Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][NH2:45])[CH2:39][CH2:38]1>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:45][CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:3])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN1CCN(CCN)CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCN4CCN(C)CC4)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-[2-(4-methyl-piperazin-1-yl)-ethyl]-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 2-(4-methyl-piperazin-1-yl)-ethylamine in an analogous manner to Example 1396. Product isolated as a yellow foam (16 mg, 25%). LCMS (m/e) 593 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.18 (s, 1H), 8.68 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.51 (d, 1H, J=8.0 Hz), 7.48-7.41 (m, 1H), 7.36 (s, 1H), 7.30-7.21 (m, 1H), 7.15-7.07 (m, 1H), 7.03 (d, 1H, J=8.0 Hz), 7.00 (s, 1H), 6.97-6.90 (m, 1H), 3.60-3.53 (m, 4H), 3.39 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.70 (m, 6H), 2.64 (t, 2H, J=5.7 Hz), 2.63-2.37 (m, 8H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:3]([N:5]1[CH2:8][CH:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6]1)=[O:4].[O:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=[N:25]1>>[NH2:1][CH:2]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:3]([N:5]1[CH2:8][CH:7]([N:9]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:29]([C:28]2[O:24][N:25]=[CH:26][CH:27]=2)=[O:30])[CH2:6]1)=[O:4]
Reactant: O=C(Cl)c1ccno1
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)N1CC(NC2CCCCC2)C1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CC(N(C(=O)c2ccno2)C2CCCCC2)C1

Procedure:
{1-[2-Amino-3-(4-chloro-phenyl)-propionyl]-azetidin-3-yl}-cyclohexylamine was acylated with isoxazole-5-carbonyl chloride in a manner similar to that described for 6 above and then the Boc protecting group removed by treatment with a solution of HCl in dioxane and MeOH to furnish isoxazole-5-carboxylic acid {1-[2-amino-3-(4-chloro-phenyl)-propionyl]-azetidin-3-yl}-cyclohexyl-amide. 1H NMR (400 MHz, CDCl3) δ 8.33–8.29 (m, 1H), 7.32–7.12 (m, 4H), 6.77–6.71 (m, 1H), 4.54 (br, 2H), 4.34–3.80 (m, 2H), 3.60–3.40 (m, 2H), 3.20–2.70 (m, 2H), 2.60–2.05 (m, 2H), 1.86–1.60 (m, 4H), 1.60–1.00 (m, 4H), 0.90–0.78 (m, 3H); MS Calcd for C22H27ClN4O3 [M+H], 431. Found, 431.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:26])([F:25])[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1.CI>O1CCCC1>[CH3:1][C:18]1([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH:15]([C:14]([F:25])([F:26])[F:13])[CH2:20][CH2:19]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(F)(F)F)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
To a solution of diisopropylamine (22.0 mL, 124.0 mmol) in tetrahydrofuran (60 mL) was added n-BuLi (2.0 M solution in hexane, 59.0 mL, 95.0 mmol) at 0° C. and the reaction mixture was allowed to stir at same temperature for 20 minutes before cooled to −78° C. Methyl 4-(trifluoromethyl)cyclohexanecarboxylate (10.0 g, 48.0 mmol) in tetrahydrofuran (60 mL) was added dropwise at −78° C. The reaction mixture was stirred at same temperature for 2 hours and then neat methyl iodide (4.5 mL, 72.0 mmol) was added dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was warmed to ambient temperature and stirred for 16 hours, before quenched with 25% aqueous ammonium chloride solution (100 mL) at 0° C. and extracted with ethyl acetate. The organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (11.2 g, 99%) as a brown colored oil: 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.32-2.28 (m, 2H), 2.01-1.80 (m, 3H), 1.42-1.08 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[C:14]([O:22]C(=O)C)=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[C:14]([OH:22])=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2O)=C(C)C1=O
Yield: 31.3 %

Procedure:
3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.036 g, 0.0963 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from diisopropyl ether to obtain the titled compound (0.010 g, 0.0301 mmol, 31%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: O=C1CCC(c2cccc(O)c2)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Yield: 60.9 %

