Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2c(cc1NC(=O)Oc1ccccc1)CCCC2
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4c(nc3OC)CCCC4)CC2)c1
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5,6,7,8-tetrahydroquinoline-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([N:17]=[N+]=[N-])[C:11]=4[CH:10]=[CH:9][N:8]=3>N1CCCCC1.CO>[CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([NH2:17])[C:11]=4[CH:10]=[CH:9][N:8]=3
Reactant: [N-]=[N+]=Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Solvent: CO
Solvent: C1CCNCC1
Product: Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Hydrogen sulfide was bubbled through a solution containing 4-azidosampangine (160 mg, 0.58 mmol) and piperidine (2 drops) in MeOH (20 mL) that was precooled to 10° C. After 30 min, the temperature of the reaction was allowed to rise to ambient temperature, and after an additional 30 min the reaction was stopped. The solvent was evaporated and the residual solids chromatographed over silica using CHCl3 /MeOH (9:1) as eluant to give 4-aminosampangine (136 mg, 95%). The chromatography of 4-aminosampangine (23) is easily monitored through its fluorescent characteristics. An analytical sample was obtained by crystallization from DMSO: mp>325° C.; UV (MeOH) 207 (log ε 4.34), 252 (log ε 4.16), 269 (log ε 4.15), 348 (log ε 3.56), 461 (log ε 4.11); IR (KBr) 3300 (br) 1725, 1625, 1585, 1560, 1505, 1460, 1385, 1335, 1300, 1125, 1070, 725 cm-1 ; 1H NMR (DMSO-d6) δ7.72 (ddd, 1 H, J=7.5, 7.5, 1.3 Hz), 7.83 (ddd, 1 H, J=7.5, 7.5, 1.3 Hz), 7.95 (br s, 2 H), 8.21 (d, 1 H, J=5.9 Hz), 8.26 (dd, 1 H, J=7.5, 1.3 Hz), 8.38 (s, 1 H), 8.75 (dd, 1 H, J=7.5, 1.3 Hz), 8.81 (d, 1 H, J=5.9 Hz); 13C NMR (DMSO-d6) 115.7 (1), 119.8 (0), 124.1 (0), 124.7 (1), 127.0 (1), 130.9 (1), 132.0 (1), 132.8 (0), 132.9 (0), 133.1 (1), 134.7 (0), 144.3 (1), 145.1 (0), 148.5 (0), 178.4 (0) ppm; Anal. calcd for C15H9N3O.H2O: C 67.92, H 4.18, N 15.83; found C 68.30, H 3.80, N 15.75.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4].[CH3:28][NH:29][CH3:30]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:29]([CH3:30])[CH3:28])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:6]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Solvent: CO
Product: COC(=O)c1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 12.90 g (0.025 mole) of 1-[2-(o-chlorobenzoyl)-4-chlorophenyl]-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester [see Example 13 (b)] and 11 ml of 33% ethanolic dimethylamine solution in 250 ml of methanol is stirred for 7 hours at room temperature. The reaction solution is thereupon concentrated in vacuo; water is added to the residue and the whole is extracted twice with methylene chloride. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo to dryness. The amorphous residue is dissolved in 130 ml of ether; the solution is allowed to stand and the reaction product then crystallises out. It is filtered off with suction and washed with ether. After drying there is obtained 1-[2-(o-chlorobenzoyl)-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 131°-134°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:10]2[CH2:9][C:8]([CH3:23])([CH3:24])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1ccc(F)c(Cl)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.8 %

Procedure:
To a stirred mixture solution of 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (348.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (316.4 mg, 95%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=334.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH2:12].[C:13]([O:17][C:18]([N-:20][S:21](N1C=CC(=[N+](C)C)C=C1)(=[O:23])=[O:22])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CCOC(C)=O.Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][S:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])(=[O:22])=[O:23]
Reactant: NC1CCc2c(F)ccc(F)c21
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NC1CCc2c(F)ccc(F)c21
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a solution of 4,7-difluoro-2,3-dihydro-1H-inden-1-amine (CAS No. 625471-13-8, 1.19 g, 11.2 mmol) in DCM (50 mL) were added [(tert-Butoxy)carbonyl]{[4-(dimethyliminio)pyridin-1(4H)-yl]sulfonyl}amide (3.70 g, 12.3 mmol) and TEA (4.66 mL, 33.5 mmol) at room temperature. The resulting solution was stirred for 75 hours at room temperature. The reaction mixture was diluted with AcOEt and 1N HCl and the layers were separated. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to afford the title compound (3.82 g, 11.0 mmol).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:25])(=[O:24])[NH:11][CH2:12][C:13]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)[CH:5]=1.[OH-].