Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4]CC1.[CH2:29]([Mg]Br)C(C)C>>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][C:7]=2[CH:6]([CH2:1][CH:5]([CH3:4])[CH3:29])[O:10]1
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: CC(C)C[Mg]Br
Product: CC(C)CC1OB(O)c2cc(NC(=O)c3ccccc3C(F)(F)F)ccc21

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with isobutyl magnesium bromide replacing cyclopentyl magnesium bromide. Data: LCMS (M/Z): 378 (M+H); 1H NMR (DMSO-d6) δ: 10.53 (s, 1H), 9.13 (s, 1H), 8.06 (d, J=1.9 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.73-7.79 (m, 1H), 7.65-7.71 (m, 2H), 7.62 (dd, J=8.2, 2.0 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 5.10 (dd, J=9.8, 3.0 Hz, 1H), 1.81-1.92 (m, 1H), 1.65 (ddd, J=13.9, 9.0, 3.1 Hz, 1H), 1.27 (ddd, J=14.1, 9.7, 4.6 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[N:3]=1.Cl.[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]2)[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[CH:34][CH:33]=[C:32]([NH:42][CH:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:2]3[N:7]4[N:8]=[C:9]([CH:11]5[CH2:16][CH2:15][N:14]([CH:17]([CH3:18])[CH3:19])[CH2:13][CH2:12]5)[N:10]=[C:6]4[CH:5]=[C:4]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[F:27])[N:3]=3)[CH2:44]2)[N:31]=1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine, 81.2 mg (0.24 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 56 mg (42% of theory) of the product as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH2:12])=[O:11])=[N:2]1.Br[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[H-].[Na+].O>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]([C:10]([NH2:12])=[O:11])=[N:2][NH:1]2
Reactant: COCCCBr
Reactant: NC(=O)c1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1cccc2[nH]nc(C(N)=O)c12
Temperature: 60 °C

Procedure:
Following the procedure for converting Compound 1e to Compound 1f, the indazole amide Compound 1e (0.31 g, 17.8 mmol) was treated with 1-bromo-3-methoxypropane (0.3 g, 19.6 mmol) in the presence of 95% NaH (0.05 g, 19.6 mmol) in DMF (50 mL) at 0° C. for 20 min and then warmed to 60° C. for 2 h. The mixture was cooled down to rt. Water was added and the aqueous solution was extracted with EtOAc several times. The organic layers were combined and washed with brine, then dried (Na2SO4) and evaporated in vacuo to an oil. The oil was purified by flash column chromatography (96:4:0.4; DCM:MeOH:NH4OH) to afford a 3-methoxypropyl indazole amide analog of Compound 1f (0.32 g, 73%). 1H NMR (CDCl3) δ 7.69 (d, J=8.13 Hz, 1H), 7.4 (m, 2H), 7.17 (m, 1H), 6.57 (bd s, 1H), 5.39 (bd s, 1H), 4.47 (t, J=6.65 Hz, 2H), 3.96 (s, 2H), 3.30 (t, J=5.78 Hz, 2H), 3.28 (s, 3H), 2.16 (m, 2H). ES-MS m/z 248 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][C:15]3=O)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1>C1COCC1>[O:7]1[C:11]2([CH2:21][CH2:20][C:14]3([CH2:18][CH2:17][NH:16][CH2:15]3)[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1CC2(CCC3(CC2)OCCO3)CN1
Yield: 94.4 %

