Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][N:12]=[N+]=[N-])=[CH:9][CH:10]=1)=[NH:4].C1COCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4]
Reactant: [N-]=[N+]=NCc1ccc(C(=N)NO)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N=C(NO)c1ccc(CN)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the azide (11-4) of Example 52 in THF/water (80 ml/5 ml) (7.8 g, 40.6 mmol) was added triphenylphosphine (12.8 g, 48.72 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed to dryness and the remaining residue was diluted with 100 ml 1N HCl and 100 ml water. The aqueous layer was extracted several times with dichloromethane. The aqueous layer was made basic (pH˜9) with an alkaline resin (Bio Rad AG 1-X8). The resin was filtered and washed thoroughly with water. The combined washings were dried under reduced pressure to give a white solid (6.60 g).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:14]1.Br>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:14]1
Reactant: Oc1ccccc1C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: Br
Solvent: CC#N
Product: Oc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24 mmol), 2-(piperidin-3-yl)phenol.HBr (61 mg, 0.24 mmol) and KHCO3 (84 mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 5.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of DCM and MeOH (1% triethylamine) as eluent to give 11 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2>C(O)C.O1CCCC1.[Pt](=O)=O>[F:1][C:2]1[CH:17]=[C:16]([CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)[NH2:18]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Reaction time: 2 h

Procedure:
Under argon, 60 mg (0.22 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1H-indazole (from example XXV) are initially charged in 5 ml of ethanol/tetrahydrofuran (1:1), 9.97 mg (0.04 mmol) of platinum(IV) oxide are added and the mixture is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtered off through CELITE (diatomaceous earth), the filtercake is washed with ethanol and the filtrate is concentrated under reduced pressure.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([NH:16][CH:13]2[CH2:12][CH2:11][N:10]([C:4]3[N:3]=[CH:2][NH:1][C:6]4=[N:7][CH:8]=[CH:9][C:5]=34)[CH2:15][CH2:14]2)=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(c3nc[nH]c4nccc3-4)CC2)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 2-(methyloxy)-4-pyridinecarboxylic acid (45.9 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E15 (40 mg); 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.50 (1H, d), 8.30 (1H, d), 8.17 (1H, s), 7.35 (1H, d), 7.20 (2H, d), 6.60 (1H, d), 4.67 (2H, dt), 4.15 (1H, m), 3.88 (3H, s), 3.20 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 353 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=[C:6]([CH3:14])[CH:5]=1)[CH3:2].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23](OC(=O)C)(=O)C>>[CH:14]([C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH2:2][CH3:23])[C:9]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1cnc(C)cc1OCC
Reactant: O=Cc1ccccc1
Product: CCCCc1cnc(C=Cc2ccccc2)cc1OCCC

Procedure:
55 g of 4-ethoxy-5-n-butyl-2-picoline and 165 ml of benzaldehyde in 181 ml of acetic anhydride are heated for 16 hours under reflux. After cooling, the mixture is evaporated, and the residue is treated with 2 N sodium hydroxide solution and extracted with ether. Distillation of the ether residue in a bulb tube at a temperature of 160°-180° in a high vacuum yields 2-styryl-4-n-propoxy-5-n-butyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:19]([O-:21])=[O:20])=[CH:4][C:3]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:19]([OH:21])=[O:20])=[CH:4][C:3]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1
Reactant: O=C([O-])C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.1 %

Procedure:
2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (80 mg) was dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave compound 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.71 (d, 2H), 7.54 (d, 2H), 6.95 (d, 1H), 6.87 (s, 1H), 3.97 (d, 2H), 3.64 (t, 1H), 2.55 (m, 2H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:23])([C:14]([N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:23])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24])[C:14]([N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(CCO)CCO)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N(CCO)CCO)=C(C)C1=O
Yield: 25.6 %

Procedure:
Oxidation as described in protocol B, using 68.4 mg (0.203 mmol) of precursor 6-hydroxy-N,N-bis(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 244 mg CAN (0.446 mmol) yielding 18.4 mg of 2-hydroxy-N,N-bis(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil (25.7%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH2:33]([N:32]([CH2:31][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([OH:30])[C:10]([F:9])([F:36])[F:37])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:34][CH3:35]
Reactant: O=C(O)c1ccsc1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1/[CH:9]=[CH:15]/[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: O=Cc1ccccc1OCCCCCl
Reactant: Cc1nc2ccccc2s1
Product: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 62.5 %

