Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([O:28]C)=O)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][CH:19]=3)[C:11](=[O:24])[N:10]([CH2:25][C:26]([NH:31][NH2:32])=[O:28])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2cccc(C(=O)OC)c2)c1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NN)c2=O)c1
Reaction time: 18 h

Procedure:
172 mg (0.41 mmol) of the compound from Example 15A were suspended in 1 ml of ethanol, and 40 μl (0.83 mmol) of hydrazine hydrate were added. The mixture was heated under reflux for 4 h and then allowed to stand at room temperature for 18 h. The reaction was concentrated under reduced pressure on a rotary evaporator and the residue was dried under high vacuum. This gave 161 mg (94% of theory) of the target compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=3)=[CH:18][CH:19]=2)=[C:10]([CH3:37])[CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:38])([CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[NH:24][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:22][N:21]=3)=[CH:18][CH:19]=2)=[C:10]([CH3:37])[CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.1 %

Procedure:
In trifluoroacetic acid (2.0 mL) and water (0.1 mL) was dissolved 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoic acid (80 mg), and the solution was stirred at room temperature for 7 hours. To the solution was added 2N aqueous sodium hydroxide solution to make a pH of the same 2 to 3, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated brine, the organic layer was separated and concentrated under reduced pressure. Isopropyl ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 2,2-dimethyl-3-({4-methyl-6′-[5-(trifluoromethyl)-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoic acid (30 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([CH2:14][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCC2CC2)c(O)c1
Yield: 7.3 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (4.14 g, 30 mmol), cyclopropylmethyl bromide (3.06 mL, 31.5 mmol), potassium carbonate (8.29 g, 60 mmol) in acetone (90 mL) is heated at 50 C overnight. After filtration, the solution is dried to a gum, which is dissolved in ethyl acetate, and washed with water. It is dried to an oil and then chromatographed to yield 0.42 g (7%) of the title compound as a white powder. MS (ESI) m/z 191.2 (M−H)−1.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19]2)=[CH:14][CH:13]=1.[NH2:26][CH2:27][CH2:28][OH:29].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:29][CH2:28][CH2:27][NH:26][C:23]([C:21]1[CH:20]=[N:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[CH3:2])=[CH:17][CH:16]=2)[CH:22]=1)=[O:24]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)O)cn2)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid hydrochloride prepared in Example 2-(1) (1.00 g), 2-aminoethanol (0.400 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.580 g), 1-hydroxybenzotriazole monohydrate (0.460 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=18:1) to give the titled compound (0.920 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[B-](F)(F)(F)F.CN(C(O[N:28]1[C:33](=O)[CH:32]=[CH:31][CH:30]=[CH:29]1)=[N+](C)C)C.CCN(CC)CC.N1CCCCC1.C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)Cl.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:7]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled suspension of 2-methoxy-4-nitro-benzoic acid (5.915 g, 30 mmol) in acetonitrile (50 ml) and CH2Cl2 (40 ml) under N2-atmosphere, TPTU (8.912 g, 30 mmol) and NEt3 (8.36 ml, 60 mmol) is added. After stirring for 40 min, piperidine (3.26 ml, 33 mmol) is added and the reaction mixture is slowly warmed up to rt. After 16 h, AcOEt (0.5 L), water (0.4 L) and saturated NaHCO3 solution (0.2 L) is added, the aqueous phase separated off and extracted 3× with AcOEt. The organic layers are washed with 10% citric acid solution, water and brine, dried (Na2SO4) and concentrated. Crystallization from AcOEt/hexane yields the title compound: m.p.: 104° C.; 1H-NMR (DMSO-d6): 7.88 (dd, 1H), 7.84 (d, 1H), 7.47 (d, 1H), 3.93 (s, H3C), 3.7-3.5 (m, 2H), 3.07 (m, 2H), 1.64-1.5 (m, 4H), 1.42 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:38])[O:10][C@@H:11]2[CH2:27][C@@H:26]3[C@@:14]([CH3:37])([C@@H:15]4[C@@H:23]([CH2:24][CH2:25]3)[C@:22]3(O)[C@@:18]([CH3:36])([C@@H:19]([C:29]5[CH:30]=[CH:31][C:32](=[O:35])[O:33][CH:34]=5)[CH2:20][CH2:21]3)[CH2:17][CH2:16]4)[CH2:13][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)Cl>N1C=CC=CC=1>[N:1]1([CH2:6][CH2:7][NH:8][C:9](=[O:38])[O:10][C@@H:11]2[CH2:27][C@@H:26]3[C@@:14]([CH3:37])([C@@H:15]4[C@@H:23]([CH2:24][CH2:25]3)[C:22]3[C@@:18]([CH3:36])([C@@H:19]([C:29]5[CH:30]=[CH:31][C:32](=[O:35])[O:33][CH:34]=5)[CH2:20][CH:21]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H](OC(=O)NCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccc(=O)oc3)CC[C@]12O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@H](OC(=O)NCCN3CCCC3)C[C@H]1CC[C@H]1C3=CC[C@H](c4ccc(=O)oc4)[C@@]3(C)CC[C@@H]12