Procedure:
A mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (21.6 g, 0.11 mole), epichlorohydrin (90 ml, 1.1 mole), and piperidine (1ml) was heated on a steam bath for 90 minutes. Evaporation of the solution under reduced pressure gave an oil which was dissolved in dichloromethane and stirred with dilute sodium hydroxide solution (60 ml). The organic phase was washed with water, dried, and evaporated under reduced pressure to a viscous oil (27 g, 96%). Purification on a silica column by elution with chloroform gave 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (16.5g, 59%) as an oil which when treated with ether gave a white solid (13.7g, 49%, m.p. 108°-112°C). The pure epoxide, recrystallised from methanol petroleum/ether (b.p. 60°-80°C), had m.p. 110°-112°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:10][CH2:9]1.Cl[C:31]1[N:40]=[C:39]2[C:34]([C:35](=[O:47])[C:36]([C:44]([OH:46])=[O:45])=[CH:37][N:38]2[CH:41]2[CH2:43][CH2:42]2)=[CH:33][C:32]=1[F:48]>>[C:26]([NH:25][CH2:24][C@@H:22]1[O:21][C:20](=[O:29])[N:19]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([C@@H:14]4[CH2:18][CH2:17][N:16]([C:31]5[N:40]=[C:39]6[C:34]([C:35](=[O:47])[C:36]([C:44]([OH:46])=[O:45])=[CH:37][N:38]6[CH:41]6[CH2:43][CH2:42]6)=[CH:33][C:32]=5[F:48])[CH2:15]4)[CH2:10][CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:23]1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN([C@@H]4CCNC4)CC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN([C@@H]4CCN(c5nc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)C4)CC3)c(F)c2)C(=O)O1

Procedure:
This compound was synthesized in analogy to the procedure described in Example 19 using 0.0 90 g N-{(5S)-3-[3-fluoro-4-(4-{(3R)-pyrrolidin-3-yl}-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.22 mmol) and 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (0.22 mmol).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of 4-fluoro-3-nitroacetophenone (165 g, 0.9 mol) in NMP (350 ml) was added 3-bromoaniline (98 ml, 0.9 mol) and triethyl amine (125.4 ml, 0.9 mol) and the reaction mixture was stirred at 80° C. for 6 hours and then left with stirring at room temperature over night. The resultant suspension was poured into ice-water and the precipitate was filtered off and washed with water and diethyl ether, successively. Drying in the air afforded the desired product (262g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCc4ccc(Cl)c(Cl)c4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 94.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.5 mg, 0.137 mmol), in 1:1 DMF:DCM (0.1 M) was sequentially treated with 3,4-dichlorobenzylamine (26.5 mg, 0.150 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.4 mg, 0.164 mmol), and 1-Hydroxy-7-azabenzotriazole (5.58 mg, 0.0410 mmol) at ambient temperature. After 16 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (69.0 mg, 0.129 mmol, 94.4% yield) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[ClH:9].[CH3:12][NH:14][CH:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1CCC(=O)CC1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCC(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (35 ml) were suspended 4-methylcyclohexanone (2.5 g), methylamine hydrochloride (1.6 g) and triethylamine (3.3 ml), and to the suspension was added sodium triacetoxy boron hydride (6.6 g) under ice-cooling. The mixture was stirred under nitrogen atmosphere at room temperature overnight. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated. To the residue was added. 4N hydrochloric acid-ethyl acetate, and the solvent was evaporated to give N, 4-dimethyl-cyclohexylamine hydrochloride (2.6 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]2[CH:19]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10][CH2:9][N:8]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccccc1C1=NCCNc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1C1=NCCNc2ccc(-c3ccncc3)cc21
Temperature: 150 °C
Yield: 41.4 %

Procedure:
A 5-mL microwave tube was charged with 7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine (85 mg), 4-pyridylboronic acid (100 mg), dichlorobis(triphenylphosphine)palladium(II) (20 mg), dimethylformamide (3.5 mL) and a saturated solution of sodium carbonate (0.5 mL). The reaction was heated to 150° C. for 360 seconds using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying agent was filtered and the filtrate was concentrated to an oil. Silica gel purification provided the title compound (5-(2-fluorophenyl)-7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine, 35 mg) as an off-white crystalline solid. H1 NMR (d6-dmso): 8.40 (d, 2H), 7.57 (dd, 1H), 7.44 (t, 2H), 7.25 (m, 3H), 7.18 (m, 1H), 7.12 (m, 1H), 6.99 (br t, 1H), 6.85 (d, 1H), 3.98 (m, 2H), 3.54 (m, 2H). Mass (ES+)=318.2 (100%).
Reaction SMILES: [NH2:1][C:2](=[S:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:10]C)=[O:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>>[F:27][C:26]([F:28])([F:29])[C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([CH2:3][C:4]3[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=3)[C:7]([O:9][CH3:10])=[O:8])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cccc(CC(N)=S)c1
Product: COC(=O)c1cccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 99.9 %

