Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[C:29]([CH3:31])=[CH2:30]>>[CH:29]([O:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Reactant: C=C(C)Br
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OC(C)C)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and 2-bromopropene following the procedure described for Example 264. 1H-NMR (CDCl3, 200.15 MHz): δ 7.14 (d, 2H, J=8.3), 6.86–6.82 (m, 6H), 4.40 (qn, 1H, J=5.9), 4.11 (q, 4H, J=5.9), 3.98 (dd, 1H, J=7.3, 4.6), 3.40 (s, 3H), 3.10 (dd, 1H, J=14.2, 4.3), 3.01–2.90 (dd, 1H, J=14.2, 7.2), 2.22 (qn, 2H, J=5.9), 1.30 (d, 6H, J=6.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([N:19]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27](=[O:29])[CH3:28])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(NCc3ccccc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1)c1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP (0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178° C.; Anal. Calc'd for C22H18FN5: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[NH2:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[NH4+].[OH-].CO>C(Cl)Cl>[NH2:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN)c3)nc12

Procedure:
1-[2-(3-Aminomethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and (3-aminomethylphenyl)boronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 75 mg (48%) of a pale brown solid. MP 176-178° C., M+H=309.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](O)=[O:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B#B.CO>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.4 %

Procedure:
To a cooled (0° C.) solution of Boc-2-carboxymorpholine (1.01 g, 4.3 mmol) in anhydrous THF under argon (25 mL) was added 10.8 mL of a 1M solution of diborane in THF. After stirring at room temperature overnight, methanol was added (10 mL) and the reaction was heated to reflux for 30 min. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with brine. The combined organic layers were dried (MgSO4) and the solvent was evaporated to yield a colorless liquid (1.2 g) that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18]Cl)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3].[CH2:21]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].CC(C)=O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CC(C)=O.CN(C)C=O.C(N(CC)CC)C>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH2:1]([N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][N:31]3[CH2:32][CH2:33][CH:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C=CCN1C(=O)CCc2c(OCC(O)CCl)cccc21
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C=CCN1C(=O)CCc2c(OCC(O)CN3CCC(Cc4ccccc4)CC3)cccc21
Reaction time: 5 h
Yield: 82 %

Procedure:
2.6 Grams of 1-allyl-5-(2-hydroxy-3-chloropropoxy)-3,4-dihydrocarbostyril, 1.5 g of triethylamine and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of dimethylformamide and the mixture was stirred at 80°-90° C. for 5 hours. The reaction mixture was poured into 80 ml of a 5%-sodium hydrogencarbonate aqueous solution and the organic layer was extracted with chloroform, and the chloroform layer was washed with water and dried. Then the chloroform was removed by distillation and the residue thus obtained was dissolved in 30 ml of acetone and further 5%-oxalic acid acetone solution was added to make the pH to 4.5 and the crystals formed were collected by filtration and washed with acetone. Recrystallization from ethanol to obtain 4.3 g (yield: 82%) of 1-allyl-5-[2-hydroxy-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless needle-like crystals. Melting point: 178°-180° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)[CH3:2].FC1C=C[C:23]([C:24]([OH:26])=[O:25])=CN=1.CCOCC>C1(C)C=CC=CC=1>[C:24]([O-:26])(=[O:25])[CH3:23].[CH3:12][CH2:13][CH2:4][CH2:5][CH2:6][CH3:11].[CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH:16]([CH3:17])[CH3:18])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: O=C(O)c1ccc(F)nc1
Agent: CCNc1ccc2c(c1)C(C(C)C)=CCC2(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)[O-]
Product: CCCCCC
Temperature: 125 °C

