Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: N#Cc1c(F)ccc(N)c1Nc1cncc(F)c1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ((S)-1-carbamoyl-ethyl)carbamic acid tert-butyl ester (1.81 g, 9.63 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (1.54 g, 8.08 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). 3-Amino-6-fluoro-2-(5-fluoropyridin-3-ylamino)benzonitrile (948 mg, 3.86 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.20 min, [M+H-tBu]+=344, 100%, [M+H]+=400, 10%.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3].C1(O)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.Cl[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][C:37]=1[F:42].ClC1C=CN=CC=1F.C(=O)(O)[O-].[Na+]>ClCCl>[F:42][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][C:36]=1[CH2:3][CH2:2][CH2:1][NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14]
Reactant: Fc1cnccc1Cl
Reactant: CCCNN1C(=O)Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: Oc1ccccc1
Solvent: O
Product: O=C1Cc2ccccc2N1NCCCc1ccncc1F
Temperature: 150 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution consisting of 1,3-dihydro-1-propylamino-2H-indol-2-one (5.06 g), phenol (13.2 g) and p-toluenesulfonic acid hydrate (0.25 g), heated at 150° C., was added 4-chloro-3-fluoropyridine hydrochloride (5.37 g). Heating was continued at 150° C. for 10.75 hours at which time additional 4-chloro-3-fluoropyridine (2.05 g) was added and heating continued an additional 6.5 hours. Upon cooling to room temperature, the reaction mixture was dissolved in dichloromethane and dilute aqueous sodium bicarbonate. The layers were separated and the organic layer extracted with dilute aqueous sodium bicarbonate (2×). The combined aqueous layers were back-extracted with dichloromethane and ether. The combined organic layers were washed with brine, dried (K2CO3), filtered, and concentrated. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) and another column (silica gel, EtOAc) afforded the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.CN.[CH2:20]([N:22](CC)CC)C.[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([NH:22][CH3:20])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CN
Solvent: CCO
Product: CNC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
A mixture of 4,4′-difluorobenzophenone (2.18 g, 10.0 mmol) in anhydrous ethanol (15 ml) was treated successively with titanium (IV) isopropoxide (5.9 ml, 20.0 mmol), methylamine hydrochloride (1.35 g, 20.0 mmol) and triethylamine (2.8 ml, 20.0 mmol).The resulting mixture was stirred at 22° C. for 18 h and then treated with sodium borohydride (0.57 g, 15.0 mmol). After 6 h at 22° C., the reaction mixture was quenched by the addition of 2N aqueous ammonia (30 ml) and the resulting precipitate was filtered and washed with dichloromethane. The organic layer was collected and extracted with 1N hydrochloric acid. The aqueous phase was then treated with 2N aqueous sodium hydroxide (pH 11) and extracted twice with dichloromethane. The combined extracts were dried (magnesium sulfate) and concentrated. Distillation of the residue in vacuo gave 2.12 g (91%) of the title amine as a clear oil: bp 85-90° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.40 (3H, s, NCH3), 4.68 (1H, s, CH benzhydryl), 7.0 (4H, m, aromatics), 7.35 (4H, m, aromatics). Anal. Calcd for C14H13F2N: C, 72.09; H, 5.62; N, 6.0. Found: C, 71.76; H, 5.76; N, 5.84.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:31][C@H:32]3[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]3)=[O:19])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(N[C@H]1CC[C@H](O)CC1)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with (trans)-4-amino-cyclohexanol (CAS Reg. No. 27489-62-9) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=466.4 [M+H+].
Reaction SMILES: [C:1]([CH2:5][C:6](OCC)=[O:7])(=O)[CH2:2][CH3:3].CS(O)(=O)=O.[CH2:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[NH:23])[CH2:17][CH3:18].[OH-].[Na+]>O.C(O)C>[CH2:2]([C:1]1[CH:5]=[C:6]([OH:7])[N:24]=[C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:16][CH2:17][CH3:18])[N:23]=1)[CH3:3]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCCOc1ccccc1C(=N)N
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(O)cc(CC)n1

