Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.C[Si]([C:40]#[N:41])(C)C>C(N(CC)CC)C.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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:40]#[N:41])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C[Si](C)(C)C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.16 mmol) prepared in Example 190c in triethylamine (0.8 mL) was added trimethylsilyl cyanide (23.8 mg, 0.24 mmol) (Aldrich), Tetrakis(triphenylphosphine)palladium (3.7 mg, Aldrich) sequentially. The reaction mixture was refluxed under nitrogen for 2 h. After cooled to room temperature, the reaction mixture was partitioned between saturated water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-cyano-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 38 mg, 46%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1C=CC=CC=1.[CH:40](OC1C=C(CC(NC(C2C=CC=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)(C)C.C(OC1C=C(CC(NC(C2C=C(OC)C=CC=2N2CCCCC2)CCC)=O)C=CC=1C(O)=O)C>>[CH2:1]([O:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:25]=[C:26]([CH3:40])[CH3:27])=[O:22])[CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OC(C)C)c1)c1ccccc1N1CCCCC1
Agent: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1cc(OC)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NC(C=C(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
The mixing ratio of 75/25 is obtained from the corresponding ratio of intensities of the particularly characteristics signals in the 400 MHz-1H-NMR spectrum (CDCl3). The position of the signals is: 3-methyl-2-buten-1-yl compound: olefinic H: 5.25 (d), CH3 : 1.64 (s) and 1.77 (s), benzylic >CH-- 6.00 (t), benzylic CH2 --; 3.52 ppm (s) 3-methyl-1-butyl compound: CH3 : 0.90 (d), benzylic >CH-- 5.35 (m), benzylic --CH2 --; 3.54 ppm (s).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)(Cl)Cl>[C:29]([O:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(O[C@@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 3.21 g of trans-4-(4-hydroxyphenoxy)-1-methyl-3-phenylpiperidine in 150 ml of dry chloroform containing 1.72 ml of triethylamine is cooled in a cold water bath under nitrogen while 0.88 ml of acetyl chloride is added via syringe. After 3.5 hours at room temperature another 0.43 ml of triethylamine and 0.22 ml of acetyl chloride are added. After an additional 30 minutes stirring, the solvent is removed in vacuo and the residue is triturated with a mixture of ether (150 ml) and hexane (100 ml). The mixture is then filtered and the solid washed once with ether. The filtrate is concentrated in vacuo to an oil which crystallizes upon standing to a pale yellow oily solid. The oil is dissolved in 50 ml of boiling hexane and filtered. The filtrate is concentrated in vacuo to an oil which crystallizes under high vacuum to a nearly colorless, crystalline solid. The solid is dissolved in 25 ml of boiling hexane and the solution is allowed to cool. After standing overnight at room temperature the mixture is filtered, the solid washed with hexane and dried to afford product as colorless crystals, mp 79.5°-82° C.
Reaction SMILES: [C:1]1(C2(C(O)=O)CCCC2)C=CC=CC=1.[CH3:15][CH:16]([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19].C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH3:15][C:16]([CH3:1])([CH3:46])[CH:17]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:18]([NH:20][C@H:21]1[C@H:28]2[C@H:24]([CH2:25][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=3)[CH2:27]2)[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CC(C)(C)C(C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 3,3-dimethyl-2-phenylbutanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4R*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 2: 1H NMR (400 MHz,) δ ppm 8.47 (t, J=6.7, 1H), 7.77 (s, 0.5H), 7.71 (d, J=7.3, 2H), 7.60 (d, J=7.7, 0.5H), 7.54 (s, 1H), 7.43 (dd, J=8.1, 16.6, 1H), 7.35-7.24 (m, 4H), 4.39-4.29 (m, 1H), 3.62 (d, J=13.6, 0.5H), 3.53 (d, J=13.5, 0.5H), 3.47 (d, J=13.6, 0.5H), 3.44 (s, 1H), 3.38 (d, J=13.5, 0.5H), 2.92 (dd, J=2.9, 9.0, 0.5H), 2.62-2.54 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.36 (m, 0.5H), 2.32 (dd, J=9.1, 12.0, 1H), 2.27 (d, J=5.2, 1H), 2.21 (d, J=5.6, 1H), 2.17-2.07 (m, 0.5H), 1.86 (ddd, J=6.4, 13.3, 21.3, 1H), 1.71 (tdd, J=6.4, 13.0, 19.3, 1H), 1.36 (ddt, J=8.2, 14.4, 20.6, 1.5H), 1.14 (d, J=1.3, 9H); MS (ESI+) m/z 459 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-1-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (2.90 g, 6.91 mmol) was dissolved in CH2Cl2 (10 ml). Trifluoroacetic acid (10 ml) was added and the mixture was stirred for 90 minutes at r.t. until analytical HPLC indicated complete consumption of the starting material. The solvent was evaporated, the residue was taken up in ethyl acetate, washed (water), and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=320.4 (M+H+), (1.73 g, 69%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13]2)=[CH:6][C:5]=1[NH:18]C(=O)OC>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13]2)=[CH:6][C:5]=1[NH2:18]
Reactant: COC(=O)Nc1cc(OC2CCC(C)C2)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CCC(Oc2cc(N)c(F)cc2Cl)C1
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Then, ethyl alcohol (20 ml) and a 2N aqueous solution of sodium hydroxide (30 ml) were added to the resulting methyl N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}carbamate (3.45 g, 11.4 mmol), followed by stirring for 3 hours under refluxing. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (50 ml×3 times). The organic layer was washed with a saturated aqueous sodium chloride solution, dried, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyaniline (1.77 g, 7.26 mmol, 63.64 yield). 1H-NMR Spectrum (CDCl3, TMS, ppm): δ1.02 and 1.10 (total 3H, d, J=6.0 Hz), 1.22-2.58 (7H, m), 3.75 (2H, br, s), 4.65 (1H, m), 6.33 (1H, d, JHF =8.0 Hz), 6.98 (1H, d, JHF =10.0 Hz).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:20]([CH2:23]OC)OC.[H-].[Na+].C(I)C>CN(C)C=O.C(O)(C)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH3:23])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(OCCc2ccccc2O)CC1
Reactant: COCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCI
Solvent: CC(C)O
Product: CCOc1ccccc1CCOC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 536.1 %