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethylcarbamate (54 mg, 0.1 mmol, 1 eq) in pyridine (3 mL) was added SOCl2(71.4 mg, 0.6 mmol) at 0° C. The mixture was stirred at this temperature for about 2 h, quenched with saturated NaHCO3, and extracted with EtOAc. The organic layers were combined, dried with Na2SO4, concentrated and purified via Preparative TLC to afford (3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl 2-(pyrrolidin-1-yl)ethylcarbamate (40 mg, 78.7%). LCMS (M+H+) m/z calculated 508.33. found 509.4. 1H NMR (CD3OD, 400 MHz) δ 7.63 (m, 2 H), 6.38 (m, 1 H), 5.36 (m, 1 H), 5.00 (m, 1 H), 3.38 (m, 2 H), 3.10 (m, 6 H), 2.90 (m, 1H), 2.60 (m, 1 H), 2.50 (m, 1 H), 2.30-1.30 (m, 21 H), 1.10(s, 3 H), 0.86 (s, 3 H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH:28]=[O:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH2:28][OH:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncc(-c2cn(C3CCNCC3)nc2CO)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Sodium tetrahydroborate (42.6 mg) and tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (550 mg) in methanol (10 ml) were stirred at room temperature for 1 hour. The reaction was incomplete and further sodium tetrahydroborate (42.6 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (2×20 ml), dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in dichloromethane (2 ml) and the solution was cooled to 0° C. and treated with trifluoroacetic acid (3 ml). The resulting solution was allowed to stir at room temperature for 1 hour and then concentrated to dryness. The residue was re-dissolved in methanolic ammonia (7N, 5 ml) and absorbed onto silica and purified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (440 mg) as a solid. The tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 4-bromo-2H-pyrazole-3-carbaldehyde (3 g), potassium carbonate (3.32 g) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.23 g) in acetonitrile (150 ml) were stirred at reflux overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to yield tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (4.10 g) as a clear colourless oil which crystallised on standing. NMR Spectrum: (CDCl3) 1.48 (s, 9H), 1.92 (dd, 1H), 1.96 (dd, 1H), 2.10-2.18 (m, 2H), 2.81-2.97 (m, 2H), 4.27 (bs, 2H), 4.28-4.38 (m, 1H), 7.543 (s, 1H), 9.96 (s, 1H); Mass spectrum: M+H+ 360.
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[NH+]1C=CC=CC=1.CN(C=[O:21])C>>[C@@H:4]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][C@H:3]1[C:1]([OH:21])=[O:2]
Reactant: CCOC(=O)C1CC1C=O
Reactant: CN(C)C=O
Agent: c1cc[nH+]cc1
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of ethyl 2-formyl-1-cyclopropanecarboxylate (6.465 g, 45.5 mmol) in dry DMF (25 ml) was treated with solid pyridinium dichromate1 (34.23 g, 90.92 mmol, added in ~5 g portions, addition time of 15 min). The resulting mixture was stirred at room temperature for 15 h. After dilution with water (200 ml), the mixture was extracted with ether (5×20 ml) and the combined organic extracts were washed with 1N HCl and brine. The organic phase was then extracted with saturated NaHCO3 (4×20 ml). The basic extracts were acidified with 1-% HCl and extracted with ether (5×20 ml). The combined ether extracts were dried on anhydrous sodium sulfate and evaporated under vacuum to give a clear oil which crystallized on standing: 4.849 g (67%); mp 50-55 (Lit.2 mp 55°-58° C.); ir νmax (CH2Cl2): 3000 (broad OH of acid), 1725 (C=O of ester) and 1700 cm-1 (C=O of acid); 1Hmr (CDCl3) δ: 11.36 (1H, s, COOH), 4.15 (2H, q, J=7, CH2 --CH3), 2.3-1.9 (2H, m, cyclopropyl), 1.5 (2H, d, J=7, cyclopropyl) and 1.27 ppm (3H, t, J=7, CH2 --CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3)c2c(N)c1OC
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=O)N3c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-chloro-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (80 mg, 0.24 mmol) (from Example 11, Step B, supra) in 1,2-dichloroethane (30 mL) was added 1,1′-carbonyldiimidazole (0.2 g, 1.21 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 3-(3-chloro-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalen-2-one as a brown solid. (Yield 50 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][N:16](CC4C=CC=CC=4)[CH2:15]3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1.[ClH:27]>[Pd].CO>[ClH:27].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 111.4 %

