Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:48])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:41]([NH:40][NH:39][C:37]([N:14]1[CH2:15][C@H:16]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=3)[N:22]=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:20]=2)[CH2:17][C@H:13]1[C:12]([NH:11][C@:6]1([C:4]([OH:5])=[O:3])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:48])=[O:38])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.6 %

Procedure:
To a solution compound 106 (0.0101 mmol) in THF-MeOH 2:3 (3 ml) was added 1M LiOH 10 equiv. The solution was kept at 50° C. for 18 hrs. After cooling to RT the sample was neutralized with HCl and concentrated to dryness. The crude material was dissolved in DCM (2 ml) and a solution of TFA: TES 1:1 (1 ml) was added. The mixture was stirred for 3 hrs at RT and then concentrated to dryness. The crude material was dissolved in MeOH and purified by Prep LCMS which gave the title compound (0.6 mg). Purity by HPLC>95%. M+H+622.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14](=O)[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][NH:25][NH2:26]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([C:14]3[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:25]([CH3:24])[N:26]=3)=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1sc(-c2cncc(F)c2)nc1C
Reactant: CNN
Solvent: CCO
Product: CCOC(=O)c1cc(-c2sc(-c3cncc(F)c3)nc2C)nn1C
Yield: 17.5 %

Procedure:
Ethyl 4-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-2,4-dioxobutanoate (6.9 g, 20.5 mmol) and methylhydrazine (0.65 g, 20.5 mmol) were heated in ethanol (250 ml) under reflux for 2 h. The product formed was filtered off with suction and the solvent of the filtrate was removed under reduced pressure. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate eluent). This gave a total of 1.24 g (17% of theory) of ethyl 3-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-5-carboxylate. As a by-product, 4.8 g (67% of theory) of ethyl 5-[2-(5-fluoropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]-1-methyl-1H-pyrazole-3-carboxylate were obtained.
Reaction SMILES: I[CH2:2][C:3]([NH2:5])=[O:4].Cl.Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:28][CH2:27]2)=[CH:13][CH:14]=1
Reactant: NC(=O)CI
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CN1CCC(Cc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 44.5 %

Procedure:
A mixture of 9.3 parts of 2-iodoacetamide, 20.0 parts of 3-[(4-fluorophenylmethyl]-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine dihydrochloride, 17.0 parts of sodium hydrogen carbonate and 200 parts of ethanol was stirred for 3 hours at at reflux temperature. The salts were filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone. The product was filtered off and dried in vacuo at 60° C., yielding 8.5 parts (44.5%) of 4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineacetamide; mp. 153.4° C. (148).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CCO>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Reactant: CN1CCNCC1
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCN3CCN(C)CC3)c2)c1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the suspension of 3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide (24 mg, 0.05 mmol) in EtOH (1 ml) was added 1-methylpiperazine (100 mg, 1 mmol) and the mixture was stirred at 80° C. overnight. The solvent was removed, residue was dissolved in EtOAc, washed by water, dried over Na2SO4. Solvent was removed, desired product was obtained as a colorless oil (18 mg, 72%). HPLC (4 minute gradient) tR1.33 min; MS m/z 503.29 [M+H]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23].[OH2:24]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:23][CH2:22][CH2:21][CH2:20][N:19]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:18][CH2:17][N:16]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:15][CH2:14][CH2:13][NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:24])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCNCCNCCCN
Reactant: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCN(CCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (460 g, 2.41 mole) in pyridine (1.5 1) at 0° C. was added a solution of 1,5,8,12-tetraazadodecane (100 g, 0.574 mole) in pyridine (100 ml) under a dry argon atmosphere, maintaining the temperature ≤50° C. The addition required 1 h. The mixture was allowed to cool to room temperature and was stirred for 2 h. H2O (3 l) was slowly added to the cooled (ice bath) mixture. The resulting brown solid was filtered and washed thoroughly with H2O. The crude product was purified by recrystallization from DMF-H2O to give 238 g (53% yield) of the product as a crude granular solid: mp 141-2° C.; 1H NMR (CDCl3) δ 1.78 (quint, J=6.2 Hz, 4 H), 2.41 (s, 6 H), 2.43 (s, 6 H), 2.97 (quart, J=6.6 Hz, 4 H), 3.15 (t, J=6.6 Hz, 4 H), 3.22 (s, 4 H), 5.31 (t, J=6.5 Hz, 2 H), 7.28 (d, J=8.3 Hz, 4 H), 7.32 (d, J=8.3 Hz, 4 H), 7.66 (d, J=8.3 Hz, 4 H), 7.72 (d, J=8.3 Hz, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9].S(=O)(=O)(O)O.O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:19])=[O:11])[S:5][C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: CO
Reactant: CCCc1sc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 36 h

