Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C(#N)C>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:9][C@H:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: COC(=O)CBr
Reactant: C[C@H](N)c1ccccc1
Solvent: CC#N
Product: COC(=O)CN[C@@H](C)c1ccccc1

Procedure:
Scheme 1 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 1, benzyl N-((1S)-1-(1H-4-imidazolylmethyl)-2-2-[(2-methyl-2-phenylpropyl)amino]-2-oxoethyl[(1S)-1-phenylethyl]amino-2-oxoethyl)carbamate. Reaction of (S)-α-methylbenzylamine with methyl bromoacetate was carried out in acetonitrile in the presence of dilsopropylethylamine as the base to give methyl-2-[(1S)-1-phenylethyl]aminoacetate. Methyl-2-[(1S)-1-phenylethyl]aminoacetate was then coupled to Cbz-His(trityl) in methylene chloride with HATU as coupling agent, and diisopropylethylamine as the base. The resulting product was saponified using lithium hydroxide at 0° C., followed by coupling with β,β-dimethylphenethylamine in methylene chloride, with HBTU as coupling agent, and diisopropylethylamine as the base. The trityl group was removed by treatment with 50% TFA in methylene chloride. The β,β-dimethylphenethylamine was prepared from benzyl cyanide, which was treated with 2 equivalents of sodium hydride in tetrahydrofuran (THF) and 2 equivalents of methyl iodide in THF followed by hydrogenation (H2, Pd/C, ammonia) and treatment with HCl to give the HCl salt.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:33])[F:34])[CH:26]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2ccc(Cl)c(C(F)(F)F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(Cl)c(C(F)(F)F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (30 mg, 0.167 mmol) with 2-bromo-N-[4-(4-chloro-3-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide (80 mg, 0.200 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 38 mg of the product as an off-white solid; 1H NMR (δ ppm, CDCl3, 300 MHz) 3.17 (s, 3H), 3.39 (s, 3H), 5.32 (s, 2H), 6.22 (s, 1H), 7.35 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.94 (s, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 12.74 (br s, 1H). APCI-MS (m/z) 498.14 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29](O)=[O:30])[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[NH2:35][CH2:36][C:37]#[N:38]>>[C:36]([CH2:37][NH:38][C:29](=[O:30])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32])#[N:35]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: N#CCN
Product: CC(C(=O)NCC#N)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and aminoacetonitrile (Aldrich and Cat. No. A5802). LCMS (M+H)+: m/z=512.2.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[NH2:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[C:23]=1[C:24]#[N:25].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.[Na].CCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[NH:21][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)#[N:25]
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Reactant: N#Cc1c(N)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](Nc3ccccc3C#N)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
To a mixture of of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg, 1.9 mmol), 2-amino-6-chloro-benzonitrile (118 mg, 1.0 mmol), and glacial acetic acid (0.36 mL, 6.0 mmol) in 1,2-dichloroethane (5 mL), sodium triacethoxyborohydride solid (590 mg, 2.8 mmol) was added and the reaction mixture stirred under nitrogen at room temperature for 24 hours. Sodium bicarbonate was added until pH 8, followed by addition of ethyl acetate. The phases were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were dried with anhydrous sodium sulfate and concentrated in vacuo. Flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 123 mg (32% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]1[CH2:26][S:23](=[O:25])(=[O:24])[O:22][CH2:21]1>O1CCOCC1>[CH2:12]([C@H:10]([NH:11][CH2:21][CH2:20][CH2:26][S:23]([OH:25])(=[O:24])=[O:22])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of L-Phenylalanine benzylester (1.8 g, 6.8 mmol) in 1,4-dioxane (10 mL) was added 1,3-propanesultone (708 mg, 6.5 mmol). The solution was stirred at reflux. After 1 hour, 20 mL of 1,4-dioxane was added to allow for good stiffing. The reaction was stirred at reflux for an additional 1 hour. It was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL). The product was suspended 80% Acetone/EtOH. The suspension was stirred at reflux for 30 seconds. The solid was filtered and dried in the vacuum oven (50° C.) affording the title compound (1.14 g, 46%). 