Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[C:13]([OH:26])[CH:12]=3)=[CH:4][CH:3]=1>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([OH:26])=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)COc3cc(O)ccc32)cc1
Solvent: CCO
Product: COc1ccc(C2c3ccc(O)cc3OCC2c2ccc(O)cc2)cc1
Yield: 46.3 %

Procedure:
3-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2H-chromen-7-ol 25.5 g (70 mmoles), 10% Pd/Al2O3 3.95 g and 200 ml of ethanol were combined in a 2-neck 500 ml round bottom flask. The reaction was hydrogenated at low pressure using standard conditions for 3 hours. The reaction was filtered through Celite to remove the catalyst, rinsed through with ethanol (300 ml). The filtrate was concentrated to 50 ml before being poured into chilled, stirred water (1.4 L). A pale orange precipitate formed which then formed a brown oil. The mixture was then extracted with diethyl ether, the combined organic layers washed with water (3×1 L), brine (1×500 ml), dried over anhydrous magnesium sulphate and filtered. The solvent was removed in vacuo to give red/brown oil. The product was recrystallised from diethyl ether (˜100 ml), to give brown solid which was rinsed with chilled diethyl ether to give off-white crystals 11.3 g. The 1H NMR spectrum and numbering scheme being shown below.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH3:32])[N:20]=[C:19]2[N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]1[CH3:43])=O)C.O>O1CCCC1>[OH:9][CH2:10][CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[CH3:32])[N:20]=[C:19]2[N:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]1[CH3:43]
Reactant: CCOC(=O)COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)c2cccc(OCCO)c2n1
Yield: 58.2 %

Procedure:
To a mixture of 0.12 g of lithium aluminium hydride (3.0 mM) and 30 ml of tetrahydrofuran, 1.5 g of the compound (3.0 mM) prepared in Step 2 dissolved in tetrahyrofuran was dropwise added at 0° C. and stirred for an hour. The reaction solution was added with water and extracted from dichloromethane. The dichloromethane layer was dehydrated, concentrated and purified by silica gel column chromatography, to give 0.80 g of the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][N:10]([CH2:15][C:16](O)=O)[CH2:11][C:12](O)=O>C(O)CO>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:12]1[CH2:11][N:10]([CH2:15][C:16]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1)[CH3:9]
Reactant: Nc1ccccc1N
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: OCCO
Product: CN(Cc1nc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1

Procedure:
2b was synthesised by an analogous procedure to that described for 2a using o-phenylenediamine (5.88 g, 54.40 mmol) and methyliminodiacetic acid (4.00 g, 27.2 mmol) in ethyleneglycol (20 ml). Yield 6.88 g (87%). 1H NMR (250.13 MHz, CD3OD, r.t.), δ 2.29 (s, 3H, NCH3), 3.92 (s, 4H, N(CH2)), 7.19-7.23 (m, J3=3.35 Hz, 4H, ArH), 7.52-7.56 (m, J3=3.35 Hz, 4H, ArH). 13C NMR (62.9 MHz, DMSO-d6, r.t.) δ 47.31 (CH3), 59.97 (NCH2), 126.66 (ArC), 157.45 (ArCq). Anal. Calc. for C17H17N5 (in %) C, 70.10; H, 5.84; N, 24.05. Found C, 70.22; H, 6.05; N, 23.76. +CI MS: (m/z): 292 ([MH+]).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[S:20][C:19]([C:21]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[O:22])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: NCCCCCCCCn1ccnc1
Product: O=C(NCCCCCCCCn1ccnc1)c1ccc(Cl)s1

Procedure:
When 1H-imidazole-1-octylamine is treated with 5-chlorothiophene-2-carbonyl chloride by the procedure of Example 36, the title compound, m.p. 95°-97° C., was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-])=O)[C:3]=1[N+:14]([O-:16])=[O:15].[C:17](OCC)(=O)[CH3:18]>>[N:11]1([C:4]2[C:3]([N+:14]([O-:16])=[O:15])=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=2[C:6]([NH2:8])=[O:7])[CH2:18][CH2:17]1
Reactant: CCOC(C)=O
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1[N+](=O)[O-]
Product: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1N1CC1
Reaction time: 3 h