Procedure:
By a reaction in the same manner as in Example 178b and using the compound (223 mg, 1.00 mmol) obtained in Example 180b and 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (267 mg, 1.0 mmol), the title compound (377 mg, 96%) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][CH2:29][C:30]2[N:35]=[C:34]3[CH2:36][O:37][C:38](=O)[C:33]3=[CH:32][CH:31]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:38]1[C:33]2[C:34](=[N:35][C:30]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:31][CH:32]=2)[CH2:36][O:37]1
Reactant: O=C1OCc2nc(CCN3CCOCC3)ccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 27 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (70 mg, 0.46 mmol) in THF (0.6 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1.0 M solution in THF, 1.2 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-(2-morpholin-4-yl-ethyl)-7H-furo[3,4-b]pyridin-5-one (80 mg, 0.32 mmol) in THF (2 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into an aqueous 10% HCl solution (40 mL). The resulting suspension is stirred at room temperature for 48 h. The yellow solid which precipitated from solution is collected by filtration and washed with 10% HCl, MeOH (3×5 mL) and Et2O (3×5 mL), and dried under vacuum overnight to give the title compound (33 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].[Cu][C:18]#[N:19]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:18]#[N:19])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OCC
Yield: 47.2 %

Procedure:
To a solution of 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (940 mg, 3.0 mmol) in 20 mL of dimethylformamide was added copper(I) cyanide (327 mg, 3.65 mmol). The reaction was stirred at reflux overnight. The reaction was diluted with methylene chloride. It was washed twice with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (359 mg, 47%). LC-MS: 254.1 [(M+H)+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Br[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in Example 3(c) by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 474 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([NH2:9])=[O:8].CO.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)(O)[O-].[Na+]>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([NH2:9])=[O:8])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)[C@@H]1CCC[C@@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
To a stirred solution of cis-2-amino-cyclopentanecarboxylic acid amide (1 g, 0.008 mol) in methanol (20 mL, 0.5 mol) and water (10 mL, 0.6 mol) at 0° C. in an ice bath was added 2,4,5-trichloropyrimidine (1.7 g, 0.0094 mol) followed by sodium bicarbonate (1 g, 0.02 mol). The reaction mixture was warmed to room and stirred at room temperature for 24 h. The reaction mixture was diluted with water (25 mL) and washed with ethyl acetate (3×50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid amide as a white solid (1.8 g, 80% yield). No further purification was needed. 1HNMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 6.73 (d, 1H, J=6.8 Hz), 5.56 (broad s, 1H), 5.44 (broad s, 1H), 4.66 (p, 1H, J=7.5 Hz), 2.97 (q, 1H, J=7.5 Hz), 2.05-2.15 (m, 3H), 1.83-1.98 (m, 2H), 1.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(CS(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(methylsulfonylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[CH3:15])([OH:8])[CH3:7])=[CH:2]1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][O:8][C:6]([C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[CH3:15])([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH3:7]
Reactant: Cc1nc(C)c(C(C)(O)c2ccoc2)o1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(C)(c1ccoc1)c1oc(C)nc1C
Reaction time: 0.33 h

Procedure:
1-(3-Furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol (2g) in dry N,N-dimethylformamide (15 ml) was added to a stirred suspension of sodium hydride (80%, 300 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 20 minutes, methyl iodide (1.5 g) was added dropwise. The mixture was allowed to warm to room temperature and after 30 minutes aqueous sodium hydrogen carbonate was added.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:25][CH:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>C(#N)C>[CH3:25][CH:26]1[N:31]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:30][CH2:29][NH:28][C:27]1=[O:32]
Reactant: CC1NCCNC1=O
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1C(=O)NCCN1Cc1nnnn1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (3 mL) was added triethylamine (0.318 mL, 2.285 mmol) and 3-methyl-2-piperazinone (87 mg, 0.762 mmol, Sigma-Aldrich). The reaction mixture was heated to 120° C. for 20 min in a microwave reactor. The reaction mixture was concentrated in vacuo. The crude product was purified by silica chromatography (Biotage SP4), eluting with an increasing gradient of (2N NH3 in MeOH) in DCM. The relevant fractions were combined and concentrate to give the title compound as white crystals (151 mg)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[NH:3]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.Cl>O1CCCC1.CN(C)C=O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Under a nitrogen stream, (R)-3-methylisothiazolidine 1,1-dioxide (149 mg) described in Preparation Example 2 was dissolved in a solution of tetrahydrofuran (5 mL) and N,N-dimethylformamide (4 mL), sodium hydride (44 mg) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 min. Then, a solution of methyl 4-bromomethylbenzoate (229 mg) in tetrahydrofuran (5 mL) was added, and the mixture was stirred under ice-cooling for 1.5 hr, and at room temperature for 2 hr. To the reaction mixture was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (159 mg).