Procedure:
N-Acetyl-4-(2-hydroxyphenethyloxy)piperidine (8.0 g.) and dimethoxyethane (0.3 g.) in dry dimethylformamide (50 ml.) were added dropwise to a stirred suspension of sodium hydride (2.96 g., 50% dispersion in mineral oil) in dry dimethylformamide (50 ml.). The suspension was stirred at room temperature for 3.5 hours, cooled to 0°-5° C. then a solution of ethyl iodide (9.6 g.) in dimethylformamide (25 ml.) added dropwise. The mixture was allowed to warm to room temperature (20° C.), then stirred at room temperature for 2 hours. Isopropanol (75 ml.) was added, the solvent removed in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried and the solvent evaporated in vacuo to give N-acetyl-4-(2-ethoxyphenethyloxy)piperidine (5.2 g.).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:30])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=2
Reactant: Brc1ccccc1-c1ccccc1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 3 h

Procedure:
The Grignard reagent prepared from 0.72 g (30 mmol) of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether is added dropwise over a period of 2 hours, while stirring (in an ultrasonic bath), to a boiling suspension of 10.0 g (29.6 mmol) of 2,7-dibromo-9-fluorenone in 100 ml of dry diethyl ether. After the addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitated solid is filtered off with suction and washed with cold ether. The magnesium complex filtered off is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring-closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid for 6 hours, after addition of 3 drops of concentrated HCl. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and is washed with glacial acetic acid and water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccc(F)cn2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCc1c(-c2ccc(F)cn2)noc1/C=C/c1ccccc1
Yield: 81.6 %