Procedure:
Reaction of 4-chloro-2,3-dinitrobenzamide [Goldstein and Schaaf, Helv. Chim. Acta. 1957, 40, 369-376] in ethyl acetate generally as described in Example L, except that the reaction time was 3 hours, gave 2-(aziridin-1-yl)-4-chloro-3-nitrobenzamide (16) as a yellow powder, mp 216° C. 1H NMR [(CD3)2SO] δ8 16 (br s, 1H CONHH), 7 71 (br s, 1H, CONHH), 7 69 (d, J=8.3 Hz, 1H, H-6), 7.25 (d, J=8.3 Hz, 1H, H-5), 2.28 (s, 4H, aziridine-H) 13C NMR δ165.53 (s), 142.59 (s), 142.49 (s), 131 65 (d), 129.71 (s), 129.00 (s), 121.37 (d), 29.40 (t). Found. C, 44.90;H, 3.49; N, 17.39. C9H8ClN3O3 requires C, 44.73;H, 3.33; N, 17.39%.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C@@H:12]([CH2:13]/[CH:14]=[C:15](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH3:16])[CH2:11][OH:10]
Reactant: C/C(=C\C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C/C(=C\C[C@H](N)CO)c1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of (4S)-2,2-dimethyl-4-((E)-3-phenyl-but-2-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.15 g) in dioxane (10 ml) at room temperature was added a 4 M solution of hydrogen chloride in dioxane (17.4 ml solution) and stirring was continued at room temperature overnight. The mixture was taken up in ethyl acetate and washed sequentially with aqueous sodium hydroxide solution (1N), water and saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/dichloromethane gradient; eluant containing 1% aq. ammonia) to yield a yellow oil, (185 mg, 28%); MS (ISP): 192.1 ([M+H]+).
Reaction SMILES: O1CCCC1.[B:6]([O:11]C)(OC)[O:7]C.[F:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>O>[F:13][C:14]1[CH:15]=[C:16]([B:6]([OH:11])[OH:7])[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: COB(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
In a second reaction vessel, 40 mL of tetrahydrofuran is cooled to -78° C., and 2.3 mL (0.021 mole) of trimethyl borate is added dropwise as the Grignard reagent of 3-fluoro-5-trifluoromethylphenyl bromide prepared above is transferred into the second reaction vessel using a cannula. The temperature of the reaction mixture is maintained below -60° C. during the additions. Upon completion of the additions, the reaction mixture is again cooled to -78° C., where it is stirred for about 45 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is then poured into about 200 mL of water and is made acidic with aqueous 5% hydrochloric acid. The mixture is extracted with four 100 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 3.3 grams of 3-fluoro-5-trifluoromethylphenylboronic acid, mp 167°-168° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].Cl.CC(OC)(C)C>C(Cl)Cl>[ClH:1].[CH3:44][S:41]([CH2:40][C:37]1[CH:38]=[CH:39][C:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([CH2:25][N:9]([CH:10]3[CH2:11][CH2:12][CH:13]([NH:16][CH3:17])[CH2:14][CH2:15]3)[C:7]([C:6]3[S:5][C:4]4[C:45]([F:50])=[CH:46][CH:47]=[C:48]([F:49])[C:3]=4[C:2]=3[Cl:1])=[O:8])[CH:27]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:43]