Procedure:
A solution of ethyl propionylacetate (0.79 g), 2-propoxybenzamidine methanesulphonate (1.45 g) and sodium hydroxide (0.60 g) in water (5 ml) and ethanol (5 ml) was stirred at ambient temperature for 22 hours. Most of the solvent was removed under reduced pressure and water (20 ml) was added. The mixture was acidified to pH 2 with concentrated hydrochloric acid and then extracted with chloroform (3×30 ml). the combined extracts were washed with dilute acetic acid, dried (magnesium sulphate) and evaporated under reduced pressure to yield a residue which was recrystallised twice from ether to yield the title compound, 373 mg, m.p. 97°-98.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH2:11]([Mg]Br)[CH3:12]>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[CH2:11][CH3:12]
Reactant: CC[Mg]Br
Reactant: Nc1cccc(Cl)c1C=O
Solvent: CCOC(C)=O
Product: CCC(O)c1c(N)cccc1Cl
Yield: 48 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (0.30 g, 1.9 mmol) and ethyl magnesium bromide (3 M in diethyl ether, 1.3 mL) to afford 0.17 g (48%) of (±)-1-(2-amino-6-chlorophenyl)propan-1-ol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([OH:22])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[CH:9][CH:8]=2)=[N:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>N1C=CC=CC=1>[C:24]([O:22][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:23])([CH3:1])[N:3]=2)=[CH:12][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccccc1C(OC(C)=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[4-(4,4-Dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl alcohol (100 mg) was dissolved in pyridine (0.4 ml), added with acetic anhydride (0.25 ml) with ice cooling and stirred at room temperature for 4 hours. After the reaction mixture was added with methanol (0.25 ml) with ice cooling and stirred at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to obtain 1-[4-(4,4-dimethyloxazolin-2-yl)phenyl]-1-(2-methoxyphenyl)methyl acetate.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]([F:48])([F:47])[C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([C:34]([F:47])([F:48])[F:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 64.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (597 mg, 1.19 mmol, 65%) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(=O)([O-])O.[Na+].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]3)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: NC1CCCC(C(=O)O)C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCC(C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
3-Aminocyclohexanecarboxylic acid (10 g, 70 mmol) was added to a solution of sodium hydrogen carbonate (7.6 g, 91 mmol) in water (100 mL). A solution of 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy-2,5-pyrrolidinedione (Fmoc-OSu; 28.3 g, 84 mmol) in tetrahydrofuran (200 mL) was added. The solution was stirred at room temperature overnight and then poured into 3 M HCl (200 mL). The mixture was extracted with ethyl acetate (100 mL then 50 mL) and the combined organic layers were washed with saturated brine (3×100 mL), dried (Na2SO4), filtered, and concentrated to approximately 200 mL. Crystallization occurred on concentration. The mixture was allowed to stand overnight, then the solid was filtered off, washed with ethyl acetate and dried in a vacuum oven at 55° C. to give 3-[N-[(9H-fluoren-9-ylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid (14.66, 57%) as a white solid.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.C(O)(=O)C.[OH-].[K+]>O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-n2cccc2)c([N+](=O)[O-])c1

Procedure:
100 g (0.75 mole) of 2,5-dimethoxytetrahydrofuran are added to a solution of 84.1 g (0.5 mole) of 4-methoxy-2-nitroaniline in 500 ml. of glacial acetic acid. The solution is refluxed for 30 minutes, poured into 2500 ml. of water, and neutralized with potassium hydroxide. A solid precipitates and is filtered, dried, and recrystallized from ether to give 1-(4-methoxy-2-nitrophenyl)pyrrole, m.p. 75.5°-76.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]1[N:31]=[C:32]([CH2:35][CH2:36][NH2:37])[S:33][CH:34]=1>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:32]2[S:33][CH:34]=[C:30]([CH3:29])[N:31]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1csc(CCN)n1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1csc(CCNCc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(4-methylthiazol-2-yl)ethanamine were reacted to give 321. [M+H]+ 504.6.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:17]=1)=[O:15])[CH3:12]>CC(=O)OCC>[CH2:11]([O:13][C:14]([C:16]1[C:21]([O:22][CH2:23][CH3:24])=[C:20]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[N:19]=[C:18]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])=[CH:35][CH:36]=2)[N:17]=1)=[O:15])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 80 %

