Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[CH3:22][CH:23]([CH3:26])[CH:24]=O.[BH3-]C#N.[Na+]>CO.CCOC(C)=O>[CH3:1][N:2]([CH2:22][CH:23]([CH3:26])[CH3:24])[CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[C:21]3[C:20]4[CH2:19][CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CN(C)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (100 mg, 0.33 mmol, 1.00 equiv) in methanol (5 ml) was added 2-methylpropanal (50 mg, 0.69 mmol, 2.00 equiv) at room temperature and the reaction solution was stirred for 1 h. Then NaBH3CN (45 mg, 0.72 mmol, 2.00 equiv) was added and stirred overnight at ambient temperature. The resulting solution was diluted with EtOAc (100 mL), washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 54.0% in 13 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give 75 mg (63%) of the desired 1-N-methyl-1-N-(2-methylpropyl)-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine as a white solid. MS: (ES, m/z): 359 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 4.07-4.09 (m, 1H), 3.02 (t, 2H), 2.99 (t, 2H), 2.54-2.59 (m, 3H), 2.37-2.39 (m, 5H), 2.18-2.21 (m, 2H), 1.95-1.99 (m, 2H), 1.81-1.85 (m, 1H), 1.45-1.61 (m, 4H), 1.01 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]1[CH2:15][O:14]1.[C:16]([O:20][C:21]([CH:23]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl([O-])(=O)(=O)=O.[Li+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[C:16]([O:20][C:21]([CH:23]1[CH2:29][CH2:28][N:27]([CH2:15][CH:13]([OH:14])[C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:26][CH2:25][NH:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)C1CCNCCN1
Reactant: COc1ccc2nccc(C3CO3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(C(O)CN3CCNC(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 100 °C

Procedure:
A mixture of 6-methoxy-4-oxiranylquinoline (400 mg, 2 mmol), [1,4]-diazepane-5-carboxylic acid tert-butyl ester (400 mg, 2 mmol, prepared as described in J. Chem. Research (S), 1991, 306, 2876), lithium perchlorate (211 mg, 2 mmol) and potassium carbonate (275 mg, 2 mmol) in DMF (5 ml) was heated at 100° C. for 4 hours. The reaction mixture was diluted with water and ethyl acetate, the aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate and concentrated. The product was purified by chromatography on silica gel (DCM/MeOH 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCN=C=NCC.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:34]([F:44])[CH:33]=1>ClCCl.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:34]([F:44])[CH:33]=1)=[O:6]
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Agent: CCN=C=NCCN(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (207 mg, 0.7 mmol) in dichloromethane (3 ml) was treated with N-[2-(dimethylamino)ethyl]-N′-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol, 1.5 eq) and stirred at room temperature for 30 minutes. A solution of ethyl (4-amino-2-fluorophenyl)acetate (207 mg, 1.05 mmol, 1.5 eq) in dichloromethane (2 ml) was added and the resulting mixture heated at 40° C. overnight. On cooling, the mixture was diluted with methanol and purified by SCX cartridge eluting with methanol to afford the title compound as a yellow oil (110 mg). MS (ES+) m/z 476 [M+H]+ (C24H2035Cl2FNO4). 1H-NMR (400 MHz, d6-DMSO) δ 1.19 (3H, t, J 7.2), 3.68 (2H, s), 4.09 (2H, q, J 7.2), 5.20 (2H, s), 7.15-7.68 (10H, m).