[Na+]>C1COCC1>[C:20]([O:19][C:17]([C:13]1([CH2:12][NH:11][S:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])(=[O:25])=[O:24])[CH2:14][CH2:15][CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(S(=O)(=O)NCC2(C(=O)OC(C)(C)C)CCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CNS(=O)(=O)c2cccc(C(=O)O)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(1-tert-butoxycarbonyl-cyclobutylmethyl)-sulfamoyl]-benzoic acid methyl ester (step 3) (1.87 g, 4.88 mmol) in THF (25 ml) was treated with 2M NaOH (aq) (24.38 ml, 48.8 mmol) and stirred at RT for 2 h. The reaction mixture was partitioned between diethyl ether and water. The aqueous portion was separated and acidified to pH 1 with 2N HCl, and extracted with EtOAc, and the combined organic portions were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product; 1H NMR (400 MHz, CDCl3) δ 8.64 (1H, s), 8.33 (1H, d), 8.12 (1H, d), 7.67 (1H, t), 5.40 (1H, t), 3.24 (2H, d), 2.38 (2H, m), 1.97 (4H, m), 1.48 (9H, s). LC-MS Rt 1.13 mins; 314.1 [M+H]+ (−tBu), Method 2minLC_v003.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@:7]2([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[OH:13])=[CH:5][CH:4]=[N:3]1.CN(C1C=CC=CN=1)C.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([C@:7]23[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:24](=[O:25])[O:14]3)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@]1(O)CCCC[C@H]1O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: Cn1nccc1[C@]12CCCC[C@H]1OC(=O)O2
Yield: 91.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 167a by using the (1R,2R)-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol (1.21 g, 6.17 mmol) prepared in Example 168a, dimethylaminopyridine (75.3 mg, 0.62 mmol), carbonyldiimidazole (3.50 g, 21.6 mmol) and toluene (20 mL), to yield the title compound (1.26 g, 92%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[CH:16]=[N:17][C@H:18]([C:24]12[O:31][CH2:30][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:26][O:25]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].O>CCOCC>[F:39][C:15]([F:14])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[C@@H:16]([NH:17][C@H:18]([C:24]12[O:25][CH2:26][C:27]([CH3:32])([CH2:28][O:29]1)[CH2:30][O:31]2)[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(C)(C)C[C@H](N=CC(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)C[C@H](N[C@@H](c1ccc(F)cc1)C(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2
Temperature: 40 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
1-Bromo-4-fluorobenzene (1.12 g, 6.4 mmol) of was dissolved in ether (20 ml) and cooled to −78° C. nBuLi (2.56 ml, 2.5M, 6.4 mmol) was added and the reaction mixture was stirred for 1 h. (2,2-Difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (1.18 g, 3.2 mmol) was added and stirring was continued for 2 h while the solution was allowed to warm up to 40° C. Water (5 ml) was added and the reaction mixture was allowed to warm to room temperature. The organic layer was separated, washed with brine and was dried over MgSO4. The solvent was evaporated and the crude was purified by flash column chromatography using silica gel and 20:80 ethylacetate:hexane as an eluent to give [2,2-difluoro-1(S)-(4-fluorophenyl)-2-pyridin-2-ylethyl]-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (265 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5]2.N1C=CN=C1C(OCC)=O.[H-].[Na+].BrC1CC2C(=CC([Cl:44])=CC=2)C1=O>ClCCl.C(OCC)(=O)C.CN(C)C=O>[Cl:44][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH:6]([N:12]3[CH:16]=[CH:15][N:14]=[C:13]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nccn1C1Cc2cc(F)ccc2C1=O
Reactant: O=C1c2cc(Cl)ccc2CC1Br
Agent: CCOC(=O)c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1nccn1C1Cc2ccc(Cl)cc2C1=O

Procedure:
The ethyl 1-(6-chloro-1-oxo-1-indanyl)imidazole-2-carboxylate can be prepared as in Example 1 for the preparation of ethyl 1-(5-fluoro-1-oxo-2-indanyl)imidazole-2-carboxylate but starting with 2.5 g of ethyl imidazole-2-carboxylate, 0.7 g of 80% sodium hydride, 5.4 g of 2-bromo-6-chloro-1-indanone and a total of 70 ml of anhydrous dimethylformamide. After silica gel chromatography with a dichloromethane-ethyl acetate mixture (70-30 by volume), 1 g of ethyl 1-(6-chloro-1-oxo-2-indanyl)imidazole-2-carboxylate is obtained which melts at 180° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (15%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:28]1([C:33]2[N:38]=[CH:37][C:36]3[CH:39]([C:42](O)=[O:43])[CH2:40][CH2:41][C:35]=3[CH:34]=2)[CH:32]=[N:31][N:30]=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[N:28]1([C:33]2[N:38]=[CH:37][C:36]3[CH:39]([C:42]([N:18]4[CH2:17][CH2:16][N:14]5[CH2:15][C@@H:10]([C:5]6[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=6[CH3:27])[N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:12][C@@H:13]5[CH2:19]4)=[O:43])[CH2:40][CH2:41][C:35]=3[CH:34]=2)[CH:32]=[N:31][N:30]=[N:29]1
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c([C@@H]2CN3CCN(C(=O)C4CCc5cc(-n6cnnn6)ncc54)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate [I-18A](250 mg, 0.668 mmol) and 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid [I-65] (201 mg, 0.868 mmol) in DMF (4 mL) was added HATU (381 mg, 1.00 mmol) followed by addition of diisopropylethylamine (350 μL, 2.00 mmol). The resulting solution was stirred at rt for 1 h. Ethyl acetate (100 mL) was added and the mixture was washed with saturated sodium bicarbonate (3×100 mL), dried over sodium sulphate, concentrated and the residue was purified by preparative TLC eluting with 10% methanol/methylene chloride to give the title compound. LC/MS: (M+1)+: 588.2.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][O:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26]>>[CH3:22][O:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])=[O:29])[C:25]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:26]
