Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:21]([C@H:23]1[O:25][CH2:24]1)Cl>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:20][CH2:21][C@H:23]3[CH2:24][O:25]3)=[C:15]([C:17](=[O:19])[CH3:18])[CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1O
Reactant: ClC[C@@H]1CO1
Product: CC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1OC[C@H]1CO1

Procedure:
(R)-(−)Epichlorhydrin (1.93 g; 0.021 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (1.92 g; 0.007 mol) and potassium carbonate (1.44 g; 0.011 mol) in acetonitrile (5 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzene sulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone as a white solid (1.456 g; 63%). A sample was recrystallized from diethyl ether-hexane: M. p. 115.1-116.8° C. Similarly, but replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin, 1-(5-benzene sulfonyl-2-(R)-oxiranylmethoxy-phenyl)-ethanone was prepared. M. p. 111.9-113.5° C. Similarly, but replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone, the above procedure gave 1-[5-(3-fluoro-benzenesulfonyl)-2-(S)-oxiranylmethoxy-phenyl]-ethanone: M. p. 112.7-114.9° C. Replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone and replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin gave 1-[5-(3-Fluoro-benzenesulfonyl)-2-(R)-oxiranylmethoxy-phenyl]-ethanone. M. p. 118.3-120.5° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:13][CH2:14][CH2:15][N:16]([CH2:24][C@H:25]([OH:30])[C@H:26]([OH:29])[CH2:27][OH:28])[CH2:17][C@H:18]([OH:23])[C@H:19]([OH:22])[CH2:20][OH:21])=O)(C)(C)C.ClCCl.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[OH:23][C@H:18]([C@H:19]([OH:22])[CH2:20][OH:21])[CH2:17][N:16]([CH2:15][CH2:14][NH:13][CH:12]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:11][CH2:10][CH2:9][NH2:8])[CH2:24][C@H:25]([OH:30])[C@H:26]([OH:29])[CH2:27][OH:28]
Reactant: CC(C)(C)OC(=O)NCCCC(NCCN(C[C@H](O)[C@H](O)CO)C[C@H](O)[C@H](O)CO)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCC(NCCN(C[C@H](O)[C@H](O)CO)C[C@H](O)[C@H](O)CO)c1ccccc1
Yield: 98 %

Procedure:
The protected amine 760 (0.12 g, 0.22 mmol) was stirred in a mixture of dichloromethane/TFA (10 mL, 1:1) for 2 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 3:1:0.3, v/v) to provide 770 (0.12 g, 98%) as a colorless oil. (300 MHz, CD3OD) δ δ 1.64 (m, 4H), 2.55 (m, 2H), 2.90 (m, 2H), 3.45 (m, 4H), 3.60 (m, 10H), 3.97 (m, 2H), 6.67 (d, 2H), 7.00 (d, 2H). m/z (APCI) 416 [C20H37N3O6+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:7][O:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1)[CH2:7][O:8][CH2:9][C:10]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(N)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
tert-Butyl 4-((3-nitro-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (118 mg, 0.24 mmol) in methanol (2.5 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 12 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated to afford 90 mg (80%). LC/MS (HPLC method 3): tR=3.10 min, 465.22 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl.O>[F:33][C:32]([F:35])([F:34])[S:29]([O:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([F:17])=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:30])=[O:28]
Reactant: Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a degassed solution of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-ol (600 mg, 2.28 mmol) and DIPEA (1.0 g, 7.74 mmol) in DCM (10 mL), Tf2O (1.3 g, 4.61 mmol) were added dropwise under N2 at 0° C. The mixture was stirred at RT for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, and concentrated. The mixture was purified by column chromatography (PE:EA=10:1) to give 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (700 mg, yield: 77.6%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.91 (br s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.51˜7.58 (m, 1H), 7.42˜7.50 (m, 1H), 7.18 (d, J=1.6 Hz, 1H), 7.06˜7.14 (m, 1H). MS (M+H)+: 395/397.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H].O1C2C=CC(CCC(N3CCCCC3)=O)=CC=2OC1>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Agent: O=C(CCc1ccc2c(c1)OCO2)N1CCCCC1
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
3-benzo-1,3-dioxol-5-ylacrylic acid (2 g) was hydrogenated in ethanol (50 ml) over 5% Pd-C under a pressure of hydrogen at 10 psi for 40 mins to give 3-benzo-1,3-dioxol-5-ylpropionic acid (1.67 g, 80% yield) as a solid, m.p. 86.1°-88.3° C. (Lit m.p. 87-88° C.)10 7.2 Synthesis of 3-benzo-1,3-dioxol-5-ylpropionic acid piperidide (RV-C03)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:35]([NH:37][CH3:38])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(Cc3ccccc3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-benzylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:3]3[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1cc2c(Cl)ncnc2s1
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(Nc3ccc(F)cc3OC3CCOCC3)ncnc2s1
Yield: 48.7 %