Procedure:
Palladium on carbon (10 wt %, 0.700 g, 0.658 mmol) was added to a solution of 2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-(phenylmethyl)morpholine (2.3 g, 6.58 mmol) and hydrochloric acid (2.78 mL, 32.9 mmol) in CH3OH (80 mL) under nitrogen, and the reaction mixture was stirred under hydrogen at 25° C. for 1.5 hours. The reaction mixture was filtered, washed by CH3OH (150 mL) and concentrated to afford an HCl salt of the title compound (1.9 g) as a brown solid. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: [CH2:1]1[O:27][C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@H:12]([OH:26])[C@H:13]3[NH:23][CH:24]=O)[CH2:5]2)[O:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:2]1[O:3][C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][C@H:12]([OH:26])[C@H:13]3[NH:23][CH3:24])[CH2:5]2)[O:27][CH2:1]1
Reactant: C[C@]12CCC3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](NC=O)[C@@H](O)C[C@@H]12)OCCO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@@H]1[C@@H](O)C[C@H]2[C@@H]3CC[C@H]4CC5(CC[C@]4(C)[C@H]3CC[C@]12C)OCCO5
Reaction time: 5 h

Procedure:
A solution of 17α-formamido-16β-hydroxy-5α-androstan-3-one ethylene acetal (5.2 g) in dry tetrahydrofuran (182 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (2.6 g) in tetrahydrofuran (78 ml) at 0° C. The cooling bath was removed and the stirred suspension was heated under reflux, and under a nitrogen atmosphere for 5 h. The mixture was cooled, water was added dropwise, and the solids were removed by filtration through dicalite. The filter was washed with hot tetrahydrofuran and the combined filtrate and washings were evaporated to give 16β-hydroxy-17α-methylamino-5α-androstan-3-one ethylene acetal as a colourless residue (5.0 g.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2/[CH:23]=[N:24]/O)=[C:5]([CH3:26])[O:4][N:3]=1>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[N:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:10]=[C:9]([CH2:20][CH2:21][CH3:22])[C:8]=2[C:23]#[N:24])=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1/C=N/O
Solvent: CC(=O)OC(C)=O
Product: CCCc1nn(-c2ccc(OC)cc2)c(-c2c(C)noc2C)c1C#N
Temperature: 140 °C
Yield: 104.9 %

Procedure:
90% of the crude (E)-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbaldehyde oxime (12 mg, 0.034 mmol) from step (e) was dissolved in acetic anhydride and heated at 140° C. for 40 minutes in the microwave. The reaction mixture was concentrated onto silica and filtered through a silica plug to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole-4-carbonitrile (12 mg, 100%).
Reaction SMILES: O[C@@H]1CN([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H](C(OC)=O)C1.CC1SC(N)=NC=1.[F:25][C@H:26]1[CH2:30][NH:29][C@H:28]([C:31]([NH:33][C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)=[O:32])[CH2:27]1>>[F:25][C@H:26]1[CH2:30][N:29]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:28]([C:31](=[O:32])[NH:33][C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH2:27]1
Reactant: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: Cc1cnc(N)s1
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1

