Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:36][CH3:37].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH2:36][CH3:37])[C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)C(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(CC)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}-2,2,2-trifluoroacetamide (400 mg, 0.79 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 38 mg, 0.95 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Iodoethane (0.095 mL, 1.19 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 60° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound (131 mg, 0.245 mmol, 31%) as a pale yellow amorphous.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:7]=[CH:8][C:9]=1[Cl:10].CCN(C(C)C)C(C)C.[CH:46](=O)[CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.[BH3-]C#N.[Na+]>C(CO)(F)(F)F>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17](=[O:26])[C:18]3[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13][N:12]2[C:27](=[O:36])[CH2:28][NH:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:46][CH2:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:34][CH2:35]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCNCC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: OCC(F)(F)F
Product: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CNC3CCN(CCCc4ccccc4)CC3)C(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound 1 obtained from Example 9 (0.4 g, 0.7 mmol) in CF3CH2OH (5 mL) was added Hunig's base (0.21 g, 1.6 mmol) at 0° C. After stirring at 0° C. for 10 min, hydrocinnamaldehyde (94 mg, 0.7 mmol) was added. The reaction was stirred at 0° C. for additional 2.5 h, and NaBH3CN (100 mg, 1.6 mmol) was added. The mixture was stirred at 0° C. and gradually warmed to RT overnight. After reaction was complete, it was worked up and purified as described in Example 7 to give the title compound as a white solid, m.p. 52°-54° C.; FAB MS [M+1]+ 35 Cl 621.3.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: CC1=COc2ccccc2C(=O)N1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=COc2ccccc2C(=O)N1CCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of 4,5-dihydro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 20 ml of dimethylformamide, then 68 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated at room temperature for 1 hour, then 0.78 ml (4 equivalents) of 1,5-dibromopentane was added and the resultant mixture was agitated for 6 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8](O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[CH2:22]([Mg]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.CCOCC.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1([CH2:19][CH3:20])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: Br[Mg]Cc1ccccc1
Reactant: CCC1(CC(=O)OC)OCC(O)c2c1[nH]c1ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1(CC(=O)OC)OCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Temperature: -78 °C
Yield: 51.5 %

Procedure:
To a solution of 1-ethyl-4-hydroxy-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid methyl ester (1 g, 3.6 mmol) in 60 mL of dry methylene chloride at -78° C. under nitrogen was added TiCl4 in one portion and then after ~10 minutes, a solution of benzyl magnesium bromide in ether was added in one portion and the reaction mixture was allowed to stir at -78° C. for ~30 minutes. The reaction was quenched with methanol (3 mL) at -78° C. and then poured into water (10 mL). The two layers were separated and the aqueous layer was then extracted with methylene chloride (2×100 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was passed through a pad of silica gel, eluting with 10% EtOAc in hexane to give 0.67 g (51.5%) of the product as an oil, which had isomer ratio of 75:25 by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9].[Br:16][C:17]1[N:22]=[C:21]([CH2:23]O)[CH:20]=[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>O1CCCC1>[Br:16][C:17]1[N:22]=[C:21]([CH2:23][N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:9])=[O:10])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)CNS(=O)(=O)c1ccccc1Cl
Reactant: OCc1cccc(Br)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cccc(Br)n1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 45, step 1, 2-chloro-N-isobutyl-benzenesulfonamide (example 42, step 1) was reacted with 6-bromo-2-pyridinemethanol (CAS [33674-96-3]), triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran to give N-(6-bromo-pyridin-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>>[CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][N:6]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12]([F:11])([F:21])[F:22])[C:5]2=[O:10])[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1c[nH]c(=O)n1C1CC1
Product: Cc1cn(Cc2ccccc2C(F)(F)F)c(=O)n1C1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 28, Step B] from 1-cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one (obtained in example 28, step A), 150 mg) by alkylation with 2-trifluoromethylbenzyl bromide (285 mg). 3-Cyclopropyl-4-methyl-1-(2-trifluoromethyl-benzyl)-1,3-dihydro-imidazol-2-one was obtained as a colorless liquid (121 mg). MS (ESI): 297.1 (MH+).
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:45]=[CH:44][C:31]2[N:32]([CH2:42][CH3:43])[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]=2[CH:29]=1.S([O-])(O)=O.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.CN(C=O)C>[ClH:57].[ClH:57].[CH2:42]([N:32]1[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]2[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]3[C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:16]=[C:2]3[CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH:45]=[CH:44][C:31]1=2)[CH3:43]
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3N)ccc21
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4cnccc43)ccc21
Temperature: 25 °C