Procedure:
To a suspension of LiAlH4 (21 g, 558.56 mmol) in anhydrous THF (500 mL) was added a solution of 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (59 g, 279.28 mmol) in anhydrous THF (400 mL) dropwise at 0° C. for 1 h. The reaction mixture was stirred at reflux for another 2 h, then quenched with water at 0° C. until no bubble escaped and filtered. The filter cake was washed with a mixture of DCM and MeOH (1/1 (v/v), 500 mL). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the product as a yellow solid (52 g, 94%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:3]([OH:25])[CH2:4][CH:5]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:8])=[O:7].[C:33](=O)([O:42][C@H:43]1[CH2:47][CH2:46][O:45][CH2:44]1)[O:34]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:26]([C@H:2]([NH:1][C:33](=[O:34])[O:42][C@H:43]1[CH2:47][CH2:46][O:45][CH2:44]1)[C@H:3]([OH:25])[CH2:4][CH:5]([O:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)[S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:7])=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinylsulfonyl)-3-pentanol (50 mg, 0.110 mmoL), 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl] carbonate (28 mg, 0.121 mmol, WO 94/05639) and N,N-diisopropylethylamine (47.8 μL, 0.274 mmol) were combined under Argon at ambient temperature in approximately 1.5 mL of acetonitrile. After stirring for approximately 16 hours at ambient temperature, the reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and aqueous potassium carbonate (5% w/v). The layers were separated and the aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed twice with 1N sodium hydrogen sulfate. The acid layers were combined and back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 1000 μM) eluting with 93:7 dichloromethane:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was crystallized with several drops of methanol. The residual solid was dried under high vacuum to provide (3S)tetrahydro-3-furanyl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinyl sulfonyl)butyl]carbamate (54 mg, 86%) as a white solid. H1-NMR (chloroform-D3): 1.61 (m, 5H), 1.86 (m, 4H), 2.09 (m, 1H), 2.97 (m, 3H), 3.20 (m, 2H), 3.80 (m, 6H), 4.83 (m, 1H), 4.93 (m, 1H), 5.14 (m, 1H), 7.28 (m, 5H), 8.13 (m, 1H), 8.31 (d, 1H), 8.69 (d, 1H), 9.05 (s, 2H). MS(ESI): 571(M+H).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1>[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]#[N:1]
Reactant: N#CBr
Reactant: CN(C)CCNc1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CCN(C#N)c1cnccn1
Reaction time: 72 h

Procedure:
A solution of cyanogen bromide (15.9 g, 0.150 mole) in 75 ml of tetrahydrofuran is added to a solution of 2-(2-dimethylaminoethylamino) pyrazine (16.6 g, 0.1 mole) and triethylamine (20.9 g, 0.15 mole) in 100 ml of tetrahydrofuran. After 72 hours, dilute sodium hydroxide is added and the mixture is extracted with ether. The extracts are concentrated and the residue is distilled under reduced pressure. N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl) cyanamide boiling at 130°-132° C. at 0.7 mm if collected.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH2:12]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13]1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:17]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:23][CH:22]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Brc1cnc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Yield: 93.8 %

Procedure:
A mixture of 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (123 mg, 443 μmol), 4-(4-morpholino)aniline (118 mg. 0.664 mmol) and N-ethyldiisopropylamine (116 mL, 0.664 mmol) is heated at reflux in 2-propanol (3 mL) for 4.5 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and citric acid (10%). The organic phase is washed once with water and brine, dried over MgSO4, filtered and evaporated to furnish the title compound (156 mg, 94%) as a yellow solid. 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 3.11 (m, 4H), 3.78 (m, 4H), 6.97 (d, 2H), 7.82 (d, 2H), 7.87 (s, 1H), 8.71 (s, 1H), 9.93 (br s, 1H). LCMS, Rt 3.32 min (96.8%) m/z (APCI) 375 (M+H)+.
Reaction SMILES: CS([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:6]1)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:29][C:25]1[CH:24]=[C:23]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH:9]=3)[NH:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)n1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc2[nH]cc(-c3cccc(Cl)c3)c2c1

Procedure:
To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (11.44 g, 25.76 mmol, see Preparation 7) in anhydrous THF (150 ml) was added tetrabutylammonium fluoride (33.5 ml, 1.0 M solution in THF). The resulting solution was refluxed under nitrogen for about 3 hrs. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with 1N HCl (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with EtOAc/hexane 1:4. The title compound was obtained as a yellow solid. Yield=8.1 g, 86%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=C(N)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C([O-])([O-])=O.[K+].[K+].IC.[CH3:22][N:23]([CH:25]=O)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:25]([N:23]([CH3:22])[CH3:24])[C:10]2[C:11]([CH:12]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: CN(C)C=O
Reactant: COc1cc(N)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc(N(C)C)c2ccccc2c1
Reaction time: 24 h