1H NMR (DMSO, 500 MHz) δ ppm 7.27 (m, 6H), 7.12 (m, 4H), 5.05 (dd, 2H, J=12.3 Hz), 4.49 (m, 1H). 3.29 (m, 1H), 3.00 (m, 1H), 2.98 (m, 1H), 2.61 (t, 2H, J=6.5 Hz), 1.97 (m, 2H). 13C (DMSO, 125 MHz) δ ppm 168.88, 135.21, 134.90, 130.00, 129.31, 129.07, 128.01, 67.98, 60.50, 49.77, 46.72, 35.87, 22.43. [α]D=+4.8° (c=0.00073 in water), ES-MS 378 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1C=CC=CC=1.O>[Cl:8][C:7]1[C:2]([O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:24])[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][O:20]3)=[O:18])=[CH:25][CH:26]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: CC(Oc1ccc(O)cc1)C(=O)N1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)N1CCCO1
Temperature: 120 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 2,3,5-trichloropyridine (18.3 g), N-[(±)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 120° C. for 4 hours. To the reaction mixture, after cooling, were added water and benzene whereby to form two layers. The organic layer so separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(±)-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionyl]isoxazolidine (31.4 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 105.5°-107.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])[N:10]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:15]([NH:14][C:12]([NH:11][C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[CH:7]=[CH:6][N:5]2[N:8]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(Br)ccn2n1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)ccn2n1

Procedure:
1-(7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-ethyl-urea (4) (80 mg, 0.28 mmol) was dissolved in dioxane (2 mL), to which was added 2 M Na2CO3 (0.30 mL) and 3-pyridinylboronic acid (38 mg, 0.31 mmol). Pd(dppf)Cl2 (13 mg) was added last, and the mixture heated under nitrogen at reflux for 1.5 h. The reaction solvent was removed under reduced pressure and the residue filtered through a plug of silica gel (5% MeOH/CH2Cl2 as eluant) to give a solid, which was triturated with Et2O. 1-Ethyl-3-(7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-urea was isolated mp. 230-233° C.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH2:30])[CH2:25]1)(=[O:23])=[O:22].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8](=[O:10])[NH:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[F:14])(=[O:22])=[O:23])[CH2:25]1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: N[C@@H]1CCCN(S(=O)(=O)c2ccccc2F)C1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCN(S(=O)(=O)c2ccccc2F)C1)c1ccc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-borono-2-fluorobenzoic acid (160 mg, 0.870 mmol), (R)-1-(2-fluorophenylsulfonyl)piperidin-3-amine (225 mg, 0.870 mmol), and DIEA (456 μL, 2.61 mmol) in THF (1450 μL) and DMF (1450 μL) was added HOAt (237 mg, 1.740 mmol) and EDC (417 mg, 2.175 mmol). After 3 h stirring at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was washed with NaHCO3, water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding (R)-3-fluoro-4-(1-(2-fluorophenylsulfonyl)piperidin-3-ylcarbamoyl)phenylboronic acid, which was used in next step reaction without purification. LCMS (m/z): 425.2 (MH+), 0.72 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:22][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1ccccc1N
Product: COc1ccc(S(=O)(=O)Nc2ccccc2Nc2ccccc2)cc1OC

Procedure:
