Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].O=C1CCC(=O)N1O[C:26](=O)[CH:27]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:28][CH3:29].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:30][CH:27]([C:26]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[N:1]=1)[CH2:28][CH3:29])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reactant: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Compound 15 (1.20 g, 5.30 mmol) was combined with 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester (2.13 g, 6.36 mmol), dimethylaminopyridine (915 mg, 7.49 mmol), and diisopropylethylamine (1.10 mL, 6.36 mmol) in toluene (15 mL). The mixture was heated to 110° C. and stirred at that temperature for 22 hours. After cooling, the reaction was purified by flash chromatography to provide the quinazolinone (16) as a pale yellow solid. MS (ES): m/z 428 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 11-1, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 16 are shown below.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[CH2:6][C@@H:5]([CH2:15][OH:16])[O:4][CH2:3]1.Cl>C(O)C.[Pd]>[CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([CH2:15][OH:16])[O:4][CH2:3]1
Reactant: C[C@@H]1CO[C@H](CO)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[C@@H]1CO[C@H](CO)CN1
Yield: 141.5 %

Procedure:
To a stirred solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methanol (1.05 g, 4.74 mmol) in ethanol (15 mL) was added hydrochloric acid (concentrated, 12M) (0.435 mL, 5.22 mmol). The mixture was purged with nitrogen to degas, then 10% palladium on carbon (Degussa Type E101 NE/W, 50% wet) (150 mg, 0.070 mmol) was added and the mixture was purged with hydrogen and then stirred under the balloon. After stirring 4 hrs, TLC (50% EtOAc-hexanes) showed no starting material, and baseline product. The mixture was degassed with nitrogen, filtered through Celite, and evaporated to dryness to afford the title compound (880 mg) as the hydrochloride salt. 1H NMR (400 MHz, D2O): δ 3.72-3.92 (m, 3H), 3.48-3.69 (m, 3H), 3.13-3.24 (m, 1H), 3.04-3.13 (m, 1H), 1.34 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:21]([O-])=O)[CH:9]=2)[N:4]=1.O.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CO.Cl>[F:1][CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:21])[CH:9]=2)[N:4]=1
Reactant: Cc1ccccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-n1c(CF)nc2ccc(N)cc2c1=O
Reaction time: 0.25 h
Yield: 84 %

Procedure:
2.5 g of 2-fluoromethyl-3-(o-tolyl)-6-nitro-4(3H)-quinazolinone are suspended in 40 ml of methanol, and a solution of 6.0 g of stannous chloride in 6.0 ml of concentrated hydrochloric acid is added dropwise thereto at 5° to 10°C for 15 minutes. The mixture is stirred at the same temperature for 15 minutes and then at room temperature for 2.5 hours. After the reaction, the mixture becomes a clear solution. The solution thus obtained is decolorized with 0.25 g of activated carbon. 200 ml of water and 100 ml of chloroform are added to the solution. Then, the solution is neutralized with sodium bicarbonate, stirred and filtered to remove insoluble materials. The chloroform layer is separated, dried and then concentrated to dryness. The residue thus obtained is crystallized with 15 ml of isopropanol, and the crystalline precipitate is collected by filtration. 1.9 g of 2-fluoromethyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[CH:16]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCO>[CH3:1][O:2][C:3](=[O:15])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: NCC1CCCCC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
Methyl(4-fluoro-3-nitrophenyl)carbamate (1.00 g, 4.67 mmol) and cyclohexylmethyl amine (0.730 mL, 5.60 mmol) were stirred in EtOH (20 mL) containing TEA (1.0 mL, 7.00 mmol) at 75° C. for 24 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 5% KHSO4 aqueous solution, saturated NaHCO3 aqueous solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 4:1/hexanes:EtOAc on silica gel. Yield: 1.05 g (73%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.04 (m, 2H), 1.25 (m, 3H), 1.69 (m, 2H), 1.77 (m, 2H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 (m, 2H), 3.78 (s, 3H), 6.46 (m, 1H), 6.84 (d, J=9.37, 1H), 7.63 (m, 1H), 8.05 (d, J=2.54 Hz, 1H), 8.09 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](I)=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3].[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].[I-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu].C(N(CC)CC)C>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:17]#[C:16][C:14]([CH3:15])([OH:18])[CH3:13])=[C:6]([F:12])[CH:5]=1)[CH2:2][CH3:3]
Reactant: C#CC(C)(C)O
Reactant: CCCc1cc(F)c(I)c(F)c1
Agent: [Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CCN(CC)CC
Product: CCCc1cc(F)c(C#CC(C)(C)O)c(F)c1
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A mixture of 2 g of 1-propyl-3,5-difluoro-4-iodobenzene, 0.626 g of 2-methyl-3-butyn-2-ol, 0.164 g of tetrakis(triphenylphosphine)palladium(0), 10 ml of triethylamine and 0.054 g of copper(l) iodide was stirred at 90° for 2 hours. Then, the cooled reaction mixture was partitioned between water and ether, the ether phase was washed several times with water, dried over magnesium sulphate, filtered over Celite and evaporated on a rotary evaporator. The residue was then chromatographed on 75 g of silica gel (eluent: 10% ethyl acetate in hexane) and again evaporated. There were obtained 1.5 g of 4-(4-propyl-2,6-difluorophenyl)-2-methylbutyn-2-ol as a yellow liquid.
Reaction SMILES: [C:1]1([C:25]2C=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.BrC1C=C(C2C=CC=C[N:39]=2)C=CC=1>>[N:39]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:1]1[CH:2]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccc(-c2ccccn2)c1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccn3)c2)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using 2-(3-Bromo-phenyl)-pyridine. Purification by MPLC (CH3CN/H2O/TFA) afforded the title compound; ES-MS: 409.2 [M+H]+; HPLC: single peak at tR=6.64 min (System 1).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20]([CH2:22]Cl)=O)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([NH2:26])=[S:25].CN1CCOCC1>CC(C)=O.CCOCC>[CH2:1]([C@H:8]([CH2:19][C:20]1[N:26]=[CH:24][S:25][CH:22]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: NC=S
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)Cc1cscn1
Yield: 75.9 %

