Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=O)=[CH:9][N:10]=2)[N:7]=1.[BH4-].[Na+].O.C([SiH](CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: COc1ccc(C(=O)c2cnc3ccc(Cl)nn23)cc1
Agent: CC[SiH](CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cc2cnc3ccc(Cl)nn23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
The compound (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-(4-methoxy-phenyl)-methanone (Stage 3.2, 2.04 g, 7.1 mmol) was suspended in ethanol (20 mL) with sodium borohydride (140 mg, 3.6 mmol) and stirred at rt for 7 h. Then water was added and the precipitate formed was filtered off. The yellow solid obtained was dried and then dissolved in TFA (50 mL). Triethylsilane (2.85 mL, 17.7 mmol) was added to the solution and it was stirred at rt for 30 min. the RM was poured into ice water. It was extracted with EtOAc and washed with aqueous 1 N sodium hydroxide solution then with brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography with DCM and MeOH. The title compound was obtained As a white solid (tR 1.1 min (conditions 2), MH+=274).
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:18]=[C:17]([NH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][NH:22][C:23]3[CH:45]=[C:44]([O:46][CH3:47])[C:26]([O:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[C:25]([O:48][CH3:49])[CH:24]=3)[C:15]=2[CH3:20])[N:10]=1>O>[NH2:8][C:9]1[N:18]=[C:17]([NH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:21][NH:22][C:23]3[CH:45]=[C:44]([O:46][CH3:47])[C:26]([O:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[C:25]([O:48][CH3:49])[CH:24]=3)[C:15]=2[CH3:20])[N:10]=1
Reactant: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OCC(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OCC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
HCl in dioxane (3.22 ml, 12.87 mmol) was added to example (6) (0.03 g, 0.051 mmol) followed by a few drops of water. The solution was allowed to stir at RT. After 3 h, the solvents were evaporated, the residue triturated with Et2O and dried under vacuum to afford the title compound (7) (22 mg, 82%). LCMS purity 96%, m/z 527 [M+H]+, 1H NMR (400 MHz, d6-DMSO) δ: 12.6 (1H, s), 9.0 (1H, s), 8.0 (1H, d, J=8.3 Hz), 7.9 (1H, s), 7.5 (3H, m), 7.2 (1H, d, J=8.8 Hz), 6.0 (2H, s), 4.3 (3H, m), 4.2 (2H, d, J=5.4 Hz), 3.7 (6H, s), 2.7 (3H, s), 1.5 (3H, m), 0.8 (6H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23](I)[CH3:24]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH2:23][CH3:24])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CCI
Product: CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 73 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.3 g) and ethyl iodide (0.12 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 14(a) to obtain the title compound (0.24 g, 73%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[Cl:18].OS(O)(=O)=O.[CH2:24]=O.[NH4+].[OH-]>>[Cl:18][C:3]1[C:4]([C:14]([F:16])([F:17])[F:15])=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH3:13])[C:7]=2[C:2]=1[NH:1][CH3:24]
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(NC)c21
Yield: 73.3 %

Procedure:
To 1.0g. of 7-amino-6-chloro-1-ethyl-2-methyl-5-trifluoromethylbenzimidazole (Example IV) dissolved in 10 ml. of concentrated H2SO4 was added 1.0g. of paraformaldehyde. The resultant mixture was stirred at 80°C. for 2 hours and then poured onto ice. The resultant brown solution was made basic by addition of concentrated NH4OH, precipitating a light brown solid. The mixture was extracted with chloroform and the chloroform extracts washed with water and dried over Na2SO4. After removal of the chloroform by evaporation, the residue was extracted with hexane and the hexane extract distilled to dryness. The solid residue was recrystallized from hexane to give 0.77g. (73.3%) of the desired product, m.p. 116.5°-119°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-(4-Nitrophenyl)-1-Butanol (2.5 g, 12.166 mmol) was dissolved in DCM (50 ml). The