Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A solution of (3-benzylamino-phenyl)-carbamic acid tert-butyl ester (1.27 g, 4.3 mmol), benzenesulphonyl chloride (1.79 ml, 14 mmol) and pyridine (1.24 ml, 15.3 mmol) in dry dichloromethane (30 ml) were heated to reflux for 15 hrs. The reaction mixture was cooled to room temperature and quenched with water and extracted with dichloromethane (3×75 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with dichloromethane to afford the title compound as a brown oil (1.09 g, 58%). HPLC retention time 6.6 mins.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:26][CH2:25][CH2:24][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCN1CCCC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (266 mg, 1.0 mmol) was treated with 3-pyrrolidin-1-yl-propylamine following general procedure B to afford 8-methoxy-4-(3-pyrrolidin-1-yl-propylamino)-quinoline-3-carboxylic acid ethyl ester (315 mg). Thus obtained amino-ester (36 mg, 0.1 mmol) was subjected to reaction with ethyl isocyanate according to general procedure C to furnish 3-ethyl-7-methoxy-1-(3-pyrrolidin-1-yl-propyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (19 mg). LCMS: m/z 383 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:42])([F:41])[CH2:33][S:34]([CH2:37][C:38](O)=[O:39])(=[O:36])=[O:35]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH:16][C:38](=[O:39])[CH2:37][S:34]([CH2:33][C:32]([F:41])([F:31])[F:42])(=[O:35])=[O:36])[C@H:12]2[S:11][CH2:10][C:9]=1[CH:18]([S:25][C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:19][CH2:20][S:21](=[O:24])(=[O:23])[NH2:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(C(CCS(N)(=O)=O)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CS(=O)(=O)CC(F)(F)F)C(=O)N12
Reaction time: 12 h

Procedure:
To a solution of 9.0 g. (0.019 mol.) of 7-amino-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g. (0.019 mol.) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g. (0.019 mol.) of dicychlohexylcarbodiimide in 100 ml. of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7-(2,2,2-trifluoroethylsulfonylacetamido)-3-[1-(2-sulfamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[C:7]([OH:14])=[N:6]2.O=S(Cl)[Cl:17].Cl>CN(C=O)C>[Cl:17][C:8]1[C:7]([OH:14])=[N:6][C:5]2[C:10]([N:9]=1)=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nc(O)c(O)nc2c1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(Cl)c(O)nc2c1
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A solution (1.53M) of the product of step 1 in DMF was treated with SOCl2 (1 eq) and heated at 110° C. After 1.5 hours, the reaction mixture was cooled and poured into aqueous HCl (1 N). The resulting precipitate was filtered and washed with H2O and Et2O. The dried solid contained predominantly the title compound as a mixture with 6-methoxyquinoxaline-2,3-diol and 2,3-dichloro-6-methoxyquinoxaline. This material was used directly in the subsequent step. MS (ES+) m/z 211 (M+H)+
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(C(C)C)CC)(C)C.[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32](O)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:16]1([CH2:22][N:23]2[C:27]3[CH:28]=[CH:29][C:30]([C:32]([N:3]4[CH2:4][CH2:5][CH2:6][O:2]4)=[O:33])=[CH:31][C:26]=3[N:25]=[C:24]2[C:35]([CH3:38])([CH3:39])[CH2:36][CH3:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCC(C)(C)c1nc2cc(C(=O)O)ccc2n1CC1CCCCC1
Reactant: C1CNOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)c1nc2cc(C(=O)N3CCCO3)ccc2n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
Following the same procedure in Example 3, Step A, using isoxazolidine hydrochoride (29.5 mg, 0.26 mmol), diisopropylethylamine (144 μL, 106.6 mg, 0.83 mmol) and a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazole-5-carboxylic acid (82.1 mg, 0.25 mmol) (for preparation, see in Example 4, Step E) in DMF (5 mL) at 0° C., and later, HATU (114.0 mg, 0.30 mmol). The mixture was stirred for 4 h at room temperature, and quenched by adding H2O (5 mL). Upon evapoartion, the desired title compound was purified by reversed-phase HPLC (C-18 column) using 20-50% CH3CN/H2O to give 94.8 mg (76%) of a white solid. 1H NMR (400 MHz, CD3OD): δ 0.86 (t, J=7.42 Hz, 3 H), 1.27 (m, 5 H), 1.66 (m, 3 H), 1.69 (s, 6 H), 1.79 (m, 2 H), 2.04 (q, J=7.49 Hz, 2 H), 2.13 (m, 1 H), 2.43 (m, 2 H), 3.94 (m, 2 H), 4.07 (t, J=6.74 Hz, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 8.00 (m, 2 H), 8.19 (s, 1 H). MS (ESI) (M+H)+=384.2. Anal. Calcd for C23H33N3O2+1.40 TFA+1.30 H2O (566.59): C, 54.69; H, 6.58; N, 7.42. Found: C, 54.66; H, 6.50; N, 7.68.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([NH2:14])=[NH:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[CH3:15].[Cl:16][C:17]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22]>>[NH2:24][CH2:23][C:20]1[C:21]([NH2:22])=[N:13][C:12]([C:10]2[CH:9]=[C:8]3[C:4]([CH:5]=[CH:6][N:7]3[CH3:15])=[C:3]([O:2][CH3:1])[CH:11]=2)=[N:14][C:19]=1[C:18]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:17]=1[Cl:16]
Reactant: COc1cc(C(=N)N)cc2c1ccn2C
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: COc1cc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)cc2c1ccn2C