Procedure:
The resultant compound from Example 34 (476.8 mg, 1.44 mmol) and thioformamide (176 mg, 2.88 mmol) in acetone (6 ml) were stirred at room temperature for 108 h. N-methylmorpholine (0.16 ml, 1.40 mmol) was added and after 20 min the mixture was diluted with ether, filtered, evaporated, and chromatographed on silica gel with 20% ethyl acetate in hexane to afford 369 mg (76%) of an oil. 1H NMR (CDCl3) δ8.70 (d,1H), 7.05-7.35 (m,10H), 6.90 (d,1H), 5.00 (d,1H), 4.95 (d,1H), 3.28-3.35 (m,1H), 3.19 (dd,1H), 2.95-3.10 (m,2H), 2.88 (dd,1H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:19]([Mg]Br)[CH3:20].C(OCC)C.CO.C(Cl)Cl>C1COCC1>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:19][CH3:20]
Reactant: CC[Mg]Br
Reactant: CNC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(O)c1ccc(-c2ccc(C(=O)NC)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
To a solution of 4-(6-formylpyridin-3-yl)-N-methylbenzamide (0.2 g, 0.8 mmol) in THF (15 mL) at −30° C. was slowly added 3.0 M ethyl magnesium bromide in diethyl ether (0.9 mL, 2.4 mmol) and the reaction mixture was stirred at rt for 3 h. After completion of the reaction as monitored with TLC (5% MeOH\DCM), the reaction mixture was quenched with sat'd. NH4Cl (50 mL) solution. The reaction mixture was extracted with EtOAc (3×50 mL), washed with water (2×50 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel 230-400μ) using 2% methanol in dichloromethane. The product was isolated as a yellow solid (0.1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.82 (d, 1H), 8.46 (d, 1H), 8.11 (dd, 1H), 7.92 (d, 2H), 7.80 (d, 2H), 7.51 (d, 1H), 5.30 (d, 1H), 4.54 (q, 1H), 2.78 (d, 3H), 1.79 (m, 1H), 1.63 (m, 1H), 0.85 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:21][C@@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: CN(C)CC(=O)O
Product: COc1cc(OC[C@H]2C[C@H](O)CN2C(=O)CN(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 73 %