solution was cooled in an ice-bath. Triethylamine (2.45 ml, 15.2 mmol) was added and then methanesulfonyl chloride (1.533 g, 13.382 mmol) was dropped in. After 1 hour, the ice-bath was removed. The mixture was stirred for 4 hours more. The reaction mixture was washed with water, sodium hydrogencarbonate aqueous solution (1%) and water (×3) and dried with magnesium sulfate. The solvent was evaporated in vacuum and the desired product (3.25 g) was obtained, yield 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7](=[CH:13][C:14]([OH:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH:4]=1.[N+](=[CH2:23])=[N-].N#N>C(OCC)C>[CH3:23][O:15][C:14](=[O:16])[CH:13]=[C:7]1[C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:3]([O:2][CH3:1])=[CH:4][C:5]2[CH:20]=[CH:19][CH:18]=[CH:17][C:6]1=2
Reactant: C=[N+]=[N-]
Reactant: COC1=Cc2ccccc2C(=CC(=O)O)c2ccsc21
Agent: N#N
Solvent: CCOCC
Product: COC(=O)C=C1c2ccccc2C=C(OC)c2sccc21

Procedure:
2 g of the product of example 2 are suspended in 20 ml ethyl ether and a freshly prepared solution of diazomethane is added at 0° C. until N2 evolution ceases. The solvent is evaporated off at 10° C. and the residue re-crystallised from ethanol to yield the title compound as a (Z,E) isomer mixture: m.p.=124°-125° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(Cc4ccccc4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O3, 449.9
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[N:26]=[C:25]([C:27]4[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=4)[CH:24]=[CH:23][C:10]=3[CH:11]([C:12]([CH3:22])([CH3:21])[C:13](=[O:20])[NH:14][C:15]3[S:16][CH:17]=[N:18][N:19]=3)[C:5]2=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:21][C:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)[O:8][C:9]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH3:34])[CH3:35])=[O:32])=[CH:36][CH:37]=3)[CH:24]=[CH:23][C:10]1=2)([CH3:22])[C:13](=[O:20])[NH:14][C:15]1[S:16][CH:17]=[N:18][N:19]=1
Reactant: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(Cl)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1
Reactant: C1COCCN1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(n2)Oc2nc(N4CCOCC4)ccc2C3C(C)(C)C(=O)Nc2nncs2)cc1

Procedure:
Using conditions described for synthesis of Example 67, the ester from Step 3 of Example 54 was reacted with morpholine and converted Example 69. 1H NMR (400 MHz, chloroform-d) δ ppm 8.88 (1H, s), 8.10 (2H, d, J=8.31 Hz), 7.56-7.61 (1H, m), 7.48-7.56 (3H, m), 7.32 (1H, d, J=8.31 Hz), 6.38 (1H, d, J=8.31 Hz), 4.44 (1H, s), 3.82 (4H, t, J=4.78 Hz), 3.47-3.63 (4H, m), 3.19 (3H, s), 3.05 (3H, s), 1.25 (6H, s); MS (ES+) m/z: 586 (M+H); LC retention time: 3.62 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:12][CH2:13][CH2:14][OH:15])=[CH:6][N:5]=1)[CH3:2].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:12][CH2:13][CH2:14][O:15][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C=NOCCO)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 74.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 570 mg of 2-(2-ethoxy-5-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 12), 1.20 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 695 mg of triphenylphosphine and 462 mg of diethyl azodicarboxylate, 1.27 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH2:22]([N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:23]
Reactant: CCNc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCN(c1ccccc1)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 22 °C