Procedure:
Methyl 4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (0.256 g, 1.12 mmol), 4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (0.236 g, 1.12 mmol) and para-toluene sulfonic acid (0.021 g, 0.01 mmol) were heated at reflux in anhydrous 1,4-dioxane (6 mL) for 4 hours. The solution was cooled, concentrated in vacuo and the crude product absorbed on to silica. The sample was purified by flash column chromatography (100% DCM→10% MeOH/DCM) to yield the title compound (0.220 g, 49%) after recrystallisation from MeOH.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]3[CH3:33])=[CH:6][CH:7]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: BrC1CCCC1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclopentane (1.00 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.05 g, 91%).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[O:5][C:4]2[CH2:8][C@H:9]([CH3:12])[CH2:10][CH2:11][C:3]1=2.CC1C2CCC(C)CC=2[O:16]C=1>>[OH:16][C:4]12[CH2:8][CH:9]([CH3:12])[CH2:10][CH2:11][C:3]1=[C:2]([CH3:1])[C:6](=[O:7])[O:5]2
Reactant: Cc1coc2c1CCC(C)C2
Reactant: CC1C(=O)OC2=C1CC[C@@H](C)C2
Product: CC1=C2CCC(C)CC2(O)OC1=O

Procedure:
The chemical structure of (6R)-4,5,6,7-tetrahydro-3,6-dimethyl-3H-benzo [b]furan-2-one is known. In fact, K. Schulte-Elte et al in Tetrahedron (1967), 23(6), 2583-2599 identified the compound of the formula (I) in a mixture of lactones resulting from the photooxidation of menthofuran. Furthermore, J. Hirsch et al in J. Org. Chem. (1967), 32(9), 2915-2916 also identified the lactone (I) from among other end products resulting from the hydrolysis of α,α′-dimethoxydihydromenthofuran. However, these authors specify that the lactone (I) oxidises very easily under the synthesis conditions described to give a hydroxylactone, 5,6,7,7a-tetrahydro-7a-hydroxy-3,6-dimethyl-4H-benzo[b]furan-2-one of the formula
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C@@H:8]2[OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:11][C@@H:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:6][CH2:7]2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: O[C@H]1CCc2ccc(Cl)cc21
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O[C@H]2CCc3ccc(Cl)cc32)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A solution of (S)-6-chloroindan-1-ol (0.45 g, 2.67 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (112 mg, 2.8 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (0.41 g, 2.94 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred, filtered, and dried. Purification by silica gel chromatography (dichloromethane) yielded 365 mg of 2-fluoro-5-((S)-6-chloroindan-1-yloxy)benzonitrile.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([CH3:12])=[N:11][C:3]=12.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([CH3:12])[CH:9]=2)=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Cc1cc2[nH]c(C)nc(Cl)c-2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2[nH]c(C)nc(N3CCOCC3)c-2n1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a 5-mL Wheaton vial was added 4-chloro-2,6-dimethylpyrrolo[3,2-d]pyrimidine (Example 46(d)) (0.10 g, 0.55 mmol) and morpholine (Aldrich Chemical Company) (0.24 mL, 2.7 mmol). A solution. of K2CO3 (0.35 g, 2.5 mmol) in water (2.5 mL) was added and the reaction mixture heated in the capped vial at reflux for 3.5 h. The reaction mixture was cooled to room temperature and the solution was filtered. The resulting precipitate was washed with H2O and hexanes and dried in a 60° C. vacuum oven to give 0.083 g (65%) of the title compound as an off-white solid. Mp: 242-243° C. 1H NMR (DMSO-d6; 500 MHz): δ 2.39 (s, 6), 3.60 (s, 4), 3.74 (s, 4), 6.07 (s, 1), 10.90 (s, 1). MS m/z: 233 (M+1). Anal. Calcd for C12H16N4O: C, 59.73; H, 7.10; N, 23.22. Found: C, 60.01; H, 6.84; N, 23.29.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH:12][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)c1ccc[nH]1
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1NC(=O)c1ccc[nH]1
Yield: 23.3 %