Procedure:
The procedure described in Example 20 was repeated using (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (185 mg) with N,N-dimethylglycine (50 mg) to give the title compound as a white solid in 73% yield; NMR spectrum (DMSO-d6) 9.93 (s, 1H), 8.45 (s, 1H), 8.15 (dd, 1H), 7.76-7.70 (m, 1H), 7.45 (t, 1H), 6.83 (s, 2H), 5.09-5.08 (m, 1H), 4.70-4.66 (m, 1H), 4.45-4.40 (m, 2H), 4.28-4.23 (m, 1H), 3.93 (s, 3H), 3.62-3.49 (m, 2H), 3.20 (d, 1H), 3.00 (d, 1H), 2.21 (s, 6H), 2.06-2.02 (m, 2H); Mass spectrum MH+ 504.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccc(Br)cc1O
Product: Fc1cccc(-c2nc3ccc(Br)cc3o2)c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 3-fluorobenzoic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:32][C:31]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[O:30][C:29]2=[O:45])=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[CH2:32][C:31]6([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]6)[O:30][C:29]5=[O:45])=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 62.5 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (133 mg, 0.45 mmole) was combined with tert-butyl 3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (158 mg. 0.45 mmole) which gave tert-butyl 3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (170 mg) in 62% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.89 (s, 1H), 8.76 (s, 1H), 8.46 (d, J=9.03 Hz, 1H), 8.38 (d, J=2.51 Hz, 1H), 7.97-7.92 (m, 1H), 6.40 (s, 1H), 4.78-4.68 (m, 1H), 3.83-3.73 (m, 2H), 3.71 (s, 2H), 3.33-3.21 (m, 2H), 3.02 (s, 6H), 2.54-2.40 (m, 2H), 2.05-1.86 (m, 6H), 1.78-1.58 (m, 4H), 1.38 (s, 9H) HR-MS m/z 605.3221 (M+H)+
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:35])[CH2:7][CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])C.O1CCCC1.C(O)C>O>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21](/[CH:20]=[CH:19]/[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:35])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCNC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)NCCC(=O)O)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A solution of LiOH (0.18 g) in water (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine ethyl ester (1.74 g) in the mixture of tetrahydrofuran (10 ml) and ethanol (10 ml) at 0° C. The reaction mixture was stirred for overnight at room temperature, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aqueous KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-β-alanine as a colorless oil (1.64 g).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH2:9]1)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24].CCOCC>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 93 %

Procedure:
tert-Butyl[(3R)-1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate (Method 40; 1.0 g, 3.26 mmol) in DCM (15 ml) was reacted with TFA (7.5 ml) at room temperature for 18 hours. Pouring into cold ether (200 ml) gave on filtration the title compound (0.97 g, 93%). NMR: 2.03-2.17 (m, 1H), 2.22-2.44 (m, 1H), 3.40-3.60 (m, 3H), 3.68-3.74 (m, 1H), 3.95-4.08 (m, 1H), 6.66 (d, 2H), 8.08 (d, 2H), 8.14 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O>[Pd].NN>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: CN(C)CCCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Product: CN(C)CCCNc1ccccc1N