Procedure:
To a solution of 4-bromo-5-propyl-2-thiophenecarboxylic acid (5.0 g, 20.07 mmol) in methanol (100 ml) was added sulfuric acid (5.35 ml, 100 mmol). The resulting solution stirred at 50° C. for 36 h. H2O (50 mL) was added the aqueous phase was washed several times with DCM. The combined organic fractions were washed with saturated NaHCO3, dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-propyl-2-thiophenecarboxylate (5.1 g, 18.61 mmol, 93° A yield) as a yellow oil: LCMS (ES) m/e 262, 264 (M, M+2)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8](OCC)=[O:9])=[CH:6][NH:5][N:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.CCOC(C)=O>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[C:7]([CH2:8][OH:9])=[CH:6][NH:5][N:4]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
Ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (5.00 g, 24 mmol) was dissolved in dry THF (50 mL). LiAlH4 (912 mg, 24.4 mmol) was added portionwise with care. The reaction mixture was stirred at RT for 3 h. MeOH (50 mL) was added dropwise and stirring continued for 30 min before concentrating in vacuo to give an off white solid. EtOAc (50 mL) was added and the solid was stirred for 30 min before filtering. The filtrate was concentrated and this procedure was repeated 4 times before the filtrates, after concentration in vacuo, were combined and purified by flash column chromatography (silica gel; eluent EtOAc:heptane, 4:1) to give the desired product (2.1 g, 12.6 mmol, 53%).
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[CH2:8][CH2:7][CH2:6][N+:5]=12.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])C#C.[C:17]1(C)C(C)=CC=CC=1>>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][C:4]2=[C:3]([C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=1
Reactant: [O-]c1on[n+]2c1CCC2
Reactant: Cc1ccccc1C
Reactant: C#CC(=O)OCC
Product: CCOC(=O)c1cnn2c1CCC2
Temperature: 125 °C

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[1,2-c]oxadiazol-7-ium-3-olate (355.4 mg, 2.82 mmol) and ethyl propiolate (0.87 mL, 8.46 mmol) in xylene (10 mL) in a round-bottom flask equipped with a condenser was heated to 125° C. overnight. The reaction mixture was concentrated in vacuo, adsorbed onto silica and purified by column chromatography (0-100% EtOAc in Heptane) to afford the title compound as a yellow oil (161 mg, 32%, more polar regioisomer). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.16 (t, J=7.3 Hz, 2H), 3.09 (t, J=7.4 Hz, 2H), 2.70-2.60 (m, 2H), 1.33 (t, J=7.1 Hz, 3H). LC-MS (ESI): m/z=181.1 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=3)=[N:14][C:13]=2[CH:12]=[C:11]([OH:26])[CH:10]=1.[O:27]1CCO[CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.O>[C:1]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[O:16][C:17]3[C:9]([Br:8])=[CH:10][C:11]([O:26][C:28](=[O:27])[CH3:29])=[CH:12][C:13]=3[N:14]=2)=[CH:19][C:20]=1[F:25])(=[O:3])[CH3:2]
Reactant: Oc1cc(Br)c2oc(-c3ccc(O)c(F)c3)nc2c1
Reactant: C1COCCO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Product: CC(=O)Oc1cc(Br)c2oc(-c3ccc(OC(C)=O)c(F)c3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56 %