Procedure:
To a solution of (E)-3-(5-fluoropyridin-2-yl)-5-styrylisoxazole-4-carboxylic acid (1.2 g, 3.7 mmol) and triethylamine (0.52 mL, 3.7 mmol) in THF (30 mL) was added dropwise at room temperature a solution of ethyl chloroformate (0.36 mL, 3.7 mmol) in THF (4 mL). After 1 h the triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The filtrate was added to a solution of sodium borohydride (354 mg, 9.4 mmol) in water (3.5 mL). After stirring for 1 h at 5° C. aqueous sodium hydroxide (1 M, 11 mL) was added. Extraction with ethyl acetate, drying over sodium sulfate, filtering and evaporation of the solvent followed by trituration with diisopropylether afforded the title compound (895 mg, 81%) as a white solid after purification by chromatography (SiO2, DCM). MS: m/e=297.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>CN1C(=O)CCC1>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][NH:27][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)CCN
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCN(C)C)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 67.1 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl)dimethylamine (37.7 mg, 0.43 mmol) in NMP (2 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 150° C. for 1 h. The mixture was evaporated under vacuum, and the resulting residue was partitioned between EtOAc and water. The contents were extracted with EtOAc, DCM and DCM/isopropanol (70:30). The combined organics were washed with water (2×) and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc and sonicated. Solids that precipitated were filtered, washed with hexanes, and dried to afford the title compound (60 mg, 65%) as a white solid. LCMS E-S (M+H)=425.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (br. s., 1 H) 8.43 (t, J=5.05 Hz, 1 H) 7.84 (s, 1 H) 7.08 (t, J=5.05 Hz, 1 H) 6.67 (s, 1 H) 5.89 (s, 1 H) 4.94 (quin, J=6.63 Hz, 1 H) 4.32 (d, J=5.05 Hz, 2 H) 3.44 (q, J=6.48 Hz, 2 H) 2.44 (t, J=6.69 Hz, 2 H) 2.17-2.22 (m, 9 H) 2.12 (s, 3 H) 1.43 (d, J=6.57 Hz, 6 H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:40]([C:37]5[CH:36]=[N:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:39][N:38]=5)=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1cnc(N2CCOCC2)cn1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1cnc(N2CCOCC2)cn1

Procedure:
The title compound, white solid (114 mg, 87%), MS (ISP) m/z=522.4 [(M+H)+], mp 200.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O-:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.N12CCCN=C1CCCCC2.[CH3:28][C:29]([CH3:37])([CH2:35][CH3:36])[C:30]([O:32][CH2:33]I)=[O:31]>C(Cl)Cl>[NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([O:14][CH2:33][O:32][C:30](=[O:31])[C:29]([CH3:37])([CH3:28])[CH2:35][CH3:36])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12
Reactant: CCC(C)(C)C(=O)OCI
Reactant: COCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)OCOC(=O)C1=C(COC)CS[C@@H]2C(N)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1.46 g (6 mmol) of 7-amino-3-methoxymethyl-3-cephem-4-carboxylate were suspended in 30 ml of methylene chloride, and 0.92 ml (6 mmol) of 1,8-diazabicyclo-(5,4,0)-undec-7-ene (DBU) was added at 0° C. After 30 minutes, 1.66 g (6.5 mmol) of iodomethyl 2,2-dimethyl-butyrate (compare preparation example 4) were added, while cooling with ice, and the mixture was subsequently stirred at room temperature for 2 hours. The precipitate which had separated out was filtered off with suction and the crude product was chromatographed (SiO2 ; toluene/ethyl acetate=1:1). 1.2 g (53%) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.FC1C=C([N+]([O-])=O)C=CC=1N1C=C(C)N=N1>>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)nn1
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Yield: 44.7 %

