (20 mL) at 0° C. was added diisobutylaluminum hydride (12.3 mL, 12.3 mmol, 1 M in toluene). After 2 h the reaction mixture was poured onto Rochelle's salt (7.91 g, 28.0 mmol) in water (100 mL) and EA (50 mL) and stirred for 1 h. The layers were split and the aqueous layer was further extracted with EA (2×30 mL). The combined organics were washed with brine (20 mL) dried over MgSO4 and evaporated. The crude material was purified by chromatography (EA/isohexanes) to afford 571 mg (46%) of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbaldehyde INT-47 as a brown oil. LCMS-ESI (m/z) calculated for C22H26N2O2: 350; found 351 [M+H]−, tR=2.34 min (Method 5).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:12][C:11]1[C:5]2[O:4][CH2:3][C@H:2]([NH:1][CH:16]([CH3:18])[CH3:15])[CH2:7][C:6]=2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=1
Reactant: CC(C)=O
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-Amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.62 g, 8.21 mmol) was dissolved in anhydrous methanol (20 mL) and to this was acetone (6.0 mL, 82.1 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (0.92 g, 14.8 mmol) was added, the pH was adjusted to 4-5 with acetic acid and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue that was used as is in the next reaction. GC-MS (70 eV) M=239 (81%).