Reaction SMILES: O[C@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6].Cl.S(Cl)([Cl:26])=O.CCO>ClCCl.O>[Cl:26][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:4][NH:5][CH3:6]
Reactant: CNC[C@@H](c1ccc2ccccc2c1)[C@H](O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CNC[C@@H](c1ccc2ccccc2c1)[C@@H](Cl)c1ccccc1

Procedure:
A mixture of (2R,3S)-3-hydroxy-N-methyl-2-(naphthalen-2-yl)-3-phenylpropan-1-amine.HCl (70 mg, 0.24 mmol) and 1 mL of thionyl chloride in 3 mL of dry dichloromethane (DCM) was stirred at room temperature for 30 minutes under nitrogen. The mass spectrum (MS) of the crude indicated clean and complete conversion. The volatiles were evaporated at reduced pressure. The product MCJ001-C1-RR was washed with dry diethyl ether, and dried under high vacuum. A white solid was obtained (74 mg, 90%) which was judged pure by 1H NMR and MS. 1H NMR (CD3OD) δ 7.84-7.71 (m, 4H), 7.65 (s, 1H), 7.49-7.41 (m, 3H), 7.32-7.10 (m, 4H), 5.37 (d, J=9.4 Hz, 1H), 3.86-3.70 (m, 4H), 2.70 (s, 3H); MS (ESI): m/z 310.30 (M+1)+; [α]D20 −11.0 (c 0.2, 9:1 EtOH:H2O).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH3:25])[CH:11]=1)[CH3:2].[ClH:34]>CCOC(C)=O.O1CCOCC1>[ClH:34].[ClH:34].[CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.375 g, 0.8 mmol) in EtOAc (4 mL) was added 4N HCl in 1,4-dioxane (0.8 mL), and the reaction was stirred at 50° C. for 1 hour. Additional 4N HCl in 1,4-dioxane (0.8 mL) was added, and the reaction was stirred for 1 hour at 70° C. The mixture was concentrated to give [5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][C@H:17]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[ClH:44].O1CCOCC1>O1CCOCC1>[NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[ClH:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-Asp(OBzl)-Ser(Bzl)-OBzl (42.1 g) was dissolved in dioxane (100 ml), added with a solution of 4M-HCl/dioxane (150 ml) and stirred for 1 hour at room temperature. The reaction mixture was evaporated under reduced pressure and the residue was crystallized from ether to give Asp(OBzl)-Ser(Bzl)-OBzl hydrochloride (33.7 g).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:14]1[O:18][C:17]([C:19]2[C:20]([NH2:37])=[N:21][CH:22]=[C:23]([C:25]3[N:29]([CH3:30])[N:28]=[C:27]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[N:26]=3)[N:24]=2)=[N:16][N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[NH2:37][C:20]1[N:21]=[CH:22][C:23]([C:25]2[N:29]([CH3:30])[N:28]=[C:27]([CH:31]3[CH2:36][CH2:35][N:34]([C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:33][CH2:32]3)[N:26]=2)=[N:24][C:19]=1[C:17]1[O:18][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[N:15][N:16]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
Ethyl 3-chloro-3-oxopropanoate (0.037 mL, 0.29 mmol) was added dropwise to a stirred solution of 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and triethylamine (0.047 mL, 0.34 mmol) dissolved in CH2Cl2 (1.5 mL) over a period of 2 minutes at 0° C. under nitrogen. The mixture was stirred at 0° C. for 10 minutes then allowed to warm to room temperature and stirred for 1 hour. The mixture was evaporated, dissolved in DMF; a white solid was filtered off and the filtrate was purified by preparative HPLC using a Waters X-Terra reverse-phase column eluting with a mixture of water (containing 0.2% ammonium carbonate) and acetonitrile to afford ethyl 3-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-oxopropanoate (80 mg, 61.7%) as a yellow solid. This material was suspended in THF (2 mL). 2N Sodium hydroxide (0.235 mL, 0.47 mmol) and water (0.5 ml) were added. The mixture was stirred at room temperature overnight. 