Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:34]1C[CH2:37][CH2:36][C@H:35]1C(NN)=O>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([C@@H:32]4[CH2:37][CH2:36][CH2:35][O:34]4)=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: NNC(=O)[C@@H]1CCCO1
Product: Cc1cc(C2CCC2)c(-c2nnc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using (S)-tetrahydrofuran-2-carbohydrazide (compound 172.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)+.
Reaction SMILES: [P:1]([O-:35])([O:31][CH2:32][CH2:33]Br)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[S:36]1[CH:40]=[CH:39][N:38]=[CH:37]1>>[P:1]([O-:35])([O:31][CH2:32][CH2:33][C:37]1[S:36][CH:40]=[CH:39][NH+:38]=1)([O:3][CH2:4][CH:5]([O:29][CH3:30])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCc1[nH+]ccs1)OC
Temperature: 60 °C

Procedure:
A mixture of 2.0 g of the phosphate ester obtained in Example 10 and 4.5 g of thiazole is stirred and warmed at 60° C. for 5 days. The thiazole is distilled off under reduced pressure, and 50 ml of methanol and 2 g of silver carbonate are added to the residue. The mixture is heated under reflux for 2 hours. After filtration, the filtrate is evaporated to dryness, and the residue is separated and purified by silica gel chromatography [eluent: chloroform-methanol-water (65:25:4)] and crystallized from chloroform-acetone to obtain the contemplated product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:23][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:9][C:5]=2[CH:4]=1.[C:34](=O)(O)[O-].[K+]>CO.S(=O)(=O)(O)O.O>[CH3:34][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:9][CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: COc1cc2nc(-c3ccccc3)n(-c3ccc(C)cc3)c2cc1OCCCCCC(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCOc1cc2c(cc1OC)NC(c1ccccc1)N2c1ccc(C)cc1
Reaction time: 2 h

Procedure:
40 mg of 6-[[5-methoxy-1-(4-methylphenyl)-2-phenyl-1H-benzimidazol-6-yl]oxy]hexanoic acid was dissolved in 2 ml of methanol, mixed with 1 drop of concentrated sulfuric acid, and the mixture was stirred for 2 hours. It was mixed with saturated potassium bicarbonate solution, diluted with water, extracted with ethyl acetate, the extracts were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([CH2:1][CH3:2])[C:4](=[O:12])[CH2:5]3)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCN1C(=O)Cc2ccccc21
Product: CCN1C(=O)Cc2cc(C(=O)C3CCCC3)ccc21

Procedure:
Prepared from readily available starting materials (N-ethyloxindole and cyclopentanecarbonyl chloride) in a manner analogous to that set forth in Preparation 18.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:11]([OH:15])[C:12](=[NH:14])[OH:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.[O:17]1CCC[CH2:18]1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:11]2[O:15][C:18](=[O:17])[NH:14][C:12]2=[O:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Cl)c(C)c1C(O)C(=N)O
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(C)c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 27, 1-(3-chloro-6-methoxy-2-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride (1.0 g., 3.4 mmoles) in 50 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-chloro-6-methoxy-2-methylphenyl)oxazolidine-2,4-dione (470 mg. 54%; m.p. 193°-195° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown oil (340 mg, 61%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[N:25]=1)[CH2:9][C:10]1[N:14]([CH:15]2[CH2:17][CH2:16]2)[C:13]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:12][N:11]=1)(C)(C)C>C(O)=O>[Cl:35][C:31]1[CH:30]=[C:29]([C:26]2[N:25]=[C:24]([C@@H:8]([NH2:7])[CH2:9][C:10]3[N:14]([CH:15]4[CH2:17][CH2:16]4)[C:13]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)=[N:12][N:11]=3)[O:28][N:27]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Solvent: O=CO
Product: N[C@@H](Cc1nnc(-c2ccncc2)n1C1CC1)c1nc(-c2cccc(Cl)c2)no1
Temperature: 50 °C
Yield: 97.8 %

Procedure:
(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (135 mg) was mixed with 96% formic acid (1.3 mL) and heated at 50° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. Purification was performed by flash column silica gel chromatography with 2-3% (2 M ammonia methanol) in dichloromethane to give 106 mg of the title compound as an off-white solid. 1H NMR (CDCl3):d ppm 8.73 (d, 2H), 8.03 (s, 1H), 7.93 (d, 1H), 7.69 (d, 2H), 7.46 (d, 1H), 7.42 (t, 1H), 5.02 (dd, 1H), 3.61 (dd, 1H), 3.49 (dd, 1H), 3.35 (m, 1H), 2.47 (br s, 2H), 1.20 (m, 2H), 0.75 (m, 2H), 0.75 (m, 2H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14](/[C:17](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:18](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:19][CH3:20])=[CH:13][CH:12]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:11]2[N:16]=[CH:15][C:14](/[C:17](/[C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)=[C:18](\[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)/[CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCOCC2)nc1)c1ccccc1
Yield: 85.8 %