Procedure:
The title compound was prepared from 1H-pyrrole-2-carboxylic acid (2 g, 18 mmol) and 2,6-dimethylaniline (2.75 g, 22.7 mmol) following the experimental procedure described in Preparation 44a. 900 mg (23% yield) of the desired compound were obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH2:23]>>[CH3:20][C:21]([CH3:25])([CH3:24])[CH2:22][NH:23][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CC(C)(C)CN
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: CC(C)(C)CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2,2-dimethylpropylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (CI): 282.2 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.66 (s, 1H); 8.39 (br s, 1H); 8.19 (d, J=6.6 Hz, 1H); 7.88 (m, 1H); 7.41 (m, 2H); 6.79 (m, 1H); 5.46 (br s, 1H); 3.40 (d, J=6.4 Hz, 2H); 1.04 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>O>[C:1]1([C:7]2[C:8]3[CH:18]([OH:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-phenylindeno[1,2-c]pyrazol-4(1H)-one (0.86 g), sodium borohydride (0.26 g) and absolute ethanol (200 ml) was stirred at ambient temperature for 72 hours. The mixture was filtered to remove a small amount of solid which was discarded and the filtrate was concentrated under reduced pressure to low volume whereupon crystals were formed. This suspension was diluted with water to approximately 250 ml and the solid was collected by filtration and recrystallized from methanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-4-ol, m.p. 269-272° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][CH:11]2[CH2:19][CH:18]3[CH:13]4[CH2:14][CH:15]5[CH:17]3[CH:16]5[CH:12]24)=[CH:4][CH:3]=1.[NH3:21]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:21])[NH:10][CH:11]2[CH2:19][CH:18]3[CH:13]4[CH2:14][CH:15]5[CH:17]3[CH:16]5[CH:12]24)=[CH:4][CH:3]=1
Reactant: S=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13
Reactant: N
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13
Reaction time: 0.25 h

Procedure:
8-[3-(p-Chlorophenyl)thioureido]tetracyclo[4,3,0,02,4,03,7 ]nonane (0.30 g.) was dissolved in ethanol saturated with ammonia (100 ml.) at room temperature and stirred with yellow mercuric oxide (0.43 g.) for 6 hours. The mixture was then boiled for 15 minutes to remove excess ammonia, filtered and the filtrate evaporated to dryness. The solid residue was recrystallised from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)guanidino]tetracyclo[4,3,0,02,4,03,7 ]nonane, m.p. 170°-171°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13]([NH:17][S:18]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[C:29]([F:42])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([NH:17][S:18]([C:21]1[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[CH:3]=[C:4]4[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]4=[N:6][CH:7]=3)=[C:29]([F:42])[CH:28]=2)=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(C=O)c3c2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 88 using 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde and N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide. MS (ESI): mass calcd. for C24H22FN3O3S, 451.14; m/z found, 452.2 [M+H]+.
Reaction SMILES: Cl.[N:2]1[C:8]2=[CH:9][CH2:10][S:11][C:7]2=[CH:6][CH:5]=[CH:4][N:3]=1.N1C(C)=CC(C)=CC=1C.NC(N)=[O:23]>C(Cl)Cl.C1COCC1>[O:23]=[C:6]1[C:7]2[S:11][CH:10]=[CH:9][C:8]=2[N:2]=[N:3][CH:4]=[CH:5]1
Reactant: NC(N)=O
Reactant: C1=CN=NC2=CCSC2=C1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=c1ccnnc2ccsc12