Procedure:
Phenyl chloroformate (0.95 ml, 1.5 eq.) was added to a stirred solution of 2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (1.15 g, 1 eq.) in EA (20 ml) and NaHCO3(sat) (20 ml). The mixture was reacted at room temperature for 2 hrs. The reaction mixture was diluted with NaHCO3(sat) and extracted with EA. The organic solution was washed with brine, was dried (MgSO4), filtered and concentrated under reduced pressure to give a crude carbamate (1.21 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=2[C:25]([N:27]([CH3:31])[CH2:28][C:29]#[CH:30])=[O:26])[C:19]([Cl:36])=[CH:18][N:17]=1>>[Cl:36][C:19]1[C:20]([NH:22][C:23]2[CH:35]=[CH:34][CH:33]=[CH:32][C:24]=2[C:25]([N:27]([CH3:31])[CH2:28][C:29]#[CH:30])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: C#CCN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Product: C#CCN(C)C(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-N-prop-2-ynyl-benzamide was prepared from 7-amino-1-methyl-1,3,4,5-tetrahydro-1-benzazepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow thin film (19 mg, 15%). LCMS (m/e) 489 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.99 (bs, 1H), 8.35 (d, 1H, J=8.2 Hz), 8.11 (s, 1H), 7.61-7.32 (m, 4H), 7.23-7.15 (m, 1H), 7.09 (d, 1H, J=8.2 Hz), 6.97 (s, 1H), 4.51-3.99 (m, 2H), 3.35 (s, 3H), 3.18 (bs, 3H), 2.72-2.61 (m, 2H), 2.42-2.29 (m, 3H), 2.23-2.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OC)cc1[N+](=O)[O-]

Procedure:
A mixture of 4-methoxy-2-nitrophenol 6 (1.69 g, 0.01 mol), potassium carbonate (2.76 g, 0.02 mol) and ethyl bromoacetate 7 (1.1 mL, 0.01 mol) in 20 mL anhydrous acetone was refluxed for overnight (12 h). The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was evaporated, the residue was diluted with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give ethyl 2-(4-methoxy-2-nitrophenoxy)acetate 8 which was purified by silica gel column chromatography using 0-50% gradient of hexane and ethyl acetate. Yellow solid (2.18 g, 85%). 1H NMR (400 MHz, CDCl3): δ 1.28 (t, J=7.2 Hz, 3H); 3.82 (s, 3H); 4.25 (q, J=7.2 Hz, 2H); 4.70 (s, 2H); 7.01 (d, J=9.2 Hz, 1H); 7.08 (dd, J=3.2, 9.2 Hz, 1H); 7.40 (d, J=2.8 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[Cl-].[NH4+].[N-:39]=[N+:40]=[N-:41].[Na+].Cl>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:41][N:40]=[N:39][N:35]=3)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: N#Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3-c3nnn[nH]3)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 120 °C
Reaction time: 12 h
Yield: 15.8 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-cyanophenyl)piperidin-3-ol (700 mg, 1.43 mmol) obtained in Step 1 in 20 ml of dimethylformamide, were added ammonium chloride (769 mg) and sodium azide (934 mg). The reaction mixture was stirred for about 12 hours at 120° C. 20 ml of water was added to the reaction mixture, which was then acidified with a concentrated hydrochloride solution. The resulting solid was filtered and dissolved in dichloromethane. The resulting residue was purified with column chromatography to give 120 mg of the titled compound.
Reaction SMILES: [CH2:1]([NH:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)[CH2:2][CH2:3][CH2:4][CH3:5].CCOCC>Br.C(O)(=O)C>[CH2:1]([NH:6][C:7](=[O:23])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCNC(=O)[C@@H]1CCCN1
Reaction time: 1 h
Yield: 117.5 %