Procedure:
Following the same procedure as described in example 3, 2-morpholinoethanol (391 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (110 mg, 86% yield). 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.01-7.18 (m, 8H), 6.79 (d, J=8.8 Hz, 2H), 6.27 (d, J=8.4 Hz, 1H), 4.29 (t, J=5.6 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 2.46-2.52 (m, 6H), 1.29-1.40 (m, 4H), 0.92 (t, J=7.6 Hz, 3H); m/z=431[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:34](=[O:35])[O:36][CH3:37])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C)c1ccc(-c2cnc(Oc3ccc(OC)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added methyl chloroformate (67 μL, 0.76 mmol, 2.3 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with an ethyl acetate/hexane gradient (0-30%) to give the title compound (112 mg, 86%). 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.45 (m, 3 H), 7.27-7.33 (m, 2 H), 7.21-7.26 (m, 2 H), 6.91-7.01 (m, 2 H), 4.73-498 (m, 1 H), 3.83 (s, 3 H), 3.66 (s, 3 H); 1.47 (d, J=6.62 Hz, 3 H) MS (DCI): m/e 385 (M+H).
Reaction SMILES: N(N=C([C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[N:16](N=O)[C:15]=2[CH:14]=[CH:13][C:12]=1CC1C=CC=CC=1)C1C=CC=CC=1)=O.Cl.[NH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.C(O)C>[Zn].C(O)(=O)C>[CH2:25]1[C:17]2[N:16]3[C:39]4[CH:40]=[CH:41][N:36]=[CH:37][C:38]=4[C:14]4[CH2:13][CH2:12][CH:11]=[C:21]([C:15]=43)[CH:20]=[CH:19][C:18]=2[CH2:22][CH2:23][CH2:24]1
Reactant: O=C1CCNCC1
Reactant: O=NN=C(c1ccccc1)c1c(Cc2ccccc2)ccc2c1CCc1ccccc1N2N=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Reaction time: 4 h

Procedure:
To a mixture of 4.5 g of N-nitrosoiminodibenzyl (5-nitroso-10,11-dihydro-5H-dibenz[b,f]azepine), 6.0 g. of 4-piperidone hydrochloride and 6.5 g. of zinc dust in 30 ml. of absolute ethanol 12 ml. of glacial acetic acid are added dropwise, with constant stirring. Occasional cooling in an icebath is required to maintain the temperature at 20°-25° during the course of the reaction. After a little over 4 hours, the unchanged zinc is filtered off, washed with a minimum of absolute ethanol, and to the combined filtrate and wash there is added with stirring 8 ml. of concentrated sulfuric acid in 50 ml. of absolute ethanol. Stirring is continued while the mixture is warmed for about ten minutes, until the alcohol begins to reflux. It is then cooled down again; the inorganic insolubles are filtered off, and approximately 500 ml. of water is added to the filtrate, resulting in a voluminous white precipitate. The whole mixture is extracted with ether, and the residual aqueous phase is warmed up to transform the precipitate into granular solids, which are then filtered off and redissolved in approximately 600 ml. aqueous acetic acid. Some warming is required to completely dissolve all material. On treating this solution with 3N aqueous ammonia, the title compound is obtained as a tan-white granular solid, m.p. 134°-137°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([O:11]CC)=[O:10])[CH:7]=1.[OH-].[Na+]>CO.Cl>[Cl:1][C:2]1[C:3]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])=[CH:4][C:5]([F:14])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2n[nH]c3ccccc23)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cc(Cl)c(NC(=O)c2n[nH]c3ccccc23)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
Ethyl (5-chloro-2-fluoro-4-(3-indazolylcarbonylamino)phenyl)acetate (531 mg, 1.41 mmol) was dissolved in methanol (50 ml). To the resulting solution was added 0.25N NaOH (12 ml, 3 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was poured in 1N HCl (100 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure for 15 hours to give (5-chloro-2-fluoro-4-(3-indazolylcarbonylamino)phenyl)acetic acid (480 mg, 98%) as a colorless crystalline powder.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])C1C=CC=CC=1>O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13]
Reactant: CON(C)C(=O)c1cccc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(O)c1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 100 g (0.37 mol) B4 in 750 ml tetrahydrofurane 10 g Pd/C (10%) were added and the mixture was hydrogenated at atmospheric pressure for 2 hours. The catalyst war filtered off and the filtrate was evaporated to yield 66.0 g B5 (98%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]3=[O:25])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:40][S:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:37]=[N:38][CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[O:25]=[C:13]1[N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:34]4[CH:39]=[N:38][CH:37]=[C:36]([NH:40][S:41]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)(=[O:43])=[O:42])[CH:35]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(Br)cc3n2)C(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)C(=O)C1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
A slurry of 1,1-dimethylethyl 4-(7-bromo-2-quinoxalinyl)-3-oxo-1-piperazinecarboxylate (1.30 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (1.35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.10 mmol), in 1,4-dioxane (6 ml) and saturated sodium bicarbonate solution (2 ml) was stirred at 100° C. for 1 hour. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (150 mg, 22%) as a tan solid. MS(ES)+ m/e 561.1 [M+H]+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][C:29]2=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>C1COCC1>[CH:21]1([CH2:27][C:28]2([CH2:37][O:36][CH2:34][CH3:35])[CH2:33][CH2:32][O:31][C:29]2=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C1OCCC1CC1CCCCC1
Reactant: CCOCCl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOCC1(CC2CCCCC2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of lithium diisopropylamide prepared from diisopropylamine (6.50 mL) and butyllithium (29.0 mL of 1.6M solution in hexanes) in THF (105 mL) was treated dropwise with 2-(cyclohexyl-methyl)-γ-butyrolactone (6.96 g) at −78° C. The reaction mixture was stirred at the same temperature for additional 30 min and then treated dropwise with chloromethyl ethyl ether (5.05 g). Upon completion of the addition, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature overnight. After that, the mixture was quenched by pouring onto a mixture of ice and 10% aqueous phosphoric acid. The formed organic phase was separated and the aqueous phase was extracted with toluene. The combined organic phases were washed with water, dried over potassium sulfate, filtered, concentrated on a rotary evaporator and purified by column chromatography (silica gel, eluent-hexane) to give 5.90 g (64%) of the title compound.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:23])([CH2:17][CH2:18]1)[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C(=O)(O)[O-].[Na+].[CH2:29]([OH:32])[CH2:30][CH3:31]>S(=O)(=O)(O)O>[CH2:29]([O:32][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH2:30][CH3:31]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
2α,3α-Epoxy-5α-pregnan-20-one (360 mg) was dissolved in 80 mL of propanol and cooled to °C. and added to a cold 1.0 mL propanol solution containing 5-drops of concentrated sulfuric acid. This reaction mixture was stirred for 30 minutes at this temperature and an additional 30 minutes at room temperature, poured into a 20% sodium bicarbonate solution and washed several times with chloroform. The combined organic phase was dried over potassium carbonate and concentrated. Purification of the crude product on a silica gel column eluting with hexane/ethyl acetate (70:30) gave the titled compound (206 mg, 50% yield) as white crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:29][CH:30]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(trifluoromethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(trifluoromethoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].B([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1)(O)O>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)=[CH:13][C:3]=1[C:4](=[O:5])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CCC(=O)O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-(4-boronophenyl)-propanoic acid gives the compound “A32”; HPLC/MS: 1.28 min, [M+H]=363;
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([S:42]([F:47])([F:46])([F:45])([F:44])[F:43])[CH:41]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:25]=[N:26][N:27](CC5C=CC(OC)=CC=5)[CH:28]=4)[CH:22]=3)[C:18]([CH3:38])=[CH:17]2)[CH:10]=1)=[O:7])#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([S:42]([F:46])([F:44])([F:47])([F:43])[F:45])[CH:41]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:28]=[N:27][NH:26][CH:25]=4)[CH:22]=3)[C:18]([CH3:38])=[CH:17]2)[CH:10]=1)=[O:7])#[N:2]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(C#N)cc(S(F)(F)(F)(F)F)c6)ccc5C)cc(C)n4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1cc(C)n2nc(-c3cn[nH]c3)cc12