Procedure:
Acetic anhydride (1.0 mL, 9.95 mmol) was added into a cold (0° C.) solution of 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol (1.24 g, 3.8 mmol), N,N-dimethylpyridin-4-amine (1.1 g, 9.18 mmol) and 1,4-dioxane (13 mL). The reaction mixture was allowed to warm up to room temperature and stirred for 20 h. Water (50 mL) was added to the reaction mixture extracted with EtOAc and dried over MgSO4. Evaporation and crystallization from EtOAc/hexane gave an off-white solid (0.87 g, 56% yield); MS m/e 408 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g of 4-(tert-butoxycarbonyl)aminopiperidine was dissolved in 50 ml of dichloromethane. After adding 1.6 ml of triethylamine and 1.2 ml of ethyl bromoacetate, the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 3.0 g of the title compound as pale yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)=[O:4].[Li+].[OH-].O.[CH3:17]O>>[CH3:17][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=2)[NH:10][N:9]=1
Reactant: CO
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1n[nH]c2ccc(C(=O)O)cc12
Yield: 95 %

Procedure:
A solution of 1H-indazole-5-carboxylic acid methyl ester (8 g, 42.1 mmol), LiOH (5.05 g, 211 mmol), in methanol (100 mL) and water (35 mL) was stirred at room temperature for 20 hours. At the end of this time the reaction mixture was concentrated, the aqueous residue was acidified (pH˜6) using 10% aqueous citric acid (150 mL) and filtered the solid to obtain the crude product, which was washed with water (3×30 ml) and dried well to give the title compound (7 g, 95%) as a pale brown solid. 1H NMR (CDCl3): δ 8.5 (s, 1H), 8.0-8.1 (d, 1H), 7.45-7.55 (d, 1H), 2.5-2.66 (s, 3H),
Reaction SMILES: [O:1]=[C:2]1[NH:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:3]21[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[CH3:27][N:17]1[CH2:16][CH:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:3]2([CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)C(=O)NCC2c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-oxo-9-phenyl-2,7-diazaspiro[4.4]nonane-2-carboxylate (commercially available) (1 g, 3.16 mmol)) in DMF (50 mL) was cooled to 0° C. and treated with sodium hydride (126 mg, 3.16 mmol)). The reaction was left to stir at 0° C. for 30 minutes and iodomethane (198 uL, 3.16 mmol) was added. The reaction mixture was left to warm to room temperature. After 3 h 30 mins, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to afford a yellow oil. Purification by chromatography on silica eluting with 0-10% MeOH in TBME afforded the following diastereomers:
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28]>>[F:31][C:26]([F:32])([C:27]([F:28])([F:29])[F:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)C(F)(F)CCCCCI
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-6,6,7,7,7-pentafluoroheptane prepared in Example 3, the same procedure as shown in Example 5 was repeated to give ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate.
Reaction SMILES: [C:1]([O:5]C(ON=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].[PH:19](=[O:22])([OH:21])[OH:20].C(C(C(C)C)C1NC1[C:29]1[N:33]=[CH:32][N:31]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1)(C)C.[CH2:57]([N:59]([CH2:62]C)[CH2:60][CH3:61])C>O1CCOCC1.O.O>[PH:19](=[O:20])([OH:22])[OH:21].[C:1]([O:5][C:62]([N:59]1[CH:60]([CH2:61][C:29]2[N:33]=[CH:32][N:31]([C:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:30]=2)[CH2:57]1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(C)C(C(C)C)C1NC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=[PH](O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC1Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON, 2.82 g) was added portionwise to a stirred solution of diisopropyl (2RS,3RS)-2,3-epimino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (2.76 g, prepared as described in Example 58) and triethylamine (2.17 ml) in dioxan-water (2:1, 75 ml). The mixture was stirred at room temperature for seven hours, allowed to stand for a further three days, diluted with water (50 ml) and extracted with chloroform (3×50 ml). The organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified using HPLC on silica, with ethyl acetate as eluant, to give diisopropyl (2RS,3RS)-2,3(N-tert-butoxycarbonylepimino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.22 g, m.p. 30-31° C.). NMR (CDCl3): δ 1.25(12H,m), 1.33(9H,s), 1.70(1H,m), 2.23(1H,m), 3.35(1H,m), 3.53(1H,d), 4.68(2H,m), 7.1-7.4(15H,m), 7.85(1H,s). IR: 1724 cm-1.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]CC3C=CC=CC=3)=O)[N:8]=2)CCCCC1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=C=O)[CH:32]=1>C(O)=O.CO.[Pd].O1CCCC1>[CH2:12]1[CH2:17][CH:16]([C:9]2([NH:20][C:21]([NH:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:15][CH2:14][CH2:13]1
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reactant: Cc1cccc(N=C=O)c1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2(C3CCCCC3)N=Cc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
5-Cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.34 g, 0.84 mmol) was dissolved in formic acid/methanol (50 ml of a 4.5% (v/v) solution), and added, over 5 min, to a stirred suspension of 10% palladium on carbon (100 mg, 30% (w/w)) in formic acid/methanol (10 ml of a 4.5% (v/v)) solution). After 45 min the catalyst was filtered off and washed sequentially with methanol and acetone. The flitrate was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and 10% sodium carbonate solution (100 ml). The organic phase was separated, dried (Na2SO4) and evaporated to give a clear oil, which was used without further purification. A solution of the crude amine (167 mg, 0.61 mmol) in anhydrous tetrahydrofuran (10 ml) was treated with m-tolylisocyanate (79 μl, 0.61 mmol) dropwise over 5 min. After stirring at ambient temperature for 1.5 h the solvent was removed under reduced pressure to leave a white solid. The solid was recrystallised from methanol to give the urea (70 mg, 28%) as a white solid. mp 207°-209° C. 1H NMR (360 MHz, CDCl3) δ 1.07-2.04 (10H, m), 2.29 (3H, s), 2.79 (1H, m), 3.40 (3H, m), 5.40 (1H, d, J=8 Hz), 6.71 (1H, d, J=8 Hz), 6.84 (2H, m), 7.07-7.30 (5H, m), 7.55 (2H, m).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH2:25][CH3:26])[CH3:24]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][O:21][N:22]=[C:23]([CH3:24])[CH2:25][CH3:26])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCC(C)=NOCCO
Product: CCC(C)=NOCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-butanone (2-hydroxyethyl) oxime, there is obtained 2-[(1-methylpropylideneamino)oxy]-ethyl 5,7- dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 351 (23), 281 (5), 237 (57), 194 (100), 114 (100), 70 (12);
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13]Cl.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:11][CH2:12][CH2:13][O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[CH3:16]
Reactant: CCNCC
Reactant: N#Cc1cccc(O)c1
Reactant: ClCCCBr
Product: CCN(CC)CCCOc1cccc(C#N)c1
Yield: 54 %