Procedure:
To a mixture of 85 mg (0.35 mmol) of ethyl-(8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 168) and 0.10 g (0.71 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. Purification was done using flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl. acetate:hexane (1:1) to give the title compound as white crystals (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7]C(CC)C#N.[OH-:32].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14][C:15]2[N:19]([CH3:20])[C:18]3[C:21]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]=2)=[C:6]([CH:13]=1)[O:7][CH2:3][CH2:4][CH2:5][C:6]([OH:7])=[O:32]
Reactant: [OH-]
Reactant: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OC(C#N)CC)n(C)c12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCN(CCC)c1cccc2nc(Nc3ccc(Cl)cc3OCCCC(=O)O)n(C)c12
Temperature: 75 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
To a solution of 63 mg (0.14 mmol) of 4-[(5-chloro-2-[[7-(dipropylamino)-1-methyl-1H-benzimidazol-2-yl]amino]phenoxy]butanenitrile in 3 mL of EtOH and 1 mL of water was added 29 mg (0.72 mmol) of sodium hydroxide pellets and the reaction was stirred at 75° C. for 48 h. To the reaction mixture was added 75 mg (1.87 mmol) of sodium hydroxide pellets and the reaction heated at 75° C. for 24 h and concentrated in vacuo to a residue. The thus obtained residue was dissolved in 5 mL of water and the pH was adjusted to 4-5 using hydrochloric acid (1N aqueous solution). The resulting slurry was filtered, and the solids were washed with water and dried under high vacuum to give 46 mg (70%) of the title compound as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Oc1ccccc1Cl
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccc2Cl)cc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 1.17 g (7.54 mmol) of 2-chloro-4-fluorobenzonitrile and 0.97 g (7.54 mmol) of 2-chlorophenol in 40 mL DMSO was combined with 3.2 g (23.16 mmol) of potassium carbonate and stirred overnight at 120° C. Then the mixture was evaporated to dryness in vacuo, the residue was mixed with water and extracted with ethyl acetate. The extracts were washed with water and saturated sodium chloride solution, dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.I[CH2:16][CH2:17][O:18][CH3:19].ClCCOC>CN(C)C=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:16][CH2:17][O:18][CH3:19])[CH:9]=1
Reactant: Oc1cccc(Br)c1
Reactant: COCCI
Agent: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.5 %

Procedure:
Anhydrous potassium carbonate (4.2 g, 30.4 mmol) was added to a stirred solution of 3-bromophenol (5.0 g, 28.9 mmol) in anhydrous dimethylformamide (100 ml). After 5 minutes, 1-iodo-2-methoxyethane (Annalen, 1967, 710, 59; 5.9 g, 31.8 mmol) was added and the reaction mixture stirred at room temperature for about 16 hours. At this point the mixture was heated at about 50° C. for approximately 72 hours, before 1-chloro-2-methoxyethane (1.8 ml, 19.8 mmol) was added and heating continued for a further 24 hours. The resulting mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to a red oil, which was purified by flash chromatography using hexane:ethyl acetate (3:1) as eluant, to furnish the title compound as a colourless oil (1.7 g, 25%). δ(CDCl3): 3.43 (s,3H), 3.74 (t,2H), 4.10 (t,2H), 6.87 (d,1H), 7.10 (m,3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6]C)[CH:4]=[CH2:5].[CH3:8]C1C=CC(S(O)(=O)=O)=CC=1.O.CCN([CH2:25][CH3:26])CC>CN(C=O)C.O>[CH3:8][CH2:1][O:2][CH:3]([O:6][CH2:25][CH3:26])[CH:4]=[CH2:5]
Reactant: CCN(CC)CC
Reactant: C=CC(OC)OC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(OCC)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A solution of diol (Molecule 2.1) (1.5 g, 7.8 mmol) in 7.5 ml of dry DMF was treated with acrolein dimethyl acetal (4.62 ml, 39 mmol) and PTSA.H2O (0.371 g, 1.95 mmol). After stirring for 24 h at room temperature the reaction was stopped by addition of 1 ml of Et3N and poured out in 200 ml of H2O. The aqueous phase was extracted with toluene (3×100 ml) and the combined organics were washed once with brine (100 ml) and dried over MgSO4. Column chromatography of the residue over silica gel (cyclohexane/ethyl acetate: 85/15) afforded Molecule 2.2 (FIG. 4) as white crystals (1.306 g, 5.67 mmol, 73%).
Reaction SMILES: [CH:1]1([C@@:6]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH:14]3[N:16]([CH3:17])[C@@H:11]2[CH2:12][CH2:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][Br:26]>CC(C)=O>[Br-:26].[CH:1]1([C@@:6]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH:14]3[N+:16]([CH3:25])([CH3:17])[C@@H:11]2[CH2:12][CH2:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C2CC[C@@H]1[C@@H](OC(=O)[C@](O)(c1ccccc1)C1CCCC1)C2
Reactant: CBr
Solvent: CC(C)=O
Product: C[N+]1(C)C2CC[C@@H]1[C@@H](OC(=O)[C@](O)(c1ccccc1)C1CCCC1)C2
Product: [Br-]
Reaction time: 48 h