The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl chloride (0.01 mol) and o-phenylene diamine by general Method C. It was purified by recrystallization from EtOH (0.65 g, 21%). EI-MS m/z 309 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:15]([CH2:16][CH3:17])=[C:14]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)[C:13]([CH2:27][CH3:28])=[C:12]([CH2:29][NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[N:32]=3)[C:11]=2[CH2:38][CH3:39])[CH:5]=[CH:4][CH:3]=1.CO[CH:42](OC)[CH2:43][C:44](=O)[CH3:45].OP(O)(O)=O>O>[CH3:42][C:43]1[N:37]=[C:33]2[C:34]([CH:35]=[CH:36][C:31]([NH:30][CH2:29][C:12]3[C:13]([CH2:27][CH3:28])=[C:14]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]5[C:22](=[N:26][C:4]([CH3:5])=[CH:3][CH:2]=5)[N:21]=4)[C:15]([CH2:16][CH3:17])=[C:10]([CH2:9][NH:8][C:6]4[CH:5]=[CH:4][C:3]5[C:2](=[N:1][C:11]([CH3:12])=[CH:10][CH:9]=5)[N:7]=4)[C:11]=3[CH2:38][CH3:39])=[N:32]2)=[CH:45][CH:44]=1
Reactant: COC(CC(C)=O)OC
Reactant: CCc1c(CNc2cccc(N)n2)c(CC)c(CNc2cccc(N)n2)c(CC)c1CNc1cccc(N)n1
Agent: O=P(O)(O)O
Solvent: O
Product: CCc1c(CNc2ccc3ccc(C)nc3n2)c(CC)c(CNc2ccc3ccc(C)nc3n2)c(CC)c1CNc1ccc2ccc(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
1,3,5-Tris[(6-amino-pyridin-2-yl)aminomethyl]-2,4,6-triethylbenzene (2b) (4.7 g, 8.9 mmol), 4,4-dimethoxy-2-butanone (26.3 mmol), and H3PO4 (50 mL) were held at 90° for 4 h and then stirred at room temperature for 2 h. The reaction mixture was poured into water (300 mL), neutralized, and extracted several times with chloroform. The collected organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified several times by column chromatography (silica gel, CHCl3/CH3OH, 7:1 to 2:1 v/v). Yield 23%. M.p. 207-208° C. 1H-NMR (400 MHz, CDCl3): δ=1.23 (t, 9H, J=7.5 Hz), 2.69 (s, 9H), 2.82 (q, 6H, J=7.5 Hz), 4.74 (br s, 3H), 4.82 (d, 3H, J=3.0 Hz), 6.58 (d, 3H, J=8.6 Hz), 7.04 (d, 3H, J=8.1 Hz), 7.72 (d, 3H, J=8.6 Hz), 7.79 (d, 3H, J=8.1 Hz). 13C NMR (100 MHz, CDCl3): δ=16.9, 23.1, 25.3, 40.6, 112.1, 115.2, 118.3, 132.9, 136.2, 136.9, 144.5, 156.7, 158.4, 161.3. HR-MS calcd for C42H44N6: 674.3719; found: 674.3714. Rf=0.89 (CHCl3/CH3OH 2:1 v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20](O)=[O:21])[S:17][C:13]=2[N:12]2[C:23]([CH3:26])=[N:24][N:25]=[C:11]2[CH:10]([CH3:27])[N:9]=1.ON1C2C=CC=CC=2N=N1.[CH2:38]([NH:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH3:40].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:38]([N:41]([CH2:42][CH2:43][CH3:44])[C:20](=[O:21])[CH2:19][CH2:18][C:16]1[S:17][C:13]2[N:12]3[C:23]([CH3:26])=[N:24][N:25]=[C:11]3[CH:10]([CH3:27])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]=2[CH:15]=1)[CH2:39][CH3:40]
Reactant: CCCNCCC
Reactant: Cc1nnc2n1-c1sc(CCC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)CCc1cc2c(s1)-n1c(C)nnc1C(C)N=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.1 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.4 ml of dipropylamine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 4 hours and furthermore stirred at room temperature for 16 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 50 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is subjected to chromatography on silica gel and then eluted with a mixture of chloroform-methanol (100:1 to 100:3). The eluate of the objective fraction is concentrated under reduced pressure to give 1 g of 3-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]propionic acid N,N-dipropylamide as pale yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24](O)=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([NH:34][C@H:35]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]5)=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1
Reactant: N[C@H]1CC[C@H](O)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)N[C@H]6CC[C@H](O)CC6)nc5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid and trans-4-aminocyclohexanol (Acros Organics, Cat. 34668). LCMS (M+H)+: m/z=543.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:18][CH:17]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