Reactant: COc1ccc(-c2ccc(CS(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CNC1CCC(N(Cc2cc(-c3ccc(CS(C)(=O)=O)cc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
tert-Butyl carbamate 199 (224 mg, 0.30 mmol) is deprotected using Method F. On removal of the solvents in vacuo, the residue is suspended in aqueous NaHCO3 (20 mL) and extracted into DCM (3×20 mL). The combined DCM phases are washed with water (2×20 μL) and brine (20 mL) then dried (Na2SO4) and reduced in vacuo. The free base thus obtained is converted to the HCl salt by Method H. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) TBME (25 mL). The resultant pale yellow precipitate is isolated by filtration, washed with TBME (10 mL) and diethyl ether (10 mL) and dried to afford the title compound.
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[F:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][C:38]([CH3:41])=[C:37]2[CH2:42][C:43]([OH:45])=O>>[Cl:24][C:22]1[CH:23]=[C:18]([CH2:17][NH:16][C:15]([NH2:30])=[N:14][C:43](=[O:45])[CH2:42][C:37]2[C:36]3[C:40](=[C:32]([F:31])[CH:33]=[CH:34][CH:35]=3)[NH:39][C:38]=2[CH3:41])[CH:19]=[C:20]([Cl:29])[C:21]=1[NH:25][C:26](=[O:28])[CH3:27]
Reactant: Cc1[nH]c2c(F)cccc2c1CC(=O)O
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C)[nH]c3c(F)cccc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(7-fluoro-2-methyl-1H-indol-3-yl)acetic acid in step 22 (A), the title compound was prepared. MS (ESI) (M+H)+=464.00 1H-NMR(500 MHz, CD3OD) δ 7.44 (s, 2 H), 7.24 (d, J=7.93 Hz, 1 H), 6.90-7.01 (m, 1 H), 6.72-6.89 (m, 1 H), 4.52 (s, 2 H), 3.93 (s, 2 H), 2.45 (s, 3 H), 2.19 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=1[CH3:20].[OH-].[Na+]>CCO.O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[CH3:20]
Reactant: COCc1ccccc1-c1ccc(C(=O)OC)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-(methoxymethyl)-2-methylbiphenyl-4-carboxylate (3 g; 11.10 mmol; 1 eq.) in EtOH (90 mL) at RT was treated with NaOH (6.66 mL; 5 M; 33.29 mmol; 3 eq.). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid which was taken up in water (100 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with HCl cc to pH 2 and it was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 12.95 (br s, 1H), 7.92-7.91 (m, 1H), 7.84-7.81 (dd, J=7.83 Hz, 1.91 Hz, 1H), 7.55-7.52 (m, 1H), 7.47-7.38 (m, 2H), 7.25-7.22 (d, J=7.86 Hz, 1H), 7.15-7.14 (m, 1H), 4.09 (m, 2H), 3.17 (s, 3H), 2.07 (s, 3H). LC/MS (Method B): 255.2 (M−H)−. HPLC (Method A) Rt 4.35 min (Purity: 96.8%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[CH3:16]
Reactant: C[Mg]Br
Reactant: Cc1cc(C(=O)c2ccccc2)ccc1Br
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)c2ccccc2)ccc1Br
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-methylphenyl)-phenylmethanone (200 mg, 0.727 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(N)cc1