Procedure:
To (1R,2S)-2-((R)-2′-cyclopentyl-2′-hydroxy 2′-phenylacetoxy)-7-methyl-7-azabicyclo[2.2.1]heptane (46 mg, 0.139 mmol) in acetone (2 mL) was added 1 mL of methyl bromide solution (2M in ether). The resulting mixture was left at room temperature for 48 hrs. The crystallized product was filtered off and dried to yield 36 mg of (1R,2S,)-2-((R)-2′-cyclopentyl-2′-hydroxy 2′-phenylacetoxy)-7,7-dimethyl-7-azoniabicyclo[2.2.1]heptane bromide (2) as a white crystalline solid, M.P. 233-234° C., 1HNMR: 7.6 (dd, 2H); 7.4 (m, 2H); 7.28 (m, 1H); 5.0 (m, 1H); 4.9 (m, 1H); 4.45 (m, 1H); 3.8 (s, 1H); 3.49 (s, 3H); 3.28 (s, 3H); 3.0 (m, 1H); 2.5-2.2 (m, 4H); 1.9-1.3 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][CH:30]=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.NS(O)(=O)=[O:40].[O-]Cl=O.[Na+].ClCl>C1COCC1.O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:19]([CH2:29][C:30]([OH:40])=[O:31])=[CH:20][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC=O
Reactant: NS(=O)(=O)O
Agent: ClCl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To the title compound of Step (B) (300 mg, 0.57 mmol) and H2NSO3H (111 mg, 1.14 mmol) in 11.4 ml THF at 0° C., an ice cooled solution of NaClO2 (103 mg, 1.14 mmol) in 11.4 ml H2O was added. The mixture was stirred at 0° C. for 2 min. 60 ml CH2 Cl2 was added. The organic layer was separated and washed with H2O and brine, dried and concentrated to afford the title compound of this step, which was relatively pure and was used in the next step without further purification.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([C:8](=[CH2:11])[CH:9]=O)[CH3:7].Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)(=O)C>[CH2:6]([C:8]1[CH:9]=[N:5][C:19]([CH3:21])=[C:13]([CH:11]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:7]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: [NH4+]
Reactant: C=C(C=O)CC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)cnc1C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
A suspension of 2 kg of ammonium acetate (26 moles) in 4.5 L of acetic acid is mechanically stirred in a 12 L 4-necked flask equipped with a condenser, and treated with 1 kg of 2-ethylacrolein (11.9 moles) in a single portion followed by 2 kg of ethyl 2-chloroacetoacetate (12.1 moles). An exotherm ensues over a period of 5 minutes to the boiling point of the solvent; this condition is maintained (under control) with air cooling for 10 minutes. After stirring overnight at ambient temperatures, the reaction mixture is filtered, the filtrate is concentrated in vacuo, and the residue is partitioned between 2:1 hexane-ethyl acetate and water. The organic phase is washed with water, then extracted thoroughly with 5% aqueous HCl. The combined aqueous extracts are washed with 2:1 hexane-ethyl acetate, made basic with concentrated NH2OH, and extracted with 2:1 hexane-ethyl acetate. The combined organic extracts are dried and concentrated in vacuo, to give an oil residue which is vacuum distilled to afford 1.4 kg of the title product, bp 90°/0.05 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]12([NH2:26])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:16]12([NH:26][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10][CH3:11])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CCCN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC(=O)NC12CC3CC(CC(C3)C1)C2)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Next, methylene chloride (208 ml) was added to a mixture of 2-[N-(t-butoxycarbonyl)-N-propylamino]acetic acid (4.52 g, 20.8 mmol) and 1-adamantaneamine (3.46 g, 22.9 mmol), and the whole was stirred at room temperature. N,N-Diisopropylethylamine (7.25 ml, 41.6 mmol) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.71 g, 22.9 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 7.88 g (quantitatively) of 2-[N′-(t-butoxycarbonyl)-N-propylamino]acetic acid N-(1-adamantyl)amide as a colorless oily matter. The obtained oily matter solidified at room temperature.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:8][CH2:9][CH2:10][CH2:11]Br>C(#N)C>[Br-:8].[Br:8][CH2:9][CH2:10][CH2:11][P+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: BrCCCBr
Reactant: CCP(CC)CC
Solvent: CC#N
Product: CC[P+](CC)(CC)CCCBr
Product: [Br-]