Procedure:
10.1 g. of o-nitrobromobenzene is reacted, analogously to Example 27, with 5.1 g. of 3-dimethylaminopropylamine, thus obtaining 6 g. of 2-(3-dimethylaminopropylamino)-nitrobenzene, b.p. 138°-141° C. at 0.1 mm Hg. By reducing 3.5 g. of this compound with hydrazine - palladium, 2.9 g. of 2-(3-dimethylaminopropylamino)-aniline is obtained in the form of an oil. 400 mg. of this diamine is reacted with the ethyl ester of 5-nitro-1-methyl-2-imidazolyl-iminocarboxylic acid, as described in Example 1, to obtain 407 mg. of 1-(3-dimethylaminopropyl)-2-(5-nitro-1-methyl-2-imidazolyl)-benzimidazole hydrochloride, m.p. 250° C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C([Li])CCC.[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=[O:36])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CCOCC>[C:37]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:32]2[CH2:35][C:34]([C:2]3[C:11]4[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=3)([OH:36])[CH2:33]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OC1(c2cc(C(F)(F)F)nc3c(C(F)(F)F)cccc23)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a solution of 4-bromo-2,8-bis(trifluoromethyl)quinoline (500 mg, 1.45 mmol) in dry ether (10 mL) at −78° C. under argon was added n-butyllithium (0.64 mL of 2.5-M, 1.6 mmol). After 20 min a solution of N-diphenylmethyl-3-azetidinone (345 mg, 1.45 mmol) in ether (5 mL) was added dropwise, the mixture stirred for 20 min, water was added and the mixture allowed to warm slowly to room temperature. The mixture was extracted with ether (3×20 mL), the combined extracts dried (MgSO4), concentrated in vacuo and the residue purified by chromatography [SiO2; heptane-EtOAc (3:1)] to give the product (738 mg, 100%) as a pale yellow foam: IR νmax (Nujol)/cm−1 3378, 2924, 1456, 1377, 1311, 1145 and 702; NMR δH (400 MHz, CDCl3) 3.74-3.79 (4H, m), 4.45 (1H, s), 7.21-7.37 (6H, m), 7.41-7.46 (4H, m), 7.65-7.69 (2H, m), 8.15 (1H, d, J 7.1 Hz) and 8.35 (1H, d, J 8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]#[N:23])=[CH:16][CH:15]=3.C([O-])(=O)C.[Na+].Cl.[OH:36][NH-:37]>C(Cl)Cl.CO>[NH2:23][C:22]1[O:36][N:37]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)[CH:21]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC#N)ccc3n(C)c21
Reactant: [NH-]O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc(N)on4)ccc3n(C)c21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution containing 300 mg (0.707 mmol) of compound 3-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-3-oxopropionitrile from Example 20A, 238 mg (2.9 mmol) of sodium acetate and 152 mg (2.2 mmol) of hydroxylamide hydrochloride in 4 ml of CH2Cl2 and 4 ml of MeOH is stirred at 50° C. for 24 h and then at ambient temperature for 18 h. The reaction medium is concentrated by adsorbing it onto silica, and purification is carried out on a silica column, elution being carried out with EtOAc/20% cyclohexane and then 100% EtOAc.
Reaction SMILES: [OH-].[K+].C[Si]([C:7]#[C:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([C:22]#[C:23][Si](C)(C)C)=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)(C)C>CO>[C:22]([C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[C:11](=[CH:10][C:9]([C:8]#[CH:7])=[CH:21][CH:20]=3)[CH2:12][C:13]=2[CH:14]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)Cc1cc(C#C[Si](C)(C)C)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc2c(c1)Cc1cc(C#C)ccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.3 %

Procedure:
Thereafter, 60 ml of 1N potassium hydroxide solution was slowly added to 10.12 g(28.2 mmol) of 2,7-di(trimethylsilylethynyl)fluorene dissolved in 150 mL of methanol. The reaction mixture was stirred for 3 h at room temperature and solvent was removed. Residue was extracted with ether and the ether layer was washed with distilled water. The washed ether layer was concentrated. The crude product was purified by column chromatography on silica gel by eluting with hexane/ethylacetate (15/1) to give 1.35 g (72%) of 2,7-diethynylfluorene of which mp was 125° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[OH:8].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].CCOCC>CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:2][C:3]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[OH:8]
Reactant: Cc1ccc(OCC(O)c2ccccn2)c(C)c1
Agent: O=[Pt]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(OCC(O)C2CCCCN2)c(C)c1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of α-[(2,4-dimethylphenoxy)methyl]pyridine-2-methanol hydrochloride (10.0 g, 0.0347 mole) in 200 ml of methanol was hydrogenated at room temperature with 1.4 g of platinum oxide for 1/2 hr. The methanol solution was filtered and solvent removed on the rotary evaporator. The resulting material was dissolved in water, made basic with 10% sodium hydroxide and the free base was extracted into methylene chloride. Removal of methylene chloride on the rotary evaporator gave a yellow oil. While standing overnight the oil crystallized to give a white solid (softens 75°-78° C., 78°-90° C. m.p.). The free base was dissolved in methanol and treated with a methanol solution of an equimolar quantity of fumaric acid. A crystalline white solid was obtained by adding ether, and upon recrystallization from methanol-ethyl ether, 5.81 g (52.9%) of crystalline white product was obtained, m.p. 208°-212° C. with decomposition.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][O:7]1)=[O:5])C.[OH-].[Na+:20]>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][C:6]2([C:4]([O-:5])=[O:3])[CH2:8][O:7]2)[CH:17]=[CH:16][CH:15]=1.[Na+:20]
Reactant: CCOC(=O)C1(CCCc2cccc(Cl)c2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C1(CCCc2cccc(Cl)c2)CO1

Procedure:
2.7 g of 2-[3-(3-chlorophenyl)propyl]oxirane-2-carboxylic acid ethyl ester are stirred with 10 ml of 1 N sodium hydroxide solution and 10 ml of ethanol at room temperature for 1 hour. The mixture is concentrated in vacuo, after which the title compound remains as a colorless glassy powder.