Procedure:
The title compound, MS: m/e=428.0 (M+H+), was prepared from 4-methoxy-1-methyl-1H-indole-6-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:41][CH:42]([CH3:46])[C:43](Cl)=[O:44].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH3:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:43](=[O:44])[CH:42]([CH3:46])[CH3:41])[CH:28]=4)[NH:23][N:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(Cc1n[nH]c2ccc(O)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 3-(2-(9-fluorenylmethoxycarbonylamino)propyl)-1H-indazol-5-ol (0.17 g, 0.41 mmol) and diisopropylehtylamine (0.06 g, 0.50 mmol), in methylene chloride (10 mL) cooled at 0° C. is added 2-methylpropionyl chloride (0.05 g, 0.5 mmol) followed by 4-dimethylaminopyridine (0.05 g, 0.40 mmol). The reaction allowed to warm to room temperature and then is stirred at room temperature. The reaction mixture is added to dilute aqueous sodium bicarbonate and extracted with ether. The combined ether extracts are washed, dried (MgSO4) and concentrated. The residue is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Solvent: CC(C)O
Product: NC(=O)c1ccc(Nc2nccc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
To a solution of 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (0.10 g, 0.37 mmol) and 4-aminobenzamide in 2-propanol (3 ml) was heated to 120° C. in a sealed vessel for 14 hours. The crude material was concentrated and purified by preparative HPLC to provide the title compound as a beige solid: LC/MS Retention Time; 6.30 min (Method A), M+1; 325.
Reaction SMILES: Cl.[NH:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[S:23]([N:2]1[C:6]([CH2:7][CH:8]=[O:9])=[CH:5][N:4]=[CH:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=CCc1cnc[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cncc2CC=O)cc1

Procedure:
A solution of 1.46 g (10 mM) of 2-(5-imidazolyl)-acetaldehyde HCl in 20 ml of dichloromethane is treated with 2.01 g (20 mM) of triethylamine and 1.9 g of p-toluenesulfonyl chloride at 25° C for about 16 hours after which the solution is washed with 3 N hydrochloric acid, water, sodium bicarbonate and water then dried and evaporated to afford 2-(1-tosylimidazol-5-yl)acetaldehyde upon recrystallization from ethyl acetate.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[C:7]12([CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Br)[CH:21]=3)[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>CN1CCCC1=O>[C:7]12([CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([O:5][CH2:4][CH2:3][OH:6])[CH:21]=3)[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]3)[CH2:14]1)[CH2:16]2
Reactant: OCCO
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCO)ncc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 0.080 g) was added to ethylene glycol (3 ml) and the resulting suspension stirred under an atmosphere of nitrogen for 30 minutes. To this mixture was added a solution of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii)) (0.192 g) in anhydrous N-methyl-2-pyrrolidinone (1 ml). The stirring bar was removed and the resulting solution heated in a MARS microwave for 15 minutes (300 Watts, 150° C.). The mixture was cooled and poured into water (50 ml) and extracted into is ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (2×10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:isohexane (1:1) to afford the sub-titled compound (0.092 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3cccc(C(F)(F)F)c3)c(Cl)nc12
Reactant: C[O-]
Agent: CO[Na]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(3-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.87 g, 1.83 mmol, Intermediate 15: step c) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene was heated in a sealed tube at 110° C. for 12 hours. Starting material was still present, therefore additional NaOCH3 (198 mg, 3.66 mmol) was added and stirring was continued at 110° C. for another 24 hours. The mixture was then cooled to room temperature, diluted with DCM, stirred at room temperature for 30 minutes, and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the white solid product was precipitated from MeOH, filtered and dried to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]O)=[CH:35][CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: OCc1ccc(F)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 4-fluorobenzyl alcohol (85.7 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50](OC)=[O:51])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([NH:2][CH3:1])=[O:51])=[N:46]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and methylamine. 1H-NMR (400 MHz, CDCl3, δ) 8.42 (d, J=6.8 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.85 (s, 1H), 7.69 (d, J=9.1 Hz, 1H), 7.50 (broad, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.29 (m, 1H), 6.87 (m, 1H), 6.34 (s, 2H), 3.08 (d, J=5.1 Hz, 3H) ppm; m/e 367, 369.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11]([C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[C:13]([O:20][CH3:21])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CCOC(=O)C(C)(OC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC)C(=O)Nc1ccc(Br)cc1C
Yield: 25 %

