Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2ccc(F)cc2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 4-fluorobenzoyl chloride, instead of benzoyl chloride, to obtain 2.63 g of 1-benzyl-4-(4-fluorobenzoylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:11][N:12]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:23]2[CH2:22][CH2:21][CH:20]([N:12]([CH3:11])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:25][CH2:24]2)=[C:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1c(Cl)nnc(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 64.9 %

Procedure:
Heat a mixture of 3,6-dichloro-4,5-dimethylpyridazine (11.0 g, 62.1 mmol), tert-butyl methyl(piperidin-4-yl)carbamate (23.3 g, 109 mmol), and powdered K2CO3 (17.2 g, 124 mmol) in DMSO (310 mL) at 120° C. for 2 d. Cool the reaction mixture, dilute with H2O, and filter off the solid. Rinse the solid with H2O, and dry under vacuum at 45° C. Dissolve the solid in CH2Cl2, and pass the solution through a pad of silica gel, eluting with CH2Cl2. Concentrate the organic layer under reduced pressure to obtain the title compound as a yellow solid (14.3 g, 65%). ES/MS m/z (35Cl) 355.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C1(C)C=CC=CC=1>[CH:22]1([CH2:21][N:20]2[C@@H:7]3[C@@H:8]([C:9]4[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=4[CH2:5][CH2:6]3)[CH2:13][C:14]2=[O:16])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CC1CCCCC1
Reaction time: 10 h
Yield: 79.9 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 1.98 ml (0.01525 mol) of aminomethyl-cyclohexane were added thereto and the mixture was boiled for 23 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 120° and 140 bar for 10 hours. After chromatography over silica gel with cyclohexane/ethyl acetate 3:1 the product was dissolved in hot isopropyl ether and crystallized at room temperature. There were obtained 3.82 g (80%) of rac-cis-3-cyclohexylmethyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 136°-137°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CCN(CC)CC.[CH2:17]([O:19][C:20](=[O:31])[CH:21]([C:28](Cl)=[O:29])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:31])[CH:21]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:28]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)=[O:29])[CH3:18]
Reactant: CCOC(=O)C(C(=O)Cl)C1CCCCC1
Reactant: c1ccc2[nH]nnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)n1nnc2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 25 %

Procedure:
A solution of 2-cyclohexyl-malonic acid monoethyl ester (2.9 g, 14 mmol; CAS Reg. No. 147596-63-2) in thionyl chloride (29 ml) was heated under reflux conditions for 2 h. The solvent was removed under reduced pressure to give chlorocarbonyl-cyclohexyl-acetic acid ethyl ester. 1,2,3-Benzotriazole (1.47 g, 12 mmol) was dissolved at ambient temperature under an argon atmosphere in CH2Cl2 (45 ml). Et3N (1.86 ml, 13 mmol) and a solution of chlorocarbonyl-cyclohexyl-acetic acid ethyl ester in CH2Cl2 (4 ml) was added. The reaction mixture was stirred at ambient temperature for 14 h, quenched with ice cold aqueous 2 N HCl and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (1.05 g, 3.3 mmol; 25%) as yellow oil. MS: m/e=316.2 [M+H+].
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:15][CH2:16][C:17](O)=[O:18]>C(Cl)(Cl)Cl.S(Cl)(Cl)=O>[N:1]1([C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:12]([O:11][CH3:10])[CH:13]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: COc1ccc(OCC(=O)O)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCC(=O)n2nnc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
To a solution of 1H-benzo[d][1,2,3]triazole (11.2 g) in CHCl3 (120 ml), thionyl chloride (1.7 ml) was added and after stirring at room temperature for 30 minutes, 2-(3,4-dimethoxyphenoxy)acetic acid (5.00 g) was added and the mixture was stirred at room temperature for 1.5 hours. The precipitate was filtered off and the filtrate was washed with an aqueous solution of 2 N NaOH; thereafter, the organic layer was dried (MgSO4), filtered and concentrated to give the titled compound (8.06 g, colorless solid.)
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:50]>>[N:1]1([C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:25]3[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:18]=[C:17]([NH2:50])[C:16]=3[N:15]=[CH:14]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCCCCn1cnc2cnc3ccccc3c21)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: Nc1nc2ccccc2c2c1ncn2CCCCCC(=O)N1CCOCC1