Procedure:
The solution of 0.591 ml (0.473 g, 4.00 mmol) of triethylphosphine in 5 ml of acetonitrile was added to the refluxing solution of 4.04 g (20.0 mmol) of 1,3-dibromopropane in 15 ml of acetronitrile over 1 hr. under argon atmosphere. After the addition was completed, the reaction mixture was refluxed for another 6 hrs. After being cooled, acetonitrile was evaporated, 15 ml of ethyl acetate was then introduced into the residue. After being stored in refrigerator for a couple of hours, the highly hygroscopic white solid was collected by filtration. Yield 1.09 g (85%). 1HNMR(DMSOd-6, ppm): 3.64 (t, J=6.7 Hz, 2 H), 2.36-2.17 (m, 8 H) 2.08-2.02 (m, 2 H), 1.13 (d t, J1=18.2 Hz, J2=7.7 Hz, 1 H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@:8]3([OH:24])[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.C(=O)(O)O.[NH2:29][NH:30][C:31]([NH2:33])=[NH:32].Cl>O1CCOCC1.O>[NH:30](/[N:29]=[C:12](/[C@@H:11]1[C@:15]2([CH3:23])[C@@:8]([OH:24])([C@H:7]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:22])[C@@H:4]([CH2:3][C@@H:2]([OH:1])[CH2:21][CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)\[CH3:13])[C:31]([NH2:33])=[NH:32]
Reactant: CC(=O)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: C1COCCO1
Solvent: O
Product: C/C(=N\NC(=N)N)[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.3 %

Procedure:
A mixture of 1.00 g of 3β,14β-dihydroxy-5β-pregnane-20-one (Templeton J. F. et al., J. Chem. Soc., Perkin Trans. 1, 1991, 823), 1.20 g of aminoguanidine hydrogencarbonate in 40 ml of dioxane and 10 ml of water acidified at pH 2.5 with 0.01M hydrochloric acid was stirred at room temperature for 3 days. The precipitate was collected by filtration and purified by flash-chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 78/20/2; the fractions containing the title compound were collected and evaporated to dryness. The crude product was ground with ethanol to give 0.40 g of the title compound (I-bk) as a white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17]([CH3:20])(C)C)(=[O:15])[NH:13][NH2:14].[C:21]1(C)C=CC=C[CH:22]=1>>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:14]1[NH:13][C:12](=[O:15])[O:16][CH2:17][CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccccc1
Product: CCCCOC(=O)NN1C(=O)c2ccccc2C1=O

Procedure:
A suspension of phthalic anhydride (30.0 g) and t-butyl carbazate (CAS No. 870-46-2) (26.8 g) in toluene (600 mL) was azeotropically refluxed using a Dean-Stark trap for 3.25 hours. The insoluble matter was removed by hot filtration. The filtrate was concentrated to about one-third volume under reduced pressure and then ice-cooled. The precipitated solid was collected by filtration. The resulting solid was dissolved in ethyl acetate (750 mL) and purified by short path NH silica gel column chromatography (100% ethyl acetate). The target fraction was concentrated, and the residue was then triturated with ethyl acetate (20 mL). The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (16.4 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[C:22]([C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (2.0 g, 11.22 mmoles) in THF at −78° C. was added 9.4 mL (2.1 eq) of n-BuLi. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was then cooled to −78° C. after which N-methoxy-N-methylacetamide (1.2 g, 1.1 eq) was added as a solution in THF. The resulting mixture was stirred at room temperature for 2 hours. It was then quenched into ice-H2O. The resulting mixture was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were washed with H2O (2×20 mL), brine (1×20 mL), then dried over MgSO4. Concentration and purification by MPLC gave N-(3-acetylpyridin-2-yl)pivalamide (1.62 g, 65%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9 H) 2.65 (s, 3 H) 7.09 (dd, J=7.76, 4.83 Hz, 1 H) 8.17 (dd, J=7.76, 1.90 Hz, 1 H) 8.64 (dd, J=4.69, 2.05 Hz, 1 H) 11.49 (br. s., 1 H).
Reaction SMILES: C(C1[C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH3:18])=[N:6][N:7]2[CH3:17])#N.Br.[C:20]([OH:23])(=[O:22])[CH3:21].[OH2:24]>>[CH3:17][N:7]1[C:8]2[C:4](=[C:21]([C:20]([OH:23])=[O:22])[C:11]([C:12]([OH:13])=[O:24])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1
Reactant: O
Reactant: CCOC(=O)c1ccc2c(c(C)nn2C)c1C#N
Reactant: CC(=O)O
Agent: Br
Product: Cc1nn(C)c2ccc(C(=O)O)c(C(=O)O)c12
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of ethyl 4-cyano-1,3-dimethyl-1H-indazole-5-carboxylate (7.03 g, 28.7 mmol), concentrated hydrobromic acid (35 mL) and acetic acid (35 mL) is stirred for 2 hours at reflux temperature, cooled, diluted with water (200 mL) and stirred for 2 hours. Filtration of the reaction mixture affords the title product as a pale blue solid (6.57 g, 97.8%), mp 228.5°-232.5° C.