Procedure:
4-Bromo-2-methylaniline (2.83 grams, 0.02 mole) and ethyl 2-(chlorocarbonyl)-2-methoxypropionate (4.12 grams, 0.02 mole), prepared in Part C, were reacted in the presence of triethylamine (1.54 grams, (0.02 mole) in 200 milliliters of methylene chloride in a manner similar to that described in Example I to give 1.73 grams (0.005 mole) of ethyl 3-[(4-bromo-2-methyl-phenyl)amino]-2-methoxy-2-methyl-3-oxopropanoate having a melting point of 99° C.-103° C.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:18]([OH:20])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(O)C>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[NH2:8][C@@:9]1([C:18]([O:20][CH2:22][CH3:23])=[O:19])[CH2:11][C@@H:10]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)C[C@@H]1c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)[C@]1(N)C[C@@H]1c1ccccc1

Procedure:
The title compound was prepared by standard methods, by esterifying commercially available (1S,2R)-1-[(tert-butoxycarbonyl)amino]-2-phenylcyclopropanecarboxylic acid with ethanol and subsequent Boc detachment with trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20])=[CH:3][C:2]=1[F:1]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(F)c(F)c1)[N+](=O)[O-]
Temperature: 4 °C
Yield: 75.6 %

Procedure:
3,4-difluorobenzaldehyde (54 g, 380 mmol), ammonium acetate (19 g, 247 mmol), and 4 Å molecular sieves (54 g) were combined in nitroethane (810 mL) and heated at reflux for 24 hours. The reaction was filtered, and concentrated in vacuo. The resultant mixture was partitioned between ethyl acetate (500 mL) and water (300 mL). The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was cooled to 4° C. for 2 hours then ethanol (100 mL) was added to give yellow crystals which were collected by filtration. (57.2 g 75.6% yield). 1H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.15-7.25 (m, 2H), 3.7 (t, 1H), 2.4 (s, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[NH2:25].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[ClH:3].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:25][C:17]2[CH:18]=[CH:19][C:20]3[NH:21][C:22]4[N:23]=[C:7]([NH:8][C:9]5[CH:10]=[CH:11][CH:12]=[C:13]([CH:26]=5)[CH2:14][CH2:15][C:16]=2[CH:24]=3)[N:6]=[CH:5][C:4]=4[Cl:3])=[O:33])=[CH:30][CH:29]=1
Reactant: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)c1ccc(Cl)cc1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine dihydrochloride and 4-chlorobenzoyl chloride as the starting materials in 66% yield. LCMS for C25H20Cl2N5O (M+H)+: m/z=476.2.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(=O)CC>[CH2:12]([O:11][C:10]([NH:9][C:5]1[C:6](=[O:8])[N:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A slurry of benzyl N-(6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)carbamate (preparation 3) (20 g, 78 mmol) in 2-butanone (500 ml) was treated with K2CO3 (53.9 g, 94 mmol) and further 2-butanone (100 ml). The resultant mixture was treated cautiously with tert-butyl 2-bromoacetate (15.2 ml, 94 mmol) and stirred at room temperature for 18 hr. The solvent was evaporated and the crude material was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, the combined organic layers washed with sat aq brine and dried over Na2SO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the crude product which was purified by recrystallisation from ethyl acetate:hexane to give the desired product (white solid, 15.1 g, 52%). 1H NMR (CDCl3) δ: 1.40 (s, 9H), 2.20 (s, 3H), 4.70 (s, 2H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (s, br, 1H), 7.90 (d, 1H). LRMS m/z=373.6 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH2:15][CH2:16]O)[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[ClH:14].[NH2:2][C:3]1[N:4]([CH2:15][CH2:16][Cl:20])[CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[CH2:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: NC1=NCC(c2ccccc2Cl)N1CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NC1=NCC(c2ccccc2Cl)N1CCCl

Procedure:
A mixture of 4.15 parts of 2-amino-5-(o-chlorophenyl)-2-imidazoline-1-ethanol hydrochloride in 22.5 parts of chloroform is treated with 3.6 parts of thionyl chloride and the whole is stirred at reflux temperature for 30 minutes. The solvent is evaporated and the residue is taken up in 15 parts of chloroform. The latter is evaporated again, yielding 2-amino-1-(2-chloroethyl)-5 (o-chlorophenyl)-2-imidazoline hydrochloride as a residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]#[N:22])([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21](=[O:24])[NH2:22])([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(Nc2ccccc2)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccccc2)(C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-cyano-3-phenylamino-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.65 mmol) in DMSO (10 ml) was added potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol). The reaction mixture was stirred at RT overnight. Further portions of potassium carbonate (76 mg, 0.54 mmol) and hydrogen peroxide (35% in water solution) (0.73 ml, 8.4 mmol) were added and stirring continued for 24 hrs. The mixture was diluted with EtOAc (10 ml) and washed with brine (30 ml). The organics were separated and the aqueous was extracted with EtOAc (10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.