Procedure:
1-(6-Morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline (3.09 g, 8.79 mmol) was treated with mCPBA (3.54 g, 15.4 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (3.26 g, 17.4 mmol) according to the method described in Part D of Example 8. The crude product was purified as described in Part C of Example 10 to provide 0.422 g of 1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 166-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21]O)=[N:6][CH:7]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl.O>[Br:48][CH2:21][C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nc(CBr)c(Sc3ccc(Cl)cn3)o2)cc1
Reaction time: 1 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.30 g, 0.89 mmol) in 3.3 mL of DCM at 0° C. was added imidazole (0.02 g, 0.36 mmol), Ph3P (0.28 g, 1.07 mmol) and CBr4 (0.36 g, 1.07 mmol). After 1 h at 0° C., water was added and the reaction mixture was extracted with EtOAc. The combined organics were washed with 10% KHSO4, satd. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The reaction was purified by flash chromatography (silica, 0-25% EtOAc/hexanes) to give 2-{[4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazol-5-yl]sulfanyl}-5-chloropyridine as white solid. LCMS [M+H]+=401.2.
Reaction SMILES: Cl.[C:2]([C:10]1[CH:11]=[C:12]([C@H:16]([NH2:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.OS(O)(=O)=O.[S-:24][C:25]#[N:26].[Na+]>C1(C)C=CC=CC=1>[C:2]([C:10]1[CH:11]=[C:12]([C@H:16]([NH:18][C:25]([NH2:26])=[S:24])[CH3:17])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: C[C@@H](N)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(N)=S)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R)-1-[(3-benzoyl)phenyl]ethylamine hydrochloride (0.52 g, 2 mmol) in toluene (15 mL), conc. H2SO4 (3 mmol) and sodium thiocyanate (0.18 g, 2.2 mmol) were added and the resulting mixture was left stirring at room temperature for 30 min. The formation of a white precipitate was observed: then the mixture was refluxed for 4 h and left stirring at room temperature overnight. The organic phase was washed with H2O (3×mL), dried over Na2SO4, filtered and evaporated under vacuum to give the N-[(1R)-1-(3-benzoylphenyl)ethyl]thiourea a dark red oil (0.53 g) pure enough (GC-Ms analysis) to be used without any further purification.
Reaction SMILES: [CH3:1][C:2]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.Cl>O>[CH3:1][C:2]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(N2CCOCC2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CC1(N2CCOCC2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0-5° C.) mixture of 11 (10.00 g, 41.44 mmol) and water (47 mL) was added 7 N aqueous HCl (47 ml, 331.50 mmol). Cooling bath was then removed and the reaction mixture was stirred at RT overnight. Then, the reaction mixture was basified to pH 9 by dropwise addition of 50% aqueous NaOH while maintaining the internal temperature <35° C. with an ice bath. The mixture was extracted with EtOAc (2×73 mL) followed by CH2Cl2 (2×71 mL). The organic extracts were dried (MgSO4) filtered and concentrated in vacuo to give a white residue that was recrystallised from CH2Cl2/hexane to afford (VII-n) (6.75 g, 83%) as a white crystalline solid; 1H NMR (400 MHz, CDCl3) δ 0.99 (s, 3H), 1.61 (td, J=13.9, 4.3 Hz, 2H), 2.09-2.19 (m, 4H), 2.55-2.65 (m, 6H), 3.74 (t, J=4.6 Hz, 4H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][NH2:34].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][NH2:34]
Reactant: NCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 59.8 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and 1,3-diaminopropane (3.3 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(3-aminopropylamino)-cholestan-3β-ol as a white solid (6.3 g, 60%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 20% yield.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[C:22]([Cl:25])(Cl)=[O:23]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.[Cl:25][C:22]([O-:23])=[O:11]
Reactant: O=C(Cl)Cl
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C([O-])Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Testosterone chloroformate was prepared as follows. To a solution of testosterone (2 g, 7.0 mmol) dissolved in tetrahydrofuran (50 ml) was added a 1.93M solution of phosgene in toluene (33 ml). The resulting solution was stirred for 4 h at room temperature, concentrated under vacuum, and the resulting residue vacuum dried for approximately 30 minutes (2.88 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: CN(C)C(=O)[C@H](CO)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.47 g) in 2-propanol (10 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-N,N-dimethyl-L-serinamide (1.50 g) and piperidinium acetate (641 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.24 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[C:16]2[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].CO>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:28][OH:29])=[C:16]2[CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 53 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.64 g, 1.9 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol), methanol (25 mL) and pyridine (1 mL) was heated to reflux for 30 min. The mixture was cooled, the methanol removed by evaporation. The product was extracted into ethyl acetate (2×50 mL) and the organic layer was washed with water and brine and dried over MgSO4. The solvent was evaporated, and the product was purified by silica gel chromatography (25% ethyl acetate-hexanes) to provide a white solid (53%): mp 171-173° C.; 1H NMR (DMSO-d6): δ 2.31 (3H, s), 5.20 (2H, s), 6.94-7. J01 (1H, m), 7.10-7.14 (2H, m), 7.23 (2H, d, J=8.9 Hz), 7.37-7.47 (5H, m), 7.52 (2H, d, J=7.4 Hz), 8.01-8.03 (1H, m), 8.41 (1 H, s), 10.66 (1H, s); MS m/z (M+H)+357. Anal. for C23H20N2O2·0.5H2O: Calc'd: C, 75.60; H, 5.79; N, 7.67. Found: C, 75.12; H, 5.53; N, 7.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([C:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]=3[O:27][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC(=O)C(C)(C)C)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.077 g, 0.20 mmol) dissolved in anhydrous dichloromethane (3 ml) is added triethylamine (0.031 ml, 0.22 mmol) then pivaloyl chloride (0.027 ml, 0.22 mmol). This mixture is stirred at room temperature for 3 hours, then diluted with dichloromethane (15 ml) and washed with distilled water (2×10 ml). Organic fractions are combined, dried over magnesium sulphate, then concentrated to give a crude oil which is purified by flash chromatography (100% hexane to hexane/ethyl acetate 9:1 ratio) to afford 2,2-dimethylpropionic acid 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester (0.090 g) as a colourless gum.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CN1CCCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Solvent: CC(=O)N(C)C
Product: CN1CCCN(c2nnc3ccc(F)cn23)CC1
Yield: 77 %