Procedure:
The procedure of Example 18 was followed starting with 4-chlorobutoxybenzaldehyde (10 g, 47 mmol) and using 2-methylbenzothiazole (6.0 ml, 47 mmol) in place of 2-methylbenzoxazole to give 10.1 g (63% yield) of (E)-2-[2-(4-chlorobutoxyphenyl)ethenyl]benzothiazole (H) as a solid, mp 98°-100° C. 1H NMR (CDCl3): δ 8.01-6.89 (m, 10H), 4.01 (t, J=5.2 Hz, 2H), 3.61 (t, J=5.2 Hz, 2H), 1.94 (m, 4H).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:32][CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: NC1CCCC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (50 mg, 127.4 μmol) and cyclopentylamine (51 μl, 0.51 mmol) in 0.5 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 38 mg of 4-cyclopentylamino-benzenesulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (white solid).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl.C(=O)(O)[O-].[Na+].Cl[C:22]1[C:27]2=[N:28][O:29][N:30]=[C:26]2[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1>C(C(C)=O)C.O>[CH3:14][CH:3]([CH2:2][S:1][C:22]1[C:27]2[C:26](=[N:30][O:29][N:28]=2)[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.03 h

Procedure:
3 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline was placed in a vial and dilute hydrochloric acid (0.1 N, 2 ml) added to dissolve same. 3 Ml of 0.1 M sodium bicarbonate solution was next added and the mixture was mixed in a vortex mixer. Thereafter, 3 ml of 1% (w/v) 4-chloro-7-nitrobenzofurazan in methyl ethyl ketone was added to the mixture, the vial was then closed and mixing was continued. The vial was held under running hot tap water, while shaking the vial, for about 2 minutes. The vial was then allowed to stand for 3 minutes, the organic (upper) layer was removed and was found to contain the title compound. The title compound was found to be fluorescent.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[C:22]1([SH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29]=O.[OH-].[Na+]>CCOCC.C(O)C.C(N(CC)CC)C>[C:22]1([S:28][CH2:29][C:11]2[C:12](=[O:20])[CH2:13][CH2:14][C@@:15]3([CH3:16])[C:10]=2[CH2:9][CH2:8][C@@H:7]2[C@@H:17]3[CH2:18][CH2:19][C@@:2]3([CH3:1])[C@H:6]2[CH2:5][CH2:4][C:3]3=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=O
Reactant: Sc1ccccc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@]12CCC(=O)C(CSc3ccccc3)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Alternatively, a mixture of androst-4-ene-3,17-dione, thiophenol, 40% aqueous formaldehyde, triethylamine and ethanol was heated under reflux for a period of about 48 hours. The cooled solution was poured into an aqueous sodium hydroxide solution and the product isolated by ether extraction. The ether extracts were washed with water and dried over magnesium sulfate. The resulting residue was triturated with hexane to remove any condensation by-product derived from the thiophenol and formaldehyde. The 4-phenylthiomethylandrost-4-ene-3,17-dione so obtained was desulfurized by dissolving in acetone and adding to a suspension of Raney Nickel in refluxing acetone. The mixture was refluxed for about 5 hours under stirring. The hot solution was filtered and the catalyst washed with boiling ethanol and water. The combined filtrates were concentrated under vacuum whereupon the product separated as a solid mass. Recrystallization from acetone/hexane yielded 4-methylandrost-4-ene-3,17-dione. A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde diethyl acetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 4-methylandrost- 4-ene-3,17-dione (0.81 g, 2.7 mmol) was refluxed for about 7 hours, i.e. until the starting material has disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alcaline (~1 hour). The organic layer was separated, neutralized with water, and dried over sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:5][CH3:6].S(O[CH2:20][C:21]1[O:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH:22]=1)(C)(=O)=O.O>CN(C=O)C>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:20][C:21]2[O:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[O:23][CH:22]=2)=[CH:12][CH:13]=1)[CH2:5][CH3:6]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: CS(=O)(=O)OCC1=COc2ccccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Oc1ccc(OCC2=COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To sodium hydride (0.53 g, 50% in oil, 11.0 mmol) in 40 ml of DMF, under N2 at 5°, is added, dropwise and with vigorous stirring, a solution of 4-(1-methylpropoxy)phenol (1.66 g, 10.0 mmol) in 10 ml of DMF. After the mixture is stirred at RT for 1 hour, a solution of 2-mesyloxymethyl-1,4-benzodioxin (2.70 g, 11.0 mmol) in 10 ml of DMF is slowly added. The resulting reaction mixture is stirred at RT for 48 hours and is then mixed with water and extracted with ether. The combined organic extracts are washed with water and with brine, dried and solvent removed and the product is purified by column chromatography to give 2-[4-(1-methylpropoxy)phenoxymethyl]-1,4-benzodioxin, MS m/e 315 (M+).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[OH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21](O)=[O:22]>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:21](=[O:22])[CH:20]([OH:19])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.8, 13.9, 19.0, 26.3, 28.8, 35.3, 35.6, 52.7, 62.9, 79.8, 104.8, 132.7, 137.9, 169.2, 172.9; MS 367.1 m/z (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH:32]([C:34]1[CH:35]=[N:36][N:37](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:38]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:32][C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (3.71 g) and 4-formyl-1-(triphenylmethyl)pyrazole (3.66 g) in 1,2-dichloroethane (80 ml) was added sodium triacetoxyborohydride (2.86 g). After stirring at room temperature for 3 hours, aqueous sodium bicarbonate solution was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (40 ml) and added to a mixture of trifluoroacetic acid (30 ml) and anisole (15 ml). After stirring for 7.5 hours at room temperature, the mixture was quenched with 10% sodium hydroxide (150 ml) and aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with aqueous sodium bicarbonate solution and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (3:7) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (2.84 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:14]=O>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:14]=[C:6](/[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)\[C:7]#[N:8])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: N#CCc1cccs1
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(/C=C(\C#N)c2cccs2)cc1OC
Yield: 48.3 %