Procedure:
The synthesis of I, J analogs of the benzodiazepines scaffold is illustrated in the following pathway. In both approaches chiral amino acid are introduced into the synthesis raising the diversity around the α carbon. Thieno diazepine I is prepared from 2-amino-3-acyl)-thiophenes 5, which reacts with pre formed Boc amino acid chloride (amino acid, BTC, collidine, THF or DCM). Deprotection of 8 (4N HCl) with concomitant ring closure leads to 2-oxothienodiazepine I. Thiophenodiazepine J can be prepared starting from 2-amino-3-carboxy-thiophenes A, which after pre activation to the thienooxzaine dione (BTC, collidine, THF or DCM)) reacts with amino ketone to obtain 9, ring closure afford 5-oxothienodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and 2-bromoacetophenone according to General Procedure B. Yield 293 mg (38%), MP 262° C.; 1H-NMR (DMSO-d6): δ 3.79 (m, 4H), 3.95 (m, 4H), 5.87 (s, 2H), 7.16 (dd, J=3.6, 5.2 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 7.59 (m, 2H), 7.50 (m, 1H), 7.81 (dd, J=1.2, 4.8 Hz, 1H), 8.12 (m, 2H), 8.23 (dd, J=2.8, 9.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 502 (M+1). Anal. (C26H20FN5O3S) C, H, N.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]1=O.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2c([nH]1)CCCC2
Product: Clc1cnc2c(n1)CCCC2

Procedure:
A solution of 5,6,7,8-tetrahydroquinoxalin-2-one (1.01 g, 0.0067 mol) in excess POCl3 (20 mL) was refluxed for 19 h under an atmosphere of dry nitrogen. The crude reaction mixture was then concentrated under reduced pressure and diluted with about 50 mL of hexanes/ethanol (1:1). After bringing the solution to 0° C., concentrated NH4OH (aq.) was added slowly to the stirring mixture until a pH of 7-8 was attained. The mixture was extracted (4×) with hexanes, and the combined oganic portions were dried (Na2SO4) and filtered. The hexanes solution was heated for 10 minutes with activated charcoal and filtered through 2 inches of silica gel (EtOAc/hexanes eluent). Evaporation of the solvents under reduced pressure yielded 2-chloro-5,6,7,8-tetrahydroquinoxaline as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].C(=O)([O-])O.[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[OH:7][C:6]1[CH:5]=[C:4]([O:9][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:3]=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2)c1
Yield: 98.4 %

Procedure:
24.8 g (200 mmol) 5-methyl-resorcinol, 200 ml ether, 400 ml sodium hydrogen carbonate solution and 28.2 ml (220 mmol) benzenesulfonyl chloride were stirred for 2 d at room temperature, the organic phase was separated, the aqueous phase was extracted with ether, the combined organic phases were dried over sodium sulfate, filtered, the solvent was removed in a vacuum and 52 g (quant.) benzenesulfonic acid-3-hydroxy-5-methyl-phenyl ester was obtained. Fp 108°-110° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:7]=1[C:15]#[N:16])=[O:5])C.[Li+].[OH-]>CO>[C:11]([C:8]1[C:7]([C:15]#[N:16])=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1onc(C(C)(C)C)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1noc(C(=O)O)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-tert-Butyl-4-cyano-isoxazole-5-carboxylic acid ethyl ester (809 mg, 3.64 mmol, prepared as described in the previous step) was dissolved in MeOH (9 mL) and 1 M LiOH (4.73 mL, 4.73 mmol) was added. The resulting mixture was stirred at room temperature for 3 h and the solvent was removed under reduced pressure. The resulting residue was dissolved in H2O (10 mL) and extracted with DCM (3×10 mL). The aqueous layer was acidified to pH ˜2 using 3 M HCl and extracted with EtOAc (3×20 mL). The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 9.90 (br. s., 1H), 1.50 (s, 9H).