Procedure:
A mixture of dimethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (3.0 g, 14 mmol) and 5% Pd—C (0.4 g) in ethyl acetate (70 mL) was hydrogenated under 50 psi hydrogen for 20 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacuo, providing 2.6 g, in quantitative yield; 1H NMR (CDCl3) δ 2.32 (s, 6H), 2.69 (t, J=5.8 Hz, 2H), 3.99 (t, J=5.8 Hz, 2H), 6.00-6.66 (m, 2H), 6.73-6.78 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([C:18]([O:20]CC)=O)=[C:6]([CH3:17])[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1.O.[OH-].[Li+]>C(O)C.O>[CH3:17][C:6]1[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:4]2[CH2:3][CH2:2][NH:1][C:18](=[O:20])[C:5]=12
Reactant: CCOC(=O)c1c(CCN)cn(COCC[Si](C)(C)C)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c2c(cn1COCC[Si](C)(C)C)CCNC2=O
Temperature: 120 °C

Procedure:
A solution of Example 93e (3.36 g, 10.29 mmol) and lithium hydroxide monohydrate (3.17 g, 76 mmol) in ethanol (47.5 mL) and water (2.5 mL) was added to 100 mL microwave reaction vessel with stir bar. The mixture was heated at 120° C. for 30 minutes in a Ethos Microsynth multimode microwave reactor (Milestone Inc.), then cooled to ambient temperature. The reaction mixture was added to 200 mL water and stirred for 15 minutes. The mixture extracted with 3×200 mL 10% methanol/dichloromethane and the combined dichloromethane extracts dried over anhydrous sodium sulfate. Filtration and solvent removal provided a brown oil which was chromatographed on a 40 g silica cartridge eluting with 0-10% methanol/dichloromethane to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][S:10][CH3:11])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].N1([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C=CN=C1>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:12])[CH:9]([S:10][CH3:11])[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:6][CH:7]=1
Reactant: CSCC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CCOC(=O)C(=O)C(SC)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 15 g of 1-(4-chlorophenyl)-2-(methylthio)ethanone (2) in 70 mL of MTBE is added a solution of 86 mL of lithium hexamethyldisilazide (LiHMDS) under nitrogen gas, while keeping the temperature at −40° C. After stirring for 1.5 hours at this temperature, 14.4 g of ethyl 2-(1H-imidazol-1-yl)-2-oxoacetate (3) in 50 mL MTBE are added at 0° C., and the mixture is left stirring overnight at room temperature. The reaction solution was filtered off and the filtrate was suspended in 80 mL of MTBE. 50 mL of 6N HCl are added to the suspension. After separation of the phase by settling, the ether phase is washed 4 times with water and then concentrated under reduced pressure to obtain 22 g (73 mmol) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[O:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH:23]([CH3:25])[CH3:24]>CN(C=O)C.Cl>[CH:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[C:4]([O:3][CH:23]([CH3:25])[CH3:24])=[O:15])=[O:1]
Reactant: CC(C)I
Reactant: O=C1OC(O)c2cccc(C(F)(F)F)c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1c(C=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
To a solution of (±)-3-hydroxy-7-(trifluoromethyl)isobenzofuran-1(3H)-one (2.2 g, 10.1 mmol) in 20 mL of DMF was added potassium carbonate (2.8 g, 20.2 mmol) followed by 2-iodopropane (1.11 mL, 11.1 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was diluted with 1N HCl to pH ˜4 and extracted with EtOAc. The organics were washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 2.3 g (87%) of the title compound which was used without purification. 1H NMR (CDCl3): δ 10.08 (s, 1H), 8.12 (d, 1H, J=7.7 Hz), 7.95 (d, 1H, J=8.2 Hz), 7.73 (t, 1H, J=7.7 Hz), 5.44-5.36 (m, 1H), 1.40 (d, 1H, J=6.6 Hz).
Reaction SMILES: [C:1]1([CH2:7][S:8][S:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>CN(C)C1C=CN=CC=1.O1CCCC1>[O:19]=[C:13]([O:12][CH2:11][CH2:10][S:9][S:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: OCCSSCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)OCCSSCc1ccccc1

Procedure:
A mixture of 5-phenyl-3,4-dithiapentanol (832 mg, 4.15 mmol), succinic anhydride (415 mg, 4.15 mmol) and 4-dimethylaminopyridine (25 mg) in dry tetrahydrofuran (20 ml) was refluxed under nitrogen overnight. The mixture was then evaporated to dryness and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].Cl[C:24]1[N:29]=[C:28]([NH:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:27]([Cl:42])=[CH:26][N:25]=1.Cl.O1CCOCC1>COCCO>[CH2:13]([N:10]1[CH2:11][C:12]2[C:2]([NH:1][C:24]3[N:29]=[C:28]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:27]([Cl:42])=[CH:26][N:25]=3)=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=2[NH:7][C:8](=[O:20])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1N)CN(Cc1ccccc1)CC(=O)N2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1ccc2c(c1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)CN(Cc1ccccc1)CC(=O)N2
Temperature: 90 °C