2N Hydrochloric acid (230 μL) was added to the mixture. The solvents were evaporated. The residue was diluted with CH2Cl2 (30 mL) and water (5 mL). The organic phase was washed with brine and dried over MgSO4. The solvents were evaporated. The resulting foam was triturated in ether. The resulting yellow solid was filtered, dried, triturated in acetonitrile (3 mL). The yellow solid was collected by filtration, dried at 40° C. to afford the title compound (50 mg, 68%) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH3:21])[CH:14]=2)[CH:10]=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>C(Cl)Cl>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C:9]2[CH:8]=[C:7]([CH:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][CH:10]=2)=[CH:14][C:15]=1[CH3:21])#[N:18]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(-c2cncc(C(N)C(F)(F)F)c2)ccc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(C)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of 4-(5-(1-amino-2,2,2-trifluoroethyl)pyridin-3-yl)-2-methylbenzonitrile (322 mg, 1.105 mmol) in CH2Cl2 (5.5 mL) at 0° C. was added triethylamine (462 μl, 3.32 mmol) and ethanesulfonyl chloride (115 μl, 1.216 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The residue was purified via Biotage (10-50% EtOAc/heptane; SNAP25 column) giving the title compound (67 mg, 16%). LC-MS (M+1) 384.1. 1H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.33 Hz, 3H) 2.63 (s, 3H) 2.96-3.19 (m, 2H) 5.47 (q, J=7.89 Hz, 1H) 7.66-7.72 (m, 1H) 7.76-7.79 (m, 1H) 7.81 (d, J=8.02 Hz, 1H) 8.24-8.43 (m, 1H) 8.76 (d, J=2.27 Hz, 1H) 8.93 (d, J=2.21 Hz, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][CH2:48][CH2:49][CH2:50][OH:51].O>CN(C=O)C>[OH:51][CH2:50][CH2:49][CH2:48][NH:47][C:17]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1)=[O:19]
Reactant: NCCCO
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCO)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred suspension of anthraquinone-2-carboxylic acid (Aldrich, 10.00 g, 39.64 mmol) in DMF (130 ml), was added (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (17.54 g, 39.66 mmol) and trethylamine (11.05 ml, 79.28 mmol). The resulting mixture (initially a clear green solution) was stirred at room temperature for 10 min. before dropwise addition of 3-amino-1-propanol (3.34 ml, 43.67 mmol). The reaction mixture (clear brown solution) was stirred at room temperature in the dark for 17 hours. The solution was poured in a thin stream into water (300 ml) containing some ice. The precipitated material was isolated by filtration and recrystallised from boiling 96% ethanol (ca. 200 ml) and gave the title compound 2 as a bright yew solid (6.93 g, 57% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([S:34][C:35]2[CH:36]=[CH:37][C:38]3[N:39]([CH:41]=[C:42]([NH:44][C:45]([CH:47]4[CH2:49][CH2:48]4)=[O:46])[N:43]=3)[N:40]=2)[CH:31]=[CH:32][CH:33]=1>CN(C)C(=O)C.O1CCCC1>[CH:47]1([C:45]([NH:44][C:42]2[N:43]=[C:38]3[CH:37]=[CH:36][C:35]([S:34][C:30]4[CH:29]=[C:28]([NH:27][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:33]=[CH:32][CH:31]=4)=[N:40][N:39]3[CH:41]=2)=[O:46])[CH2:48][CH2:49]1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(-c2ccccc2)n1
Yield: 65.3 %

Procedure:
Using 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (186 mg, 0.92 mmol), tetrahydrofuran (2.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (80 μL, 0.92 mmol), N-{6-[(3-aminophenyl)thio]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (200 mg, 0.61 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (203 mg, 65%) was obtained as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([N:33]3[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]3)=[C:26]3[CH:32]=[CH:31][S:30][C:27]3=[N:28][CH:29]=2)=[O:22])[N:20]=1>C(Cl)Cl>[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:25]2[C:24]([NH:23][C:21]([C:19]3[N:20]=[C:16]([C:10]4[C:9]([F:8])=[CH:14][CH:13]=[CH:12][C:11]=4[F:15])[S:17][CH:18]=3)=[O:22])=[CH:29][N:28]=[C:27]3[S:30][CH:31]=[CH:32][C:26]=23)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (118.2 mg, 0.2068 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (33.5 mg, 34%). LCMS calc. for C22H20F2N5OS2 (M+H)+: m/z=472.1. found 472.