Procedure:
To a solution of 3-methoxy-1-aminonaphthalene (U.S. Pat. No. 7,018,431 B2, 0.13 g) in DMF (5 mL), K2CO3 (0.31 g) and iodomethane (0.09 mL) were added. After stirring for 24 hours, the reaction was partitioned between water (30 mL) and EtOAc (30 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated. The crude reaction purified over silica gel (gradient of EtOAc in heptane) to provide the title compound (0.14 g) as a clear oil: 1H NMR (DMSO-d6) δ 7.99 (d, 1H); 7.74 (d, 1H), 7.40 (ddd, 1H), 7.30 (ddd, 1H), 6.95 (d, 1H), 6.67 (d, 1H), 3.83 (s, 3H), 2.78 (s, 6H); MS expected 202 (C13H16NO, M+1), found 202.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)=[O:22].C1COCC1>C(N(CC)CC)C>[CH3:19][NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:24]1)=[O:22]
Reactant: CNC(=O)[C@@H]1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Yield: 86 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3R)—N-methylpiperidine-3-carboxamide (Preparative Example 31) by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (3R)—N-methylpiperidine-3-carboxamide. After 3 hr the reaction mixture was evaporated in vacuo and filtered with the aid of water. The resulting solids were then washed with a 1 N aqueous HCl solution followed by water. The material was air dried to afford product as a colorless solid (157 mg, 86%). LC/MS 6.00 min, [M+1]+ 402.
Reaction SMILES: S([CH2:11][N+:12]#[C-:13])(C1C=CC(C)=CC=1)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:24]([O:26][C:27](=[O:46])[CH:28]=[CH:29][C:30]1[C:35]([CH2:36][N:37]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:25]>C1COCC1>[CH2:24]([O:26][C:27]([C:28]1[C:29]([C:30]2[C:35]([CH2:36][N:37]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:13][NH:12][CH:11]=1)=[O:46])[CH3:25]
Reactant: CCOC(=O)C=Cc1ncccc1CN(C)Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c[nH]cc1-c1ncccc1CN(C)Cc1ccccc1
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A solution of 2.3 g (11.6 mmol) of tosylmethyl isocyanide in 25 mL of anhydrous THF is cooled to −50° C. under a nitrogen atmosphere. To this solution is added dropwise 23 mL (11.6 mmol) of potassium bis(trimethylsilyl) amide (0.5M solution in toluene) keeping the temperature <−50° C. After addition is complete this mixture is stirred for a 0.5 hour. To this mixture a solution of 1.8 g (5.8 mmol) of 3-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-acrylic acid ethyl ester dissolved in 10 mL of anhydrous THF is added dropwise maintaining a temperature <−50° C. After addition is complete the reaction mixture is quenched with 10 mL of water and extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is redissolved in approximately 100 mL of ethyl acetate and 100 mL of water. The pH of the mixture is adjusted to 2.0 with 1N HCL. The ethyl acetate layer is separated from the water layer. An additional 100 mL of ethyl acetate is added to the water layer and the pH adjusted to 9.0 with 1N NaOH. The ethyl acetate layer is separated from the water layer, dried (Na2SO4) and evaporated to yield 1.9 grams of 4-{3-[[benzyl-methyl-amino]-methyl]-pyridin-2-yl}-1H-pyrrole-3-carboxylic acid ethyl ester. 1H NMR (CDCl3) δ 8.5 (m, 1H), 8.0 (m, 1H), 7.35 (s, 6H), 7.30 (m, 5H), 7.20 (m, 1H), 6.60 (s, 1H), 4.0 (q, 2H), 3.42 (s, 2H), 3.38 (s, 2H), 2.0 (s, 3H), 1.0 (t, 3H). Mass spectrum: m/e=350.3 (p+1). TLC (10/1 chloroform/methanol) Rf=0.35. Step 9:
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@:20]([CH3:21])([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CC(C)([O-])C.[K+].C([O:31][N+:32]([O-])=[O:33])(C)C>CC(C)=O.CCCCCC>[OH:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@:20]1([CH3:21])[C:14](=[C:15]([N+:32]([O-:33])=[O:31])[C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CC(C)O[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