Procedure:
5 g of N-benzyloxycarbonyl-L-proline n-pentylamide were dissolved in 20 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred for 1 hour. 150 ml of dry ether were then added. A clear oil precipitated out and was allowed to settle. The ether was decanted off and the oil washed with a further 100 ml of dry ether. Evaporation yielded 3.4 g (82%) of L-proline n-pentylamide in the form of an oil.
Reaction SMILES: C([NH:8][C:9](=[O:27])[C@H:10]([CH:24]([CH3:26])[CH3:25])[NH:11][C:12](=[O:23])[CH:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][C:15]([NH:17][OH:18])=[O:16])C1C=CC=CC=1.FC(F)(F)C1C=CC(CNC(=O)[C@H](C(C)C)NC(=O)C(CC(C)C)CC(NO)=O)=CC=1.C(NC(=O)[C@H](C(C)C)NC(=O)C(CC(C)C)CC(NO)=O)CC1C=CC=CC=1.C(N(C(=O)C(CC(C)C)CC(NO)=O)[C@H](C(O)=O)CCCC)C1C=CC=CC=1.C(NC(=O)[C@H](CCCCN)NC(=O)C(CC(C)C)CC(NO)=O)C1C=CC=CC=1.C(NC(=O)[C@H](CCSC)NC(=O)C(CC(C)C)CC(NO)=O)C1C=CC=CC=1>>[OH:18][NH:17][C:15](=[O:16])[CH2:14][CH:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([NH:11][C@H:10]([C:9]([NH2:8])=[O:27])[CH:24]([CH3:25])[CH3:26])=[O:23]
Reactant: CC(C)CC(CC(=O)NO)C(=O)N[C@H](C(=O)NCc1ccccc1)C(C)C
Agent: CC(C)CC(CC(=O)NO)C(=O)N[C@@H](CCCCN)C(=O)NCc1ccccc1
Agent: CC(C)CC(CC(=O)NO)C(=O)N[C@H](C(=O)NCCc1ccccc1)C(C)C
Agent: CC(C)CC(CC(=O)NO)C(=O)N[C@H](C(=O)NCc1ccc(C(F)(F)F)cc1)C(C)C
Product: CC(C)CC(CC(=O)NO)C(=O)N[C@H](C(N)=O)C(C)C

Procedure:
##STR4## N-benzyl-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-valinamide: ##STR5##N-(4-trifluoromethylbenzyl)-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-valinamide: ##STR6## N-phenethyl-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-valinamide: ##STR7## N-benzyl-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-norleucine: ##STR8## N-benzyl-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-lysinamide: ##STR9## N-benzyl-Nα-(N-hydroxy-2-isobutylsuccinamoyl)-L-methioninamide: ##STR10##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH2:14]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCCCCCNCCCCCC
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)C(CC)C(=O)c1ccc(Br)cc1

Procedure:
To a solution of 5.00 g of 4'-bromo-4-chlorobutyrophenone in 3 ml of toluene was added 11.1 ml of di-n-hexylamine and heated under reflux for 3 hours. After diluting with toluene, the reaction mixture was extracted with a 2N aqueous solution of hydrochloric acid. The extract was neutralized with a mass of sodium hydroxide and extracted with methylene chloride. Next, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, thereby giving 4.88 g of crude 4'-bromo-di-n-hexylaminobutyrophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of mixture of cis isomer of methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (4 g, 9.09 mmol) in acetonitrile (50 mL) was added cesium carbonate (5.9 g, 18.18 mmol) and methyl iodide (6.45 g, 45.45 mmol). The resulting reaction mixture was heated at 80° C. for 7 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving desired compound (1.4 g, 34%).