After a mixture of ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetate (618 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetic acid (502 mg, yield: 86%). This was, recrystallized from ethanol-hexane. Melting point: 125–126° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][C:8]([CH3:10])=O.[NH2:11][O:12][CH:13]1[CH2:16][N:15]([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1>C(O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]2[CH2:16][CH:13]([O:12]/[N:11]=[C:8](\[CH3:10])/[CH2:7][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:14]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)Cc1ncccn1
Reactant: NOC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Product: C/C(Cc1ncccn1)=N\OC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 100.7 %

Procedure:
A solution of 1-pyrimidin-2-ylacetone (27 mg, 0.2 mmol; which may be prepared as described in Step 1) and 3-(aminooxy)-1-(diphenylmethyl)azetidine (51 mg, 0.2 mmol; which may be prepared as described in Step 3) in ethanol (2 mL) under nitrogen was stirred at 80° C. overnight. The crude mixture was concentrated to dryness to give the title compound (75 mg, quantitative) as a brown oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.CCCCCC>CCOCC>[F:14][C:7]([F:6])([F:13])[C:8]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[O:10]
Reactant: CNCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCOCC
Solvent: CCCCCC
Product: CNCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
N-Methyl ethylenediamine (15 g, 202.3 mmol) was added dropwise to a stirred solution of ethyl trifluoroacetate (28.7 g, 204.34 mmol) in dry Et2O (50 mL) at 0° C. The resulting solution was stirred at room temperature for 2 hours. Hexane (75 mL) was added and the solution was left at −20° C. for 16 hours to produce a white precipitate which was removed by filtration, washed with Et2O (100 mL) and dried in vacuo for 3 hours to afford the title compound (29.4 g, 85%). 1H NMR (300 MHz, CDCl3) δ 3.42 (t, J=5.8 Hz, 2H), 2.80 (t, J=5.9 Hz, 2H), 2.43 (s, 3H); mass spectrum (API-TIS) 171 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][CH2:23][C:24](=O)[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C@@H:18]([C:38]([O:40][CH3:41])=[O:39])[CH2:17]1>N1C=CC=CC=1>[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[CH:7][C:6]=1[C:13]#[C:14][CH2:15][N:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][CH2:23][C:24](=[N:2][OH:3])[C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[C@@H:18]([C:38]([O:40][CH3:41])=[O:39])[CH2:17]1
Reactant: NO
Reactant: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2F)CC[C@H]1CCC(=NO)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
0.834 g of hydroxylamine hydrochloride is added, with stirring and under an inert atmosphere, to a mixture of 3.5 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3oxo-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 35 cm3 of pyridine at a temperature in the region of 20° C. The mixture is stirred for 5 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue is taken up in 300 cm3 of ethyl acetate and 100 cm3 of water. After standing for 16 hours, the mixture is extracted with 3 times 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 3 times 100 cm3 of water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. 3.35 g of methyl (3R,4R)-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]-4-[3-hydroxyimino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate are obtained.
Reaction SMILES: C([NH:9][C:10]([NH:12][C@H:13]1[CH2:18][C@H:17]2[CH2:19][C@@H:14]1[CH2:15][C:16]2([F:21])[F:20])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO.O>[F:21][C:16]1([F:20])[CH2:15][C@H:14]2[CH2:19][C@@H:17]1[CH2:18][C@@H:13]2[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)N[C@H]1C[C@H]2C[C@@H]1CC2(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=S)N[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-benzoyl-3-((1R,2S,4R)-5,5-difluorobicyclo-[2.2.1]heptan-2-yl)thiourea (˜1.80 mmol) and potassium carbonate (1.49 g, 10.8 mmol) in methanol (5.0 mL), water (2.5 mL), and tetrahydrofuran (2.5 mL) was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was washed with brine, conc. in vacuo, and purified by flash column chromatography (0 to 65% of ethyl acetate in hexanes) to give the title compound as a white solid. MS m/z: 207.0 (M+H)+.