Procedure:
A solution of Intermediate 24b (451 mg, 2.50 mmol) and 1-methyl-[1,4]diazepane (1.14 g, 10.0 mmol) in DMA (10 mL) was heated in the microwave at 175° C. for 6 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% (2M NH3 in MeOH) in DCM, to give the title compound as a brown oil (480 mg, 77%). LCMS (Method 3): Rt 0.44 min, m/z 250 [MH+].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=1.[H-].[Na+].[C:23]([C:27]1[CH:28]=[C:29]([C:33](Cl)=[O:34])[N:30]([CH3:32])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([C:27]1[CH:28]=[C:29]([C:33]([N:15]([C:13]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])[N:14]=2)[C:33]([C:29]2[N:30]([CH3:32])[N:31]=[C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:28]=2)=[O:34])=[O:34])[N:30]([CH3:32])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)N(C(=O)c1cc(C(C)(C)C)nn1C)c1nc(-c2ccccc2C(F)(F)F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (200 mg, 0.706 mmol, prepared as described in Example 22, STEP B) in THF (15 mL) was treated with NaH (84.7 mg, 2.12 mmol) at room temperature for 1 h. The resulting mixture was treated with a solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (156 mg, 0.777 mmol) as a solution in THF (6 mL) and allowed to stir at room temperature for 15 min. The mixture was quenched with saturated aqueous NH4Cl (25 mL) and extracted twice with EtOAc (35 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 5 min, then 1:99 to 1:9 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-[3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C30H32F3N7O4: 612.3 (M+H); Measured: 612.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:55][C:56]1([CH3:71])[CH2:61][NH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][NH:69][CH3:70])=[CH:64][CH:63]=2)=[N:58][CH2:57]1>ClCCCl>[CH3:55][C:56]1([CH3:71])[CH2:61][NH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][N:69]([CH3:70])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:64][CH:63]=2)=[N:58][CH2:57]1
Reactant: CNCc1ccc(C2=NCC(C)(C)CN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCC(C)(C)CN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (55 mg, 0.15 mmol), EDCI (35 mg, 0.18 mmol), HOAt (25 mg, 0.18 mmol), DIPEA (0.156 mL, 0.89 mmol) and 1-[4-(5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]-N-methylmethanamine (43 mg, 0.13 mmol) in DCE (1 mL). The crude product was purified using prep method C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[C:13]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[O:14]1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:9]([C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:13](=[O:14])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:22])=[CH:7][C:6]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(N)cc1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2C(=O)c3ccccc3C2=O)cc1O
Temperature: 110 °C
Reaction time: 13 h
Yield: 83.7 %

Procedure:
A mixture of 5-amino-2-tert-butyl-phenol (300 mg, 1.82 mmol), isobenzofuran-1,3-dione (283 mg, 1.91 mmol), triethylamine (759 μL, 5.45 mmol) in toluene (5.0 mL) was stirred at 110° C. for 13 h. The reaction mixture was cooled, diluted with ethyl acetate (15 mL), and washed with 10% aqueous NaHCO3(10 mL) and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(4-tert-butyl-3-hydroxyphenyl)isoindoline-1,3-dione (450 mg, 84% yield) as a light brown solid which was used for next reaction without further purification. 1H NMR (400.0 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.96 (m, 2H), 7.90 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.79 (dd, J=2.1, 8.3 Hz, 1H), 1.38 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>O1CCCC1.[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 98.8 %

Procedure:
A solution of 3-(3,5-difluorophenyl)propenoic acid (0.0435 mol) in tetrahydrofuran (100 ml) and a slurry of 10% palladium on carbon (1.5 g) in ethyl acetate were shaken together under 50 psi hydrogen for 4 hours. The mixture was filtered and concentrated to yield 8 g (99%) of a yellow oil.