Procedure:
To a solution of 6-amino-4-benzyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (75 mg, 0.25 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.25 mmol) in 2-methoxyethanol (2 mL) was added 4N HCl-dioxane (0.20 mL). The mixture was heated to 90° C. for two hours whereupon LCMS showed complete consumption of the aniline. After being cooled to room temperature, triethylamine was added to pH 9 and the crude product was purified by preparative tlc (7% MeOH-DCM) to afford N-{(1R,2R)-2-[2-(4-benzyl-7-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-6-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a light brown foam; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.02 (s, 2H), 7.35 (m, 5H), 7.10 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.78 (m, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 3.70 (s, 3H), 3.65 (s, 2H), 3.60 (s, 2H), 3.26 (s, 2H), 2.89 (s, 3H), 1.97 (m, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.25 (m, 2H); MS (m/e) 601 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:42])=[C:32]([C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=3[F:42])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1c(C(F)(F)F)ccc(Cl)c1F
Product: Fc1c(Cl)ccc(C(F)(F)F)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-chloro-2-fluoro-6-trifluoro methyl-benzaldehyde. MS (ESI) m/z 587.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc(OCCCN2CCCCC2)nc1
Solvent: CO
Product: Nc1cnc(OCCCN2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
5-nitro-2-(3-piperidin-1-yl-propoxy)pyrimidine (100 mg, 0.38 mmol) was dissolved in a mixed solvent of methanol (2 mL) and distilled water (2 mL), sodium dithionite (Na2S204) (655 mg) was added, and the mixture stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated, and the target compound (60 mg, 68%) was obtained as a yellow oily residue.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[NH:4][C:5](=[O:20])[C:6](=[O:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+].Br[CH2:27][CH:28]([OH:32])[CH2:29][CH2:30]Br>C(#N)C>[CH2:12]([N:7]1[CH:8]2[CH:3]([CH:2]([N:1]3[CH2:30][CH2:29][CH:28]([OH:32])[CH2:27]3)[CH2:11][CH2:10][CH2:9]2)[NH:4][C:5](=[O:20])[C:6]1=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCCC2C1NC(=O)C(=O)N2Cc1ccccc1
Reactant: OC(CBr)CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1NC2C(N3CCC(O)C3)CCCC2N(Cc2ccccc2)C1=O
Reaction time: 24 h

Procedure:
(4aRS,5SR,8aRS)-5-Amino-1-benzylperhydroquinoxaline-2,3-dione (144 mg, 0.53 mmol) was dissolved in acetonitrile (16 ml), and NaHCO3 (300 mg, 3.57 mmol) and racemic 1,4-dibromobutan-2-ol (purity 85%, 1.15 g, 4.20 mmol, 0.57 ml) were added. After 24 hours, NaHCO3 was separated off and the mixture was evaporated in vacuo. The solid was taken up in CH2Cl2 and the mixture was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. The crude product was purified by flash chromatography over silica gel 60 (40-63 μm, (Merck) Ø 2 cm, acetone/MeOH/Et2NH 9.5:0.5:0.1, l=17 cm, V=5 ml). A pale yellow solid was isolated.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][NH2:12].C=O.[C:15](O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:10][CH2:11][NH:12][CH2:15]2
Reactant: COc1cccc(CCN)c1F
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: ClCCl
Product: COc1ccc2c(c1F)CCNC2
Temperature: 25 °C

Procedure:
To 1.0 g (5.9 mmol) 2-(2-fluoro-3-methoxy-phenyl)-ethylamine and 0.66 mL (8.9 mmol) formaldehyde (37% solution in water) in 10 mL DCM are added slowly 0.91 mL (12 mmol) TFA and the resulting mixture is stirred at r.t. over night. The reaction mixture is purified by HPLC (ACN/H2O/NH4OH).