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)C(OC)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (84%). White solid. MS: m/e=530(M+H+).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[O:8])[CH3:7])(=[O:4])=[O:3].[Br:9]Br>CC(O)=O.ClCCl>[Br:9][CH:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6](=[O:8])[CH3:7]
Reactant: BrBr
Reactant: CC(=O)CS(C)(=O)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(Br)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.1 %

Procedure:
To a solution of methanesulphonylacetone (0.5 g, 3.67 mmol) in AcOH (7.34 mL) and dichloromethane (11.02 mL) in a round bottom flask was added bromine (0.189 mL, 3.67 mmol) dropwise. The reaction mixture was stirred at rt 90 min. Solvent was removed in vacuo. The residue was taken up in ether and washed with saturated aqueous sodium bicarbonate (2×). The organics were concentrated in vacuo. 1-Bromo-1-(methylsulfonyl)propan-2-one (0.332 g, 42% yield) was isolated as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[C:3]1=[O:20]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[N:18][CH:17]=[N:16][CH:15]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)N(c2cncnc2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2cncnc2)CC1C(=O)O
Yield: 97.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (601 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromopyrimidine (477 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1466 mg, 4.50 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.7 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (349 mg, 42%). LC/MS [M+H]+=279. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (630 mg, 2.264 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylic acid (assume ˜2.2 mmol) which was used in the next step. LC/MS [M+H]+=223.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][Cl:12])[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: ClCCCNc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N(CCCCl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Thionyl chloride (4.4 mL) was added to a solution of 3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at room temperature, and the reaction solution was stirred at 60° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ice and a saturated sodium bicarbonate solution were added, followed by extraction with ethyl acetate (200 mL). Heptane (100 mL) was added to the resulting extract to prepare a mixed solution. The solution was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=2:1) to obtain (4-chlorophenyl)-(3-chloropropyl)amine. (4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45 mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL) were added at 0° C., and the reaction solution was stirred at room temperature for 15 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70 g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65 mL) was added at room temperature, and the reaction solution was heated under reflux for 17 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 2.19 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1.[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH2:15]3)[N:3]=1
Reactant: Clc1nc(Nc2ccc3c(c2)CCC3)c2nc[nH]c2n1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(Nc2ccc3c(c2)CCC3)c2ncn(C3CCCC3)c2n1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
(2-Chloro-9H-purin-6-yl)-indan-5-yl-amine (857 mg, 3 mmol) was dissolved in dry DMF (10 mL). NaH (94 mg, 3.9 mmol) was added in portions and the resulting mixture was stirred for 1 h. Cyclopentyl bromide (760 mg, 5.1 mmol) was then added and the reaction was stirred overnight at 80° C. under N2. After cooling, H2O (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined extracts were washed with brine (2×25 mL), dried over MgSO4, and evaporated. The residue was purified by flash chromatography (95:5 CH2Cl2/Et2O) to afford the title compound as a white powder (738 mg, 69.5%). TLC (95:5 CH2Cl2/Et2O): RF=0.38.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[NH:14][CH2:13][CH2:12][O:11][C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[N:14]([C:24](=[O:26])[CH3:25])[CH2:13][CH2:12][O:11][C:10]=3[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Fc1cncc(-c2cnc3c(c2)OCCN3)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCOc2cc(-c3cncc(F)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To a solution of 7-(5-fluoro-pyridin-3-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (350 mg, 1.5 mmol) (which is synthesized according to the procedure for Step 1 of Example 12) in DCM (100 mL) is added pyridine (1.7 g 18 mmol), then acetyl chloride (710 mg 9.1 mmol) is added dropwise. The solution is stirred at room temperature for 16 hrs and the solvent is removed. The residue is purified by preparative HPLC to give 54 mg of the titled product.