Yield: 40 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 24 mg, 0.085 mmol), N-ethylaniline (75 μl, 0.595 mmol, Alfa Aesar, Ward Hill, Mass.), and NaHMDS (1.0M in THF; 595 μl, 0.595 mmol) and heating at 22° C. for 30 min. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(ethyl(phenyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.14 Hz, 3H) 2.80 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.90, 2.45 Hz, 2H) 4.10 (q, J=7.24 Hz, 2H) 5.35 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.33-7.37 (m, 2H) 7.39-7.45 (m, 2H) 7.51-7.56 (m, 2H) 7.72 (dd, J=8.02, 1.17 Hz, 1H) 7.99 (dd, J=7.63, 1.37 Hz, 1H) 8.35 (s, 1H) 12.12 (br. s., 1H). MS (ESI, pos. ion) m/z: 384.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([Cl:18])[C:3]=1[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1)=O.O>CC(O)=O>[C:27]([C:24]1[CH:23]=[C:22]([C:20]2[NH:19][C:3]3[C:4]([Cl:18])=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[CH:7][C:2]=3[N:1]=2)[O:26][N:25]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C(=O)Nc2c(N)cc(-c3ccccc3C(F)(F)F)nc2Cl)on1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3cc(-c4ccccc4C(F)(F)F)nc(Cl)c3[nH]2)on1
Temperature: 100 °C

Procedure:
3-tert-Butyl-isoxazole-5-carboxylic acid [4-amino-2-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-amide (73.9 mg, 0.168 mmol, prepared as in the previous step) was dissolved in AcOH (1 mL) and the resulting solution was heated to 100° C. for 14 h. The resulting mixture was cooled to room temperature and poured into H2O (20 mL). The aqueous phase was extracted with DCM (3×10 mL) and the combined extracts were washed with sat NaHCO3 solution (20 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in POCl3 (1 mL) and heated for 16 h at 100° C. The resulting mixture was cooled to room temperature and poured onto ice (˜20 mL). After the POCl3 had been consumed, the precipitate was isolated by filtration and washed with H2O (2×20 mL). The solid was dissolved in DCM (25 mL) and the solution was dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the crude product was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-2:3 EtOAc/hexanes to yield 2-(3-tert-butyl-isoxazol-5-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.68 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.30 (s, 1H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H16ClF3N4O: 421.1 (M+H). Measured: 421.1.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]([F:28])([F:27])[C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[C:21]([F:28])([F:27])[F:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)C(F)(F)F
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(F)(F)F
Yield: 40 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 1,1,1-trifluoro-2-methylbut-3-yn-2-ol (US2005/250741 A1) to give the titled compound as a white solid (80 mg, 40%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH2:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@H](O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](OCC(=O)OC(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 16.6 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7-diene (150 mg, 0.267 mmol) was treated in tetrahydrofuran (2.7 ml) with sodium hydride (60% in oil, 65 mg, 1.625 mmol), 15-crown-5 (16 mg, 0.268 mmol) and tert-butyl bromoacetate (316 mg, 1.62 mmol) in the same manner as shown in Example 17(1) (heated at reflux for 17 hours), followed by work up and separation using preparative thin layer chromatography (0.5 mm×5 plates, hexane:ethyl acetate=5:1, developed once and then 0.5 mm×2 plates, hexane:ethyl acetate=7:1, developed twice) to give the titled compound (30 mg, 17%) as a colorless foam.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH:2]=[CH2:3].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCNc1cccc(CCC(=O)OCC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCNc1cccc(CCC(=O)O)c1

Procedure:
A 4 g. sample of ethyl 3-(allylamino)hydrocinnamate is hydrolyzed with 1.6 g. 85% potassium hydroxide in 60 ml. 95% ethanol by refluxing the solution for 5 hours. The solution is cooled, diluted with 100 ml. water and acidified to pH 4.5 with 37% hydrochloric acid. The precipitate is collected, dried in vacuo and crystallized from acetone to yield the title compound as white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)[CH2:11]1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH:12]([O:14][C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH3:24])[CH:20]=2)[CH2:13]1