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:40]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:42])=[O:41])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added benzenesulfonyl chloride (31.8 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The organic layer was dried on sodium sulfate and evaporated to dryness to obtain the title compound. Yield: 20 mg (29.7%); 1H NMR (CDCl3, 300 MHz): δ 9.59 (s, 1H), 8.198-8.227 (d, 2H, J=8.7 Hz), 7.958-7.989 (d, 1H, J=8.7 Hz), 7.70-7.723 (d, 2H, J=6.9 Hz), 7.57-7.69 (m, 4H), 7.40-7.436 (d, 2H, J=8.7 Hz), 6.97-6.981 (d, 1H, J=2.1 Hz), 1.79 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[NH:4][C:5]1[C:6]([C:17]([OH:19])=[O:18])=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]2=O>CO.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:3]=1[N:4]=[C:5]1[C:10](=[CH:11]2)[CH:9]=[CH:8][CH:7]=[C:6]1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cccc2c(=O)c3cccc(F)c3[nH]c12
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2cc3cccc(F)c3nc12
Yield: 90 %

Procedure:
Reduction of the known [Rewcastle and Denny, Synthesis, 1985, 217] 5-fluoro-9-oxoacridan-4-carboxylic acid as above gave 5-fluoroacridine-4-carboxylic acid (90%), mp (MeOH/H2O) 295-298° C. (dec). 1H NMR [(CD3)2SO] δ 7.74-7.80 (m, 1 H, ArH), 7.90-7.96 (m, 2 H, ArH), 8.19 (d, J=8.6 Hz, 1 H, ArH), 8.61 (dd, J=8.6, 1.2 Hz, 1 H. ArH), 8.81 (dd, J=7.0, 1.0 Hz, 1 H, ArH), 9.65 (s, 1 H, H-9). Anal. (C14H8FNO2) C, H, N, F.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)C(C)C)(C)C.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.Cl>CN1CCN(C)C1=O.O.CCOC(C)=O>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
To a solution of ethyl 5,6-dichloronicotinate (10.0 g) and N,N-diisopropylethylamine (17.4 mL) in 1,3-dimethyl-2-imidazolidinone (100 mL) was added tert-butyl (3R)-3-amino-1-piperidinecarboxylate (10.9) at ambient temperature and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was poured into a mixture of AcOEt and water. The separated organic layer was added ice-water and the mixture was adjusted to pH 3.5 with 1N-HCl. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-piperidinyl]amino}-5-chloronicotinate (16.74 g).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=[O:2].[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][OH:47])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.CN.O>C1COCC1>[CH3:4][NH:3][C:1](=[O:2])[O:47][CH2:46][CH2:45][C:41]1[N:40]([CH2:39][CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][C:26]3[N:27]=[C:23](/[CH:22]=[CH:21]/[C:18]4[CH:19]=[CH:20][C:15]([C:14]([F:48])([F:13])[F:49])=[CH:16][CH:17]=4)[O:24][CH:25]=3)=[CH:31][CH:32]=2)[CH:44]=[CH:43][N:42]=1
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
1,1′-Carbonyldiimidazole (143 mg) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (300 mg) in THF (3 ml) at 0° C., and the mixture was stirred at the same temperature for 3 hr. A solution (2.0 M; 1.47 ml) of methylamine in THF was added to the reaction mixture at 0° C., and the mixture was stirred at the same temperature for 3 hr and at room temperature for 30 min. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and recrystallized from diethyl ether-acetone-hexane to give the titled compound (310 mg) as a colorless crystal powder.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCN(C2CCNCC2)CCN1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C38H48N7O3Cl2 [(M+H)+] 720.3190, observed 720.3190.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:27]3[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=3)[CH2:37][CH2:36]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 81.3 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.