By the method of example 1, testosterone (2.88 g, 10 mM), potassium tert-butoxide (3.40 g, 30 mM) and iso-propylnitrate (1.01 ml) are reacted to yield 17β-hydroxy-4-nitroandrost-4-en-3-one, m.p. 158°-160° C. (acetone-hexane)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][N:56]([CH3:61])[S:57](Cl)(=[O:59])=[O:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:57]([N:56]([CH3:61])[CH3:55])(=[O:59])=[O:58])[CH2:49][CH2:48]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and dimethylsulfamoyl chloride as starting materials in 48% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.02 (s, 1H), 9.40 (m, 2H), 9.02 (s, 1H), 8.31 (m, 2H), 8.21 (s, 1H), 7.68 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.58 (m, 2H), 2.99 (m, 4H), 2.85 (m, 2H), 2.72 (s, 6H), 2.32 (m, 2H), 1.91 (m, 1H), 1.77 (m, 2H), 1.25 (m, 2H). LCMS for C26H32ClN8O3S (M+H)+: m/z=571.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][O:35][CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:38][CH2:37][CH2:36][O:35][CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: COCCO
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: CNc1ncnc2c1nc(OCCOC)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)purin-9-yl)phenyl]urea and 2-methoxyethanol by the same techniques as in Example 136.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(N1C(O[C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=CC(C2C=CC=C(C(NS(CC(F)(F)F)(=O)=O)(C)C)C=2)=N1)C.[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH2:51]>CN(C=O)C>[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH:51][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:18]=[CH:19][CH:20]=1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Reactant: NCC1CCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCO1)c1ccccc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
(1-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (52 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (38 mg, 0.29 mmol, 3 equiv) were added to a stirring solution of 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid (50 mg, 0.10 mmol, 1 equiv) in DMF (1 mL). 1-(tetrahydrofuran-2-yl)methanamine (20 mg, 0.20 mmol, 2 equiv) was then added and the mixture was stirred at 22° C. for 16 hours. The mixture was purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H phenyl]-1H-pyrazol-5-yl}oxy)-N-(tetrahydrofuran-2-ylmethyl)benzamide (38% yield). Calc'd (M+1)+: 595.2. Found: 595.1
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)[CH3:34]>ClCCl>[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][CH:38]=1)[CH3:34]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.15 g, 0.40 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.139 ul, 1.0 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid ethyl ester (92.0 mg, 0.48 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1Hindol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid ethyl ester as a white solid. (Yield 0.14 g, 60.8%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:13].[Cl:14][CH2:15][CH2:16][N:17]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Na].C(O)C>[ClH:14].[ClH:13].[CH2:18]([N:17]([CH2:16][CH2:15][N:10]1[C:9](=[O:12])[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:11]1)[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCCN(CCOc1ccccc1)Cc1ccccc1
Reactant: O=c1ccc(-n2ccnc2)n[nH]1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1ccc(-n2ccnc2)nn1CCN(CCOc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
2.43 g (0.015 mole) of 6-(1-imidazolyl)-3(2H)-pyridazinone are dissolved in the solution of 0.35 g (0.015 g-atom) of sodium in 12 ml of absolute ethanol and the solution is stirred at room temperature for 15 minutes. To the thus-obtained suspension, the base liberated from the solution of 4.89 g (0.015 mole) of N-(2-chloroethyl)-N-(2-phenoxyethyl)-N-benzylamine hydrochloride [dissolved in 12 ml of absolute ethanol by adding a solution of 0.35 g (0.015 g-atom) of sodium in 12 ml of absolute ethanol] is added, thereupon the mixture is stirred at room temperature for 30 minutes and then boiled under reflux while stirring for 4 hours, set aside overnight at room temperature and evaporated. The residue is taken up in 200 ml of chloroform, filtered, the organic solution is washed with water, dried and evaporated under reduced pressure. The residue weighing 5.82 g is dissolved in absolute acetone and a calculated amount of ethanolic hydrogen chloride solution is added, diluted with isopropanol and kept in the refrigerator overnight. The precipitate is filtered off, washed with acetone and dried to give 5.9 g (80% yield) of the aimed product, m. p. 153°-156° C.