Reactant: O=c1ccc(OC2CN(c3cccc(CO)c3F)C2)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(OC2CN(c3cccc(CO)c3F)C2)ccc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) and potassium carbonate (200 mg) were added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added CHCl3 and water. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one (106 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.CO[C:22]1[CH:23]=[C:24]([CH:26]=[C:27](OC)[C:28]=1OC)[NH2:25].CCOC(C)=O>C(O)(C)C>[C:24]1([NH:25][C:2]2[N:3]=[CH:4][C:5]3[CH2:11][N:10]([C:12]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:9][CH2:8][C:6]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=[CH:22][CH:23]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(c1cccnc1)N1CCc2nc(Nc3ccccc3)ncc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3,4,5-trimethoxyaniline (0.021 g, 0.0498 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 54.8% yield (0.021 g, 0.049 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][N:34]([CH3:50])[CH2:35][CH2:36][O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42](C(O)=O)=[CH:41]2.CCN=C=NCCCN(C)C>CC(N(C)C)=O.O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22]([C:42]3[NH:43][C:44]4[C:40]([CH:41]=3)=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:34]([CH3:50])[CH3:33])=[CH:46][CH:45]=4)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
A suspension of 14 (0.20 g, 0.47 mmol) in cooled (0° C.) dioxane (5 mL) was saturated with HCl, allowed to warm to r.t. over 2 h and evaporated. 5-[2-(Dimethylamino)ethoxy]-1-H-indole-2-carboxylic acid hydrochloride (0.13 g, 0.47 mmol) [Milbank et al., J. Med. Chem., 1999, 42, 649], EDCI (0.27 g, 1.42 mmol) and DMA (3 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 20 h. The mixture was partitioned between EtOAc and 5% NaHCO3 solution. The aqueous layer was extracted with EtOAc (×3). The EtOAc extracts were dried (brine, Na2SO4). Flash chromatography (Alumina, EtOAc/MeOH; 49:1, then 9:1) gave 2-[(2-{[5-(benzyloxy)-1-(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-f]quinolin-3-yl]carbonyl}-1H-indol-5-yl)oxy]-N,N-dimethylethanamine (17b) (0.22 g, 84%) as a yellow solid: mp 176–179° C.; 1H NMR [(CD3)2SO]δ 11.68 (s, 1 H), 8.79 (dd, J=4.1, 1.5 Hz, 1 H), 8.41 (dd, J=8.6, 1.5 Hz, 1 H), 8.29 (s, 1 H ), 7.56 (m, 3 H), 7.40 (m, 4 H), 7.17 (d, J=2.3 Hz, 1 H ), 7.11 (d, J=1.5 Hz, 1 H), 6.92 (dd, J=9.0, 2.4 Hz, 1 H), 5.32 (s, 2 H), 4.82 (dd, J=10.7, 9.6 Hz, 1 H), 4.58 (dd, J=10.9, 2.1 Hz, 1 H), 4.32 (m, 1 H), 4.05 (t, J=5.7 Hz, 2 H), 4.04 (m, 1 H), 3.93 (dd, J=11.2, 6.9 Hz, 1 H), 2.65 (t, J=5.8 Hz, 2 H), 2.23 (s, 6H); 13C NMR [(CD3)2SO]δ 160.3, 154.5, 153.0, 147.3, 142.3, 137.4, 136.7, 131.6, 131.3, 130.6,128.4, 127.9, 127.7, 127.4, 125.1, 122.4, 116.2, 116.0, 113.1, 105.5, 103.1, 102.0, 70.0, 66.9, 66.2, 57.8, 54.9, 47.7, 45.5, 40.7.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OCCCC)=O)[CH2:21][CH2:20]2)[NH:18][CH:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][CH:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCOC(=O)N1CCC2(CC1)NC(CCSC)C(=O)N2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCCC1NC2(CCNCC2)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (7.8 g, 68.0 mmol) was added dropwise to a solution of tert 1-butyl benzyl-3-(2-methylsulfanylethyl)-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (1.5 g, 3.5 mmol) in CH2Cl2 (10 ml) at 0° C. and the mixture was stirred for 15 min at this temperature. After warming to RT, the reaction solution was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted to pH 7 to 8 using saturated aqueous NaHCO3 solution, the organic phase was separated off, and the aqueous phase was extracted with CH2Cl2 (2×10 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed by distillation. Workup was carried out by means of column chromatography to give 1-benzyl-3-(2-methylsulfanyl-ethyl)-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 655 mg (58% of theory).