Procedure:
At 90° C., 115 mg (0.23 mmol) of the compound of Example 56A were stirred in 1.5 ml of trifluoroacetic acid for 60 min. The reaction was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 21). The product fractions were combined, concentrated almost completely under reduced pressure and made alkaline with a little saturated aqueous sodium bicarbonate solution. The resulting precipitate was filtered off, washed with water and dried under high vacuum. This gave 60 mg (46% of theory) of the title compound.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH2:15]Cl)[CH:14]=1.O>CN(C=O)C>[Br:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH:12]=[N:11][CH:10]=1
Reactant: CCC(N)=O
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)NCc1cncc(Br)c1
Yield: 82 %

Procedure:
To a solution of propionamide (146 mg, 2.0 mmol) in DMF (10 mL) was added NaH (61 mg, 2.4 mmol) at 0° C. and reaction mixture was stirred for 10 min before the addition of 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A], 412 mg, 2.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour before water was added. Then, the reaction mixture was extracted with EtOAc and combined organic layers were dried by anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give title compound (400 mg, 82%) as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:12].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18].[BH4-].[Na+].Cl>CO.C(N(CC)CC)C>[ClH:12].[CH3:13][O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)CCN
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCNCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71 %

Procedure:
A mixture of p-nitrobenzaldehyde (1.51 g), β-alanine methyl ester hydrochloride (1.40 g), triethylamine (1.6 ml) and methanol (20 ml) is stirred at room temperature for 25 minutes. The mixture is ice-cooled, and sodium borohydride (807 mg) is added thereto. The mixture is stirred at the same temperature for 10 minutes. The mixture is acidified with 10% HCl, and extracted with ethyl acetate. The aqueous layer is neutralized with 10% NaOH, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is dissolved in ether, and a HCl-ether solution is added thereto. The precipitates are collected and recrystallized from methanol to give N-(p-nitrobenzyl)-β-alanine methyl ester hydrochloride (1.95 g, 71.1%) as pale yellow plates, m.p. 219.5°-220° C. (decomp.).