Procedure:
3-Methyl-1,2,4-triazole (34.5 g, 0.416 mol) and 3,4-difluoronitrobenzene (46 ml, 0.416 mol) were reacted as described for Intermediate 22. Chromatography on silica gel with 5-50% ethyl acetate in hexanes and recrystallisation from ethyl acetate/hexanes gave the title compound as light yellow crystals (41.3 g), m.p. 113.8° C.-114.3° C. The other two isomers were also isolated.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:23])CC>C(Cl)Cl>[C:1]([C:3]1([F:23])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(C#N)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(F)(C#N)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-cyano-3-hydroxypiperidine-1-carboxylate (5.7 g, 25.1 mmol) in DCM (50 mL) cooled to −78° C., DAST (4.85 g, 30.1 mmol) was added drop-wise and the resulting solution stirred at −78° C. for 1 hour. The reaction was warmed to 0° C. and stirred for an additional 1 hour. The reaction mixture was diluted with DCM and quenched with sat. aq. NaHCO3. The combined extracts were dried by Na2SO4, filtered and concentrated in vacuo to afford crude title compound as a pale yellow oil 5.5 g. MS (m/z): 129 (M+H-Boc)+
Reaction SMILES: [CH3:1][N:2](C)[C:3](N(C)C)=[O:4].C(Cl)(Cl)=O.[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])C=[C:17]([Cl:22])[C:15]=1N>C1(C)C=CC=CC=1>[Cl:21][C:19]1[CH:20]=[C:14]([Cl:13])[CH:15]=[C:17]([Cl:22])[C:1]=1[N:2]=[C:3]=[O:4]
Reactant: CN(C)C(=O)N(C)C
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(Cl)cc(Cl)cc1Cl

Procedure:
1,1,3,3-tetramethylurea (1.52 ml, 12.75 mmoles) was added to a solution of phosgene (50.0 g, 505.43 mmoles) dissolved in toluene (150 ml). The resulting solution was stirred for 10 min. at which time 2,4,6-trichloroaniline (10.0 g, 50.90 mmoles) was added. The solution was heated to a temperature of 70°-80° C. for 1.5 hr. and then refluxed for 1.5 hr. while phosgene was bubbled in. After removing excess phosgene under reduced pressure, the clear upper layer solution was collected by decantation from the bottom oil layer, and the bottom oil layer was discarded. The solution was then evaporated to give a solid. The solid was dried under a vacuum to give a white solid (11.3 g, 99.3 pct). This product was recrystallized from dry carbon tetrachloride to give a colorless crystalline compound, m.p. 65°-66° C.; Infrared (IR): γ max 2,282 cm-1 (NCO); nuclear magnetic resonance (NMR) (chloroform-d): τ, 2.7 (2-proton singlet, H-3,5, aromatic protons).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24].[CH3:27][NH2:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:28][CH3:27])=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[F:20])[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24]
Reactant: O=C(O)c1cn(-c2cc(O)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.1 %

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and an aqueous solution (about 40%; 550 mg) of methylamine were added to pyridine (1,200 mg), and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (173 mg) as a pale brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25](O)=[O:26])[C:22]=1[CH3:23].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[C:19]([CH:28]([F:30])[F:29])=[N:20][N:21]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]2=3)=[O:26])[C:22]=1[CH3:23]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1c(Cl)c(C(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.10 mmol), 2-(4-chloro-3-difluoromethyl-5-methyl-pyrazol-1-yl)acetic acid (0.023 g, 0.10 mmol) and NEt3 (0.065 mL, 0.46 mmol) in DMF (0.6 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water and partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.032 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.44 (m, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 6.67 (d, J=54 Hz, 1H), 5.11 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.30 (s, 3H), 2.10 (m, 2H); MS: (ES) m/z calculated for C19H17ClF3N5O [M+H]+ 424.1, found 424.1.