Procedure:
2-Thiopheneacetonitrile (246 mg) was condensed with 3,4-dimethoxybenzaldehyde (332 mg) through Method B (production step 2), to thereby yield the target product (yield: 262 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16].CC(O)=O>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=1)[CH3:12]
Reactant: CCC(=O)CC(=O)c1ccc(C)cc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Yield: 176.6 %

Procedure:
To a solution of 1-(4-methylphenyl)pentane-1,3-dione (370 mg, 1.9 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3, then extracted by EtOAc (10 mL×3). The combined organic layers were washed with 20 mL brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (560 mg, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.33 (3H, m), 2.38 (3H, s), 2.76 (2H, m), 6.33 (1H, s), 7.15 (4H, m), 7.31 (1H, m), 7.82 (1H, s), 8.42 (1H, m). [M+H] Calc'd for C18H16N4, 289; Found, 289.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30](Cl)[N:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[C:30]([NH:3][C@H:4]([C:6]2[N:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]3[C:14]([CH2:15][C:16]#[N:17])=[C:13]([F:18])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:29]=[CH:28][N:27]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CC#N)c2n1-c1ccccc1
Temperature: 90 °C
Yield: 106.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]acetonitrile dihydrochloride (100 mg, 0.27 mmol) in IPA (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (44 mg, 0.28 mmol) and DIPEA (139 μL, 0.82 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 345 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.73 (1H, dd, J=8.8, 4.8 Hz), 7.67 (1H, d, J=7.2 Hz), 7.63-7.58 (1H, m), 7.56-7.45 (4H, m), 7.18 (1H, dd, J=10.6, 8.8 Hz), 7.14 (2H, br s), 5.22 (1H, quin, J=5.2 Hz), 3.38-3.21 (2H, m), 1.47 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.56 min, [M+H]+=413
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)[CH2:6][CH2:5]CC[CH2:2]1.[N:25]1[CH:26]=CN2CC[NH:31][CH2:30][C:29]=12>>[N:31]1[CH:30]=[CH:29][N:25]2[CH2:26][CH2:2][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[CH:15]=[C:16]([CH2:20][S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)[CH2:6][C:5]=12
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCCC3)n2)c1
Reactant: c1cn2c(n1)CNCC2
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCn4ccnc4C3)n2)c1

Procedure:
B46 was prepared following the procedure reported for B1 using Al and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine. MS (ES) C16H18N8O2S requires: 386. found: 387 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([I:7])[CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[I:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1cc(I)cn1
Product: CN(C(=O)On1cc(I)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, oil).