Procedure:
According to a similar manner as that in Reference Example 78 except that 3-cyanophenol, 1-bromo-3-chloropropane, and diethylamine were used, 3-[3-(diethylamino)propoxy]benzonitrile (54%) was obtained as a crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].C([N:15](CC)[CH:16]([CH3:18])C)(C)C.Cl.C(#[N:24])C>ClCCl>[C:16]([CH2:18][NH:24][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])#[N:15]
Reactant: CC#N
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccc(F)cc1O
Agent: Cl
Solvent: ClCCl
Product: N#CCNC(=O)c1ccc(F)cc1O
Temperature: 35 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
A solution of 4-fluorosalicylic acid chloride (Example 1, 10 g, 57.3 mmol) in dichloromethane (114 mL) was treated with N,N-diisopropylethyl amine (25 mL, 143 mmol) and acetonitrile hydrochloride (7.95 g, 85.9 mmol). After stirring at 35° C. for 24 h, the solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed successively with 2 N HCl and saturated aq NaCl. The resulting solution was dried over MgSO4, filtered and concentrated. The resulting solid was suspended in dichloromethane, filtered and rinsed with heptane to give N-cyanomethyl-4-fluoro-2-hydroxy-benzamide (7.20 g, 65%): 1H NMR (DMSO-d6 300 MHz) δ 12.16 (br s, 1 H), 9.17 (t, J=5.3 Hz, 1 H), 7.88 (dd, J, =8.7 Hz, J2=6.3 Hz, 1 H), 6.81–6.73 (m, 2 H), 4.32 (d, J=5.7 Hz, 2 H).