Procedure:
(2S,4S)-4-Hydroxy-N-(5-methylthiazol-2-yl)pyrrolidine-2-carboxamide 65A was prepared from (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate and 5-methylthiazol-2-amine as described for 65B. LC/MS [M+H]+: 228; Ret time (Method F): 0.55 min.
Reaction SMILES: [O:1]=[C:2]([C:6]([CH2:25][O:26][Si](CC)(CC)CC)([CH2:16][O:17][Si](CC)(CC)CC)[CH2:7][O:8][Si](CC)(CC)CC)[CH2:3][C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:26][CH2:25][C:6]([CH2:7][OH:8])([CH2:16][OH:17])[C:2](=[O:1])[CH2:3][C:4]#[N:5]
Reactant: CC[Si](CC)(CC)OCC(CO[Si](CC)(CC)CC)(CO[Si](CC)(CC)CC)C(=O)CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)C(CO)(CO)CO

Procedure:
To a stirred solution of 3-oxo-5-(triethylsilyloxy)-4,4-bis((triethylsilyloxy)methyl)pentanenitrile (1 equivalent) in anhydrous THF at 0° C. is added tetrabutylammonium fluoride (1-5 equivalents) then stirring is continued at rt until the reaction is substantially complete as monitored by LCMS or TLC. Water is added followed by extraction with EtOAc. The combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 5-hydroxy-4,4-bis(hydroxymethyl)-3-oxopentanenitrile.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:22][CH:21]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (45.0 mg, 0.200 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a slightly brown solid (34.8 mg, 45%) having the following characteristics.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([NH:24]C(=O)C(F)(F)F)[CH:3]=1.O1CCOCC1.[Cl-].[Na+]>N1CCCCC1>[NH2:24][C:4]1[CH:3]=[C:2]([CH3:1])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(NC(=O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
1.22 g (0.0029 mol) of 1-benzyl-piperidin-4-yl 4-methyl-2-trifluoroacetamido-benzoate were suspended in 60 ml of 1N aqueous piperidine in an ultrasound bath for 1/2 hr., treated with 10 ml of dioxan and subsequently stirred at room temperature for 20 hrs. Subsequently, the mixture was heated to 50° for 5 hrs. The suspension was treated with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2). 0.82 g (87%) of 1-benzyl-piperidin-4-yl 2-amino-4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:16]=[C:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:10](=[O:17])[CH:9]=1)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:6][CH2:7][C:8]1[CH:16]=[C:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:10](=[O:17])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc2n(c(=O)c1)CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1cc(CO)cc2n1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A solution of 7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2,3-dihydro-5(1H)-indolizinone (3.93 g, 14.09 mmol) in tetrahydrofuran (100 ml) was treated with acetic acid (1.61 ml, 28.17 mmol) and tetrabutylammonium fluoride (1M in THF, 21 ml, 21.13 mmol) and stirred at room temperature for 1 h before being evaporated. The residue was chromatographed on silica eluting with 0-20% methanol in dichloromethane to give the desired product (1.87 g, 80%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cncnc1
Product: O=C(c1ccc(-c2cncnc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 5-Pyrimidine boronic acid. MS (M+H) 355.2
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[N:17]=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH2:17][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[NH2:2]
Reactant: CC(C)c1ccc(-n2ncc(N=O)c2N)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(-n2ncc(N)c2N)cc1

Procedure:
6.0 g (22.5 mmol) of 5-amino-1-(4-isopropylphenyl)-4-nitroso-1H-pyrazole hydrochloride from Step 2.2 in 150 mL of ethanol was hydrogenated for 6 hours on 0.6 g of Pd/C (10%) at 8 bar of hydrogen pressure. The catalyst was filtered off, and the filtrate was concentrated to a total volume of about 20 mL. After the addition of 40 mL of a 3-molar ethanolic hydrochloric acid solution and agitation in an ice bath, the product crystallized out. Suction filtration and washing with 50 mL of ethyl acetate gave 5 g (17.2 mmol, 77% of the theoretical) of 4,5-diamino-1-(4-isopropylphenyl)-1H-pyrazole dihydrochloride as a colorless product.