Procedure:
A DMF solution (4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.37 g), and sodium hydrogensulfite (0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound (0.47 g) as a white amorphous solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:11]([O:10][C:8]([C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
1.63 g of tert-butyl trans-4-hydroxycyclohexanecarboxylate (8.14 mmol, 1 eq.) and 1.62 g of ethyl 6-hydroxynicotinate (10.58 mmol, 1.3 eq.) are placed in 24 mL of tetrahydrofuran at room temperature. 3.20 g of triphenylphosphine (12.21 mmol, 1.5 eq.) are added, followed by dropwise addition of 2.37 mL of diisopropyl azodicarboxylate (12.21 mmol, 1.5 eq.) to the reaction medium with stirring. After 1 hour at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed successively with sodium hydroxide solution and than with water, dried over magnesium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 3% to 30%. 1.3 g of ethyl cis-6-(4-tert-butoxycarbonylcyclohexyloxy)-nicotinate are obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: COc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 33.1 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 155 mg, 0.77 mmol), 5-bromo-2-chloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39, 180 mg, 0.59 mmol), and DIEA (181 mg, 1.48 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 33%). LC-MS, 409 (M+1). 1H NMR δ 12.03 (s, 1H), 9.38 (s, 1H), 8.82 (s, 2H), 7.97-8.12 (m, 2H), 5.60 (s, 1H), 5.13 (s, 1H), 3.75 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:29](OCC)C.[H-].[Na+].CI>C1COCC1>[CH3:29][N:12]1[CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=2)[N:10]=[C:11]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Add tert-butyl 4-(4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (540 mg, 1.36 mmol) to diethyl ether (100 mL) and cool to 0° C. Add sodium hydride (55 mg, 1.5 mmol, 60% in mineral oil) to the mixture followed by methyl iodide (0.142 mL, 2.72 mmol). Stir the mixture for 1 h at 0° C. and warm to room temperature. Add THF (40 mL) and stir the mixture for 12 h. Concentrate the mixture, and purify the residue by silica gel chromatography (120 g RediSep column, elute with a gradient of 0% to 100% ethyl acetate:hexane, over 40 min, 85 mL/min) to provide tert-butyl 4-(1-methyl-4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (425 mg, 76%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C:29]1=[O:33]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:32][CH2:31][CH2:30][C:29]5=[O:33])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1CCCN1
Product: O=C(c1ccc(N2CCCC2=O)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (510 mg) described in Preparation Example 143 and pyrrolidin-2-one (131 μL) and by the reaction and treatment in the same manner as in Example 1, the title compound (297 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:8]2[C:6]3[N:7]=[C:2]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][S:25](=[O:28])[CH2:24][CH2:23]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:15][CH:16]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(CSc2ncnc3c(N4CCS(=O)CC4)nc(Cl)nc23)cc1
Product: COc1ccc(CSc2ncnc3c(N4CCS(=O)CC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-methoxybenzyl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 217°-219° C.) and piperazine.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC[C@@H](N)C4)C3)[C@H](C)[C@H]12

Procedure:
730 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.75 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1.0 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 120 mg of the title compound, as a powder.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].Cl.[CH3:36][O:37][CH:38]1[CH2:41][NH:40][CH2:39]1>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][N:40]4[CH2:41][CH:38]([O:37][CH3:36])[CH2:39]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: COC1CNC1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Agent: Cl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCN5CC(OC)C5)ccn34)c12

Procedure:
Prepared according to the procedure for Example 128 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 127, Steps A-B) and 3-methoxyazetidine hydrochloride. MS (ES+APCI) m/z=524 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1ccc(CCl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)cc1
Yield: 93.3 %

Procedure:
By the method of Example 1, Step I, 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 0.87 g (0.0038 mole) of methyl 2-(4-chloromethylphenoxy)propionate were reacted in the presence of 0.2 g of 1,4,7,10,13,16-hexaoxacyclooctadecane in 25 mL of N,N-dimethylformamide, yielding 0.80 g of methyl 2-[4-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxy-methyl]phenoxy]propionate as a colorless oil that solidified upon standing, m.p. 83°-85° C. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH=8.0 Hz); 4.90 (s, 2H); 6.78-7.38 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[N:21]=1>CN(C)C=O>[Cl:26][C:22]1[N:21]=[C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cccc(CBr)n1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccc(Cl)n1
Yield: 91 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (226 mg), N,N-dimethylformamide (5 ml), potassium carbonate (193 mg) and 2-(bromomethyl)-6-chloropyridine (335 mg) according to the similar method described in Production Example 4 was obtained 365 mg of 2-((6-chloro-2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (the present invention compound (8)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J15) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a light yellow solid (250 mg).
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41](=[O:52])[CH2:42][CH2:43][CH:44](N)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48]>CCCCCCC.C(OCC)(=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][CH2:45][CH:44]([NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH2:43][CH2:42][C:41]([O:40][CH3:39])=[O:52]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)CCC(N)CCC(=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CCC(CCC(=O)OC)NC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-heptanedioic acid dimethyl ester (J. Am. Chem. Soc. 2005, 127 (50), 17877-17887) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (69%). MS